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nasdaq:gild
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Gilead
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Apr 19th, 2022 12:00AM
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Dec 18th, 2019 12:00AM
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https://www.uspto.gov?id=US11304948-20220419
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Quinazoline compounds
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Described herein are compounds of Formula (I) and tautomers and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds.
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11304948
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1. A pharmaceutical composition comprising a compound of formula (I):
wherein
Q is
X1, X2, and X3 are each independently N or C(R11), provided that, at most 2 of X1, X2, and X3 are N;
R1 is —H, —CN, —OR, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R2 is —CN;
R3 is —H, —ORa, —SRa, —NRaRb, —NHC(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R4 is —H or —ORa;
R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R6 is —H;
R7 is C1-6alkyl, halogen, or —ORa;
R8 is C1-6alkyl, halogen, or —ORa;
R9 is —H, C1-6alkyl, orc C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R11 is —H, C1-6alkyl, or C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R11 is independently —H, —CN, —ORa, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, which may be same or different, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R12 is independently C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SR, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, or —NO2; wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, and —NO2, groups, which may be same or different;
each Ra and Rb is independently —H, —NH2, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl, wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R13 groups, which may be same or different; or Ra and Rb together with the atoms to which they are attached form a 5-10 membered heterocycle; and
each R13 is independently —CN, halogen, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, or 5-10 membered heterocyclyl,
or a tautomer or a pharmaceutically acceptable salt thereof; and
one, two, three, or four additional therapeutic agents independently selected from raltegravir, Truvada® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine+tenofovir disoproxil fumarate+emtricitabine), Cobicistat, Atripla® (efavirenz+tenofovir disoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir), ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid, lamivudine+nevirapine+zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.
2. The pharmaceutical composition of claim 1, wherein Q is
3. The pharmaceutical composition of claim 1, wherein X1, X2, and X3 are each CH.
4. The pharmaceutical composition of claim 1, wherein X1, X2, and X3 are C(R11); each R11 is independently selected from —H, —CN, —ORa, halogen, and C1-6alkyl; and R1 is selected from —H, —CN, —ORa, halogen, and C1-6alkyl.
5. The pharmaceutical composition of claim 1, wherein R3 is —H, —ORa, —CRaRb, —NHC(O)NRaRb, C1-6alkyl, or C1-6 heteroalkyl.
6. The pharmaceutical composition of claim 1, wherein R3 is —NH2 or —OH.
7. The pharmaceutical composition of claim 1, wherein R4 is —H, and R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, or C1-6alkyl.
8. The pharmaceutical composition of claim 1, wherein R4, R5, and R6 are —H.
9. The pharmaceutical composition of claim 1, wherein R7 is C1-6alkyl.
10. The pharmaceutical composition of claim 1, wherein R8 is C1-6alkyl.
11. The pharmaceutical composition of claim 1, wherein R7 and R8 are C1-6alkyl.
12. The pharmaceutical composition of claim 1, wherein R7 and R8 are methyl.
13. The pharmaceutical composition of claim 1, wherein R9 is —H or C1-6alkyl.
14. The pharmaceutical composition of claim 1, wherein R10 is —H or C1-6alkyl.
15. The pharmaceutical composition of claim 1, wherein Q is
16. The pharmaceutical composition of claim 1, wherein the compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, is a compound of formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
17. The pharmaceutical composition of claim 1, wherein one of the additional therapeutic agents is selected from tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority benefit to U.S. Application Ser. No. 62/096,748, filed Dec. 24, 2014, the disclosure of which is herein incorporated by reference in its entirety.
BACKGROUND
While progress has been made in treating HIV and AIDS, HIV infection remains a global health concern. As part of such treatments, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have often been employed, particularly as part of highly active antiretroviral therapy (HAART) treatment regimens. Though potent, drawbacks exist for many of the known NNRTIs as their use has been associated with mutations in the HIV virus that may result in drug resistance. As such, there remains a need for further development of potent NNTRIs.
Described herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, compositions and formulations containing such compounds, or pharmaceutically acceptable salts thereof, and methods of using and making such compounds, or pharmaceutically acceptable salts thereof.
SUMMARY
In certain embodiments, the present disclosure relates to compounds of Formula (I) or a tautomer thereof,
wherein
Q is
X1, X2, and X3 are each independently N or C(R11), provided that, at most 2 of X1, X2, and X3 are N;
R1 is —H, —CN, —ORa, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R2 is —H, —CN, —ORa, —NRaRb, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R3 is —H, —ORa, —SRa, —NRaRb, —NHC(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R4 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NRaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NRaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6, heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R6 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NRaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R7 is C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, halogen, —ORa, —CN, or —NO2, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R8 is C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, halogen, —ORa, —CN, or —NO2, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R9 is —H, C1-6alkyl, or C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R10 is —H, C1-6alkyl, or C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R11 is independently —H, —CN, —ORa, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, which may be same or different, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R12 is independently C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, or —NO2; wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, and —NO2, groups, which may be same or different;
each Ra and Rb is independently —H, —NH2, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10 heteroaryl, or 5-10 membered heteroaryl, wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R13 groups, which may be same or different; or Ra and Rb together with the atoms to which they are attached form a 5-10 membered heterocycle; and
each R13 is independently —CN, halogen, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, or 5-10 membered heterocyclyl;
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the current disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In certain embodiments, the current disclosure relates to an article of manufacture comprising a unit dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In certain embodiments, the current disclosure relates to a method of inhibiting reverse transcriptase in a subject in need thereof, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.
In certain embodiments, the current disclosure relates to a method for treating or preventing an HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In certain embodiments, the current disclosure relates to a method for preventing an HIV infection in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, such as a subject who has one or more risk factors known to be associated with contracting the HIV virus.
In certain embodiments, the current disclosure relates to a method for treating or preventing an HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
In certain embodiments, the current disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy.
In certain embodiments, the current disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating or preventing an HIV virus infection in a subject.
In certain embodiments, the current disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing an HIV virus infection in a subject.
Additional embodiments of the present disclosure are disclosed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows results of resistance profile against HIV-1 RT (Reverse Transcriptase) mutants of certain compounds.
DETAILED DESCRIPTION
The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience to indicate the point of attachment to a parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a chemical structure or a dashed line drawn through a line in a chemical structure indicates a point of attachment of a group. A dashed line within a chemical structure indicates an optional bond. A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
When trade names are used herein, it is intended to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
As used herein and in the appended claims, the singular forms “a” and “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays, and so forth.
“Alkyl” as used herein is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., (C1-20)alkyl) or an alkyl group can have 1 to 10 carbon atoms (i.e., (C1-10)alkyl), or an alkyl group can have 1 to 8 carbon atoms (i.e., (C1-8)alkyl), or 1 to 6 carbon atoms (i.e., (C1-6 alkyl), or 1 to 4 carbon atoms (i.e., (C1-4)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, —CH3), ethyl (Et, —CH2CH3), 1-propyl (n-Pr, n-propyl, —CH2CH2CH3), 2-propyl (i-Pr, i-propyl, —CH(CH3)2), 1-butyl (n-Bu, n-butyl, —CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, —CH2CH(CH3)2), 2-butyl (s-Bu, 5-butyl, —CH(CH3)CH2CH3), 2-methyl-2-propyl (i-Bu, t-butyl, —C(CH3)3), 1-pentyl (n-pentyl, —CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl (CH(CH2CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 3-methyl-1-butyl (—CH2CH2CH(CH3)2), 2-methyl-1-butyl (CH2CH(CH3)CH2CH3), 1-hexyl (CH2CH2CH2CH2CH2CH3), 2-hexyl (—CH(CH3)CH2CH2CH2CH3), 3-hexyl (—CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (—C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3, and octyl (—C(CH2)7CH3).
The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 annular carbon atoms, 6 to 14 annular carbon atoms, or 6 to 12 annular carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-12 membered aryl), the atom range is for the total ring (annular) atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.
“Arylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical as described herein (i.e., an aryl-alkyl-moiety). The alkyl group of the “arylalkyl” includes alkyl groups that are 1 to 6 carbon atoms (i.e. aryl(C1-C6)alkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl and the like.
“Boronic acid” refers to the group —B(OH)2.
“Boronic acid ester” refers to an ester derivative of a boronic acid compound. Suitable boronic acid ester derivatives include those of the formula —B(OR)2 where each R is independently alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl. Additionally, the two R groups of —B(OR)2 may be taken together to form a cyclic ester, e.g. having the structure
where each R may be the same or different. Examples of boronic acid ester include boronic acid pinacol ester and boronic acid catechol ester.
“Cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms. The term “cycloalkyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.
“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.
The term “heteroalkyl” as used herein refers to an alkyl as defined herein, wherein one or more of the carbon atoms of the alkyl are replaced by an O, S, or NRq, (or if the carbon atom being replaced is a terminal carbon with an OH, SH or N(Rq)2) wherein each Rq is independently H or (C1-C6)alkyl. For example, (C1-C8)heteroalkyl intends a heteroalkyl wherein one or more carbon atoms of a C1-C8 alkyl is replaced by a heteroatom (e.g., O, S, NRq, OH, SH or N(Rq)2), which may the same or different. Examples of heteroalkyls include but are not limited to methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl and N,N′-dimethylpropylamine. A heteroatom of a heteroalkyl may optionally be oxidized or alkylated. A heteroatom may be placed at any interior position of the heteroalkyl group or at a position at which the group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH2OCH3, —CH2CH2NHCH3, —CH2CH2N(CH3), —CH3, —CH2SCH2CH3, —S(O)CH3, —CH2CH2S(O)2CH3, —CH2CH2OCH3, —CHCHN(CH3)CH3, —CH2NHOCH3 and —CH2OC(CH3)3.
The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur, the term also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, the term includes single aromatic rings of from about 1 to 6 annular carbon atoms and about 1-4 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycloalkyls, (to form for example a 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), cycloalkyls (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-20 annular carbon atoms and about 1-6 annular heteroatoms. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thionaphthenyl.
“Heterocycloalkyl” or “heterocyclyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocycloalkyl group has from 5 to about 20 annular atoms, for example from 5 to 14 annular atoms, for example from 5 to 10 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The term also includes single saturated or partially unsaturated rings (e.g., 5, 6, 7, 8, 9, or 10-membered rings) having from about 4 to 9 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycloalkyl groups include, but are not limited to, azetidine, aziridine, imidazolidine, imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.
“Hydroxy” or “hydroxyl” refers to the group —OH.
“Oxo” refers to a double-bonded oxygen (═O). In compounds where an oxo group is bound to an sp2 nitrogen atom, an N-oxide is indicated.
It is understood that combinations of chemical groups may be used and will be recognized by persons of ordinary skill in the art. For instance, the group “hydroxyalkyl” would refer to a hydroxyl group attached to an alkyl group.
The terms “optional” or “optionally” mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
“Tautomers” as used herein refers to isomers of a compound that differ from each other in the position of a proton and/or in electronic distribution. Thus, both proton migration tautomers and valence tautomers are intended and described and it is understood that more than two tautomers may exist for a given compound. Examples of tautomers include, but are not limited to, enol-keto tautomers:
imine-enamine tautomers:
lactam-lactim tautomers:
amide-imidic acid tautomers:
amino-imine tautomers:
and tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring —NH— moiety and a ring ═N— moiety such as present in pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles (see, e.g., Smith. March's Advanced Organic Chemistry (5th ed.), pp. 1218-1223, Wiley-Interscience, 2001; Katritzky A, and Elguero J. et al., The Tautomerism of Heterocycles, Academic Press (1976)).
“Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
“Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion (e.g. a sodium or potassium), an alkaline earth ion (e.g. calcium or magnesium), or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
“Subject” and “subjects” refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.
As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. For example, a method that “delays” development of AIDS is a method that reduces the probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons may be based on clinical studies, using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods, such as confirming an individual's HIV+ status and assessing the individual's T-cell count or other indication of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or presence of an opportunistic condition that is known to be associated with AIDS (e.g., a condition that is generally not present in individuals with functioning immune systems but does occur in AIDS patients). Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset.
As used herein, “prevention” or “preventing” refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop. Thus, “prevention” relates to administration of a therapy (e.g., administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject (e.g., administration of a therapeutic substance to an subject in the absence of detectable infectious agent (e.g., virus) in the subject). The subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder. Thus, the term “preventing HIV infection” refers to administering to a subject who does not have a detectable HIV infection an anti-HIV therapeutic substance. It is understood that the subject for anti-HIV preventative therapy may be an individual at risk of contracting the HIV virus.
As used herein, an “at risk” individual is an individual who is at risk of developing a condition to be treated. An individual “at risk” may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s). For example, individuals at risk for AIDS are those having HIV.
As used herein, the term “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
Except as expressly defined otherwise, the present disclosure includes all tautomers of compounds detailed herein, even if only one tautomer is expressly represented (e.g., both tautomeric forms are intended and described by the presentation of one tautomeric form where a pair of two tautomers may exist). For example, if reference is made to a compound containing a lactam (e.g., by structure or chemical name), it is understood that the corresponding lactim tautomer is included by this disclosure and described the same as if the lactim were expressly recited either alone or together with the lactam. Where more than two tautomers may exist, the present disclosure includes all such tautomers even if only a single tautomeric form is depicted by chemical name and/or structure.
Compositions detailed herein may comprise a compound of the present disclosure in a racemic or non-racemic mixture of stereoisomers or may comprise a compound of the present disclosure as a substantially pure isomer. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).
It is understood by one skilled in the art that this disclosure also includes any compound disclosed herein that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D).
Disclosed are also compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
Compounds of a given formula described herein encompasses the compound disclosed and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated forms thereof, unless otherwise specified.
Depending on the particular substituents, the compounds of Formula I may exist in tautomeric forms. It is understood that two or more tautomeric forms may exist for a given compound structure. For example, a compound of Formula I (where R3 is —OH) may exist in at least the following tautomeric forms:
As is understood by those of skill in the art, various other tautomeric forms may exist and are intended to be encompassed by the compounds of Formula I. Some descriptions herein expressly refer to “tautomers thereof” but it is understood that, even in the absence of such language, tautomers are intended and described. Further, it is understood that the compounds of Formula I may shift between various tautomeric forms or exist in various ratios of each form based on the particular environment of the compound.
The compounds disclosed herein may contain chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof. Accordingly, the present disclosure includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present disclosure.
The compounds of the present disclosure may be compounds according to Formula (I) with one or more chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof.
The present disclosure includes both racemic mixtures of a compound of formula I and isolated isomers of Formula (I) or any variation thereof. Where more than one chiral center is present in a compound of the present disclosure, some, none, or all of the chiral centers may be enantiomerically enriched. Thus, mixtures of a compound of Formula (I) may be racemic with respect to one or more chiral centers and/or enantiomerically enriched with respect to one or more chiral centers.
The present disclosure relates to a compound of formula (I)
wherein
Q is
X1, X2, and X3 are each independently N or C(R11), provided that, at most 2 of X1, X2, and X3 are N;
R1 is —H, —CN, —ORa, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R2 is —H, —CN, —ORa, —NRaRb, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R3 is —H, —ORa, —SRa, —NRaRb, —NHC(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R4 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NRaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NRaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R6 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, —OC(O)NRaRb, —CH2C(O)NRaRb, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R7 is C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, halogen, —ORa, —CN, or —NO2, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R8 is C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, halogen, —ORa, —CN, or —NO2, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R9 is —H, C1-6alkyl, or C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R10 is —H, C1-6alkyl, or C3-10cycloalkyl, wherein each C1-6alkyl and C3-10cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R11 is independently —H, —CN, —ORa, —C(O)ORa, halogen, C1-6alkyl, C3-10cycloalkyl, or C1-6heteroalkyl, which may be same or different, wherein each C1-6alkyl, C3-10cycloalkyl, and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R12 is independently C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, or —NO2; wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, and —NO2, groups, which may be same or different;
each Ra and Rb is independently —H, —NH2, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl, wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R13 groups, which may be same or different; or Ra and Rb together with the atoms to which they are attached form a 5-10 membered heterocycle; and
each R13 is independently —CN, halogen, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, or 5-10 membered heterocyclyl;
or a tautomer or a pharmaceutically acceptable salt thereof.
In certain embodiments in formula (I), R2 is —H, —CN, —ORa, or C1-6alkyl.
In certain embodiments in formula (I), R2 is —CN.
In one variation, the present disclosure relates to compounds of formula (II), which are compounds of formula (I):
wherein
Q is
X1, X2, and X3 are each independently N or C(R11), provided that, at most 2 of X1, X2, and X3 are N;
R1 is —H, —CN, —ORa, —C(O)ORa, halogen, or C1-6alkyl, wherein C1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R3 is —H, —ORa, —NRaRb, —NHC(O)NRaRb, C1-6alkyl, or C1-6heteroalkyl, wherein each C1-6alkyl and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R4 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, C1-6alkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, C1-6alkyl, or C1-6heteroalkyl, wherein each C1-6alkyl and C1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R6 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, C1-6alkyl, or C1-6 heteroalkyl, wherein each C1-6alkyl and C1-6heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R7 is C1-6alkyl, C1-6heteroalkyl, halogen, —ORa, —CN, or —NO2, wherein each C1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R8 is C1-6alkyl, C1-6heteroalkyl, halogen, —ORa, —CN, or —NO2, wherein each C1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R9 is —H or C1-6alkyl, wherein C1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
R10 is —H or C1-6alkyl wherein C1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R11 is independently —H, —CN, —ORa, —C(O)ORa, halogen, or C1-6alkyl, which may be same or different, wherein Chalky 1 is optionally substituted with 1, 2, 3, 4, or 5 R12 groups, which may be same or different;
each R12 is independently C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, or —NO2; wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, —ORa, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —SRa, —S(O)1-2Ra, —S(O)2F, —S(O)2NRaRb, —NRaS(O)2Rb, —N3, —CN, and —NO2, groups, which may be same or different;
each Ra and Rb is independently —H, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl, wherein each C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R13 groups, which may be same or different; or Ra and Rb together with the atoms to which they are attached form a 5-10 membered heterocycle; and
each R13 is independently —CN, halogen, C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, or 5-10 membered heterocyclyl,
or a tautomer or a pharmaceutically acceptable salt thereof.
In certain embodiments in formula (I) and (II), Q is
In certain embodiments in formula (I) and (II), Q is
In certain embodiments in formula (I) and (II), X1, X2, and X3 are each independently N or C(R11), wherein 2 of X1. X2, and X3 are N. In certain embodiments. X1, X2, and X3 are each independently N or C(R11), wherein one of X1, X2, and X3 is N. In certain embodiments, X1, X2, and X3 are each independently N or C(R11), wherein none of X1, X2, and X3 is N.
In certain embodiments in formula (I) and (II), X1, X2, and X3 are each C(R11).
In certain embodiments in formula (I) and (II), X1, X2, and X3 are each CH. In certain embodiments, X1 is N; X2 is C(R11); and X3 is C(R11). In certain embodiments, X1 is N; X2 is CH; and X3 is CH.
In certain embodiments in formula (I) and (II), X1 is N; X2 is N; and X3 is C(R11).
In certain embodiments, X1 is N; X2 is C(R11); and X3 is N. In certain embodiments. X1 is C(R11); X2 is N; and X3 is C(R11).
In certain embodiments in formula (I) and (II), R1 is —H or C1-6alkyl. In certain embodiments, R1 is —H. In certain embodiments, R1 is C1-6alkyl. In certain embodiments, R1 is methyl.
In certain embodiments in formula (I) and (II), X1, X2, and X3 are C(R11); each R11 are independently selected from —H, —CN, —ORa, halogen, and C1-6alkyl; and R1 is selected from —H, —CN, —ORa, halogen, and C1-6alkyl. In certain embodiments, X1, X2, and X3 are C(R11); each R11 are —H; and R1 is —H.
In certain embodiments in formula (I) and (II), X1 is N; X2 is C(R11); and X3 is C(R11); each R11 are independently selected from —H, —CN, —ORa, halogen, and C1-6alkyl; and R1 is selected from —H, —CN, —ORa, halogen, and C1-6alkyl. In certain embodiments, X1 is N; X2 is C(R11); and X3 is C(R11); each R11 are —H; and R1 is selected from —H and C1-6alkyl. In certain embodiments, X1 is N; X2 is C(R11); and X3 is C(R11); each R11 are —H; and R1 is —H.
In certain embodiments in formula (I) and (II),
of formula (I) or (II) is selected from
In certain embodiments in formula (I) and (II),
of formula (I) or (II) is
In certain embodiments,
of formula (I) or (II) is
In certain embodiments,
of formula (I) or (II) is
In certain embodiments in formula (I) and (II), R3 is —H, —ORa, —NRaRb, —NHC(O)NRaRb, C1-6alkyl, or C1-6 heteroalkyl. In certain embodiments, R3 is —H, —ORa, —NRaRb, or —NHC(O)NRaRb.
In certain embodiments in formula (I) and (II), R3 is —NRaRb or —ORa. In certain embodiments, R3 is —NH2 or —OH.
In certain embodiments, R3 is —NRaRb. In certain embodiments, R3 is —NRaRb, wherein each Ra and Rb is independently —H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with 1, 2, 3, 4, or 5 R13 groups. In certain embodiments. R3 is —NRaRb, wherein each Ra and Rb is independently —H or C1-6alkyl. In certain embodiments, R3 is —NRaRb, wherein each Ra and Rb is independently —H, methyl, butyl, or cyclopropylmethyl. In certain embodiments, R3 is —NH2.
In certain embodiments in formula (I) and (II), R3 is —ORa. In certain embodiments, R3 is —OH.
In certain embodiments in formula (I) and (II), R3 is —H. In certain embodiments, R3 is —NHC(O)NRaRb. In certain embodiments. R3 is —NHC(O)NH2.
In certain embodiments in formula (I) and (II), R4 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, or C1-6alkyl. In certain embodiments. R4 is —H or —ORa.
In certain embodiments in formula (I) and (II), R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, or C1-6alkyl. In certain embodiments. R5 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, or C1-6alkyl.
In certain embodiments in formula (I) and (II), R6 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, or C1-6alkyl. In certain embodiments in formula (I) and (II), R6 is —H.
In certain embodiments in formula (I) and (II), two of R4, R5, and R6 are —H and one of R4, R5, and R6 is —H, —ORa, halogen, —NO2, —CN, —NRaRb, —NHC(O)NRaRb, or C1-6alkyl. In certain embodiments, two of R4, R5, and R6 are —H and one of R4, R5, and R6 is —H, —ORa, halogen, —NO2, —NRaRb, or C1-6alkyl. In certain embodiments, two of R4, R5, and R6 are —H and one of R4, R5, and R6 is —H, —OCH3, halogen, —NO2, —NH2, or methyl.
In certain embodiments in formula (I) and (II), R4, R5 and R6 are —H.
In certain embodiments in formula (I) and (II), R7 is C1-6alkyl, C heteroalkyl, halogen, —ORa, —CN, or —NO2. In certain embodiments, R7 is C1-6alkyl, halogen, or —ORa.
In certain embodiments in formula (I) and (II), R8 is C1-6alkyl, C heteroalkyl, halogen, —ORa, —CN, or —NO2. In certain embodiments, R8 is C1-6alkyl, halogen, or —ORa.
In certain embodiments in formula (I) and (II), R7 and R8 are the same and are selected from C1-6alkyl, C1-6heteroalkyl, halogen, —ORa, —CN, and —NO2. In certain embodiments, R7 and R8 are the same and are selected from C1-6alkyl, halogen, or —ORa.
In certain embodiments in formula (I) and (II), R7 and R8 are —ORa. In certain embodiments, R7 and R8 are methyl.
In certain embodiments in formula (I) and (II), R7 and R8 are —ORa. In certain embodiments, R7 and R8 are —OCH3.
In certain embodiments in formula (I) and (II), R7 and R8 are halogen. In certain embodiments, R7 and R8 are fluoro.
In certain embodiments in formula (I) and (II), R9 is —H or C1-6alkyl. In certain embodiments, R9 is —H or methyl.
In certain embodiments in formula (I) and (II). R10 is —H or C1-6alkyl. In certain embodiments in formula (I) and (II), R10 is —H or methyl.
In certain embodiments in formula (I) and (II), R9 is —H or C1-6alkyl; and R10 is —H or C1-6alkyl. In certain embodiments, R9 is —H or methyl; and R10 is —H or methyl. In certain embodiments in formula (I) and (II), R9 and R10 are —H.
In certain embodiments in formula (I) and (II), Q is selected from
In certain embodiments in formula (I) and (II), Q is
It is understood that any variable for Q of formula (I) and (II) may be combined with any variable of R3 in formula (I) and (II), the same as if each and every combination were specifically and individually listed. For example, in one variation of formula (I) and (II), Q is
and R3 is —NH2. In another variation, Q is
and R3 is —OH.
It is understood that any variable for R7 of formula (I) and (II) may be combined with any variable of R3 in formula (I) and (II), the same as if each and every combination were specifically and individually listed. For example, in one variation of formula (I) and (II), R7 is methyl and R3 is —NH2. In another variation, R7 is methyl and R3 is —OH.
It is understood that any variable for R8 of formula (I) and (II) may be combined with any variable of R3 in formula (I) and (II), the same as if each and every combination were specifically and individually listed. For example, in one variation of formula (I) and (II), R8 is methyl and R3 is —NH2. In another variation, R8 is methyl and R3 is —OH.
It is understood that any variable for R4, R5, and R6 of formula (I) and (II) may be combined with any variable of R3 in formula (I) and (II), the same as if each and every combination were specifically and individually listed. For example, in one variation of formula (I) and (II), R4, R5, and R6 are each —H; and R3 is —NH2. In another variation, R4, R5, and R6 are each —H; and R3 is —OH.
It is understood that any variable for X1, X2, and X3 of formula (I) and (II) may be combined with any variable of R3 in formula (I) and (II), the same as if each and every combination were specifically and individually listed. For example, in one variation of formula (I) and (II), X1, X2, and X3 are each CH; and R3 is —NH2. In one variation of formula (I) and (II), X1 is N; X2 is CH; and X3 is CH; and R3 is —NH2. In another variation. X1 is N; X2 is CH; and X3 is CH; and R3 is —OH. In another variation, X1, X2, and X3 are each CH; and R3 is —OH.
It is understood that any variable for R1 of formula (I) and (II) may be combined with any variable of R3 in formula (I) and (II), the same as if each and every combination were specifically and individually listed. For example, in one variation of formula (I) and (II), R1 is hydrogen and R3 is —NH2. In another variation, R1 is hydrogen and R3 is —OH.
In certain embodiments of formula (I) and (II), where R3 is —NH2, the compounds may have any one or more of the following structural features:
a) X1, X2, and X3 are each CH;
b) R7 is methyl;
c) R8 is methyl;
d) Q is
and
e) R4, R5, and R6 are each —H.
In one variation, the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, all) of features (a)-(e). In a particular variation, the compounds conform to feature (a). In another variation, the compounds conform to features (a), (b), and (c). In another variation, the compounds conform to features (a) and (d). In another variation, the compounds conform to features (a) and (e).
In certain embodiments of formula (I) and (II), where R3 is —OH, the compounds may have any one or more of the following structural features:
a) X1 is N; X2 is CH; and X3 is CH;
b) R7 is methyl;
c) R8 is methyl;
d) Q is
and
e) R4, R5, and R6 are each —H.
In one variation, the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, all) of features (a)-(e). In a particular variation, the compounds conform to feature (a). In another variation, the compounds conform to features (a), (b), and (c). In another variation, the compounds conform to features (a) and (d). In another variation, the compounds conform to features (a) and (e).
In certain embodiments of formula (I) and (II), where Q is
the compounds may have any one or more of the following structural features:
a) X1, X2, and X3 are each CH or X1 is N; X2 is CH; and X3 is CH;
b) R3 is-NH2 or —OH;
c) R7 and R8 are methyl;
d) R4, R5, and R6 are each —H.
In one variation, the compounds conform to at least one of features (a)-(d). In another variation, the compounds conform to two or more (and in certain variations, all) of features (a)-(d). In a particular variation, the compounds conform to feature (a). In another variation, the compounds conform to features (a) and (b). In another variation, the compounds conform to features (a), (b), and (c). In another variation, the compounds conform to features (a), (b), and (d).
The present disclosure relates to the following compounds or a pharmaceutically acceptable salt thereof.
Structure
Compound ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
The present disclosure relates to the following compound or a tautomer or a pharmaceutically acceptable salt thereof:
The present disclosure relates to the following compound or a pharmaceutically acceptable salt thereof:
and tautomers thereof such as
Pharmaceutical Compositions
Pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with conventional carriers (e.g., inactive ingredient or excipient material) which may be selected in accord with ordinary practice. Tablets may contain excipients including glidants, fillers, binders and the like. Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. All compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 5th edition. American Pharmacists Association, 1986. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. In certain embodiments, the composition relates to a solid dosage form, including a solid oral dosage form. The pH of a composition may range from about 3 to about 11, but is ordinarily about 7 to 10.
While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical compositions. The compositions, both for veterinary and for human use, comprise at least one compound of formula (I), together with one or more acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and one other therapeutic ingredient. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the composition and physiologically innocuous to the recipient thereof.
The compositions include those suitable for various administration routes, including oral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of formula (I) or a pharmaceutical salt thereof) with one or more inactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.). The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
Compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
The amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5 to about 95% of the total compositions (weight:weight).
It should be understood that in addition to the ingredients particularly mentioned above the compositions of these embodiments may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.
In certain embodiments, a composition comprising an active ingredient disclosed herein (a compound of formula (I) or a pharmaceutically acceptable salt thereof) in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that compositions comprising a compound of formula (I) in certain embodiments do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of formula (I) or any other active ingredient administered separately, sequentially or simultaneously with a compound of formula (I). It is also understood that any of the methods, kits, articles of manufacture and the like detailed herein in certain embodiments do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of formula (I) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any one of formula (I).
Methods of Use
Disclosed herein is a method of inhibiting an HIV reverse transcriptase in an individual in need thereof, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the individual. In certain embodiments, the individual in need thereof is a human who has been infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but who has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk for developing AIDS. In certain embodiments, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS. In certain embodiments of the methods disclosed herein, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual separately, sequentially or simultaneously with another active ingredient for treating HIV, such as HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase. HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.
In certain embodiments, a method for treating or preventing an HIV viral infection in an individual (e.g., a human), comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual is disclosed.
In certain embodiments, a method for inhibiting the replication of the HIV virus, treating AIDS or delaying the onset of AIDS in an individual (e.g., a human), comprising administering a compound of any formula (I), or a pharmaceutically acceptable salt thereof, to the individual is disclosed.
In certain embodiments, a method for preventing an HIV infection in an individual (e.g., a human), comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual is disclosed. In certain embodiments, the individual is at risk of contracting the HIV virus, such as an individual who has one or more risk factors known to be associated with contracting the HIV virus.
In certain embodiments, a method for treating an HIV infection in an individual (e.g., a human), comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual is disclosed.
In certain embodiments, a method for treating an HIV infection in an individual (e.g., a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase. HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof is disclosed.
In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in medical therapy of an HIV viral infection (e.g. HIV-1 or the replication of the HIV virus (e.g. HIV-1) or AIDS or delaying the onset of AIDS in an individual (e.g., a human)) is disclosed.
In certain embodiments, a compound of any of formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating an HIV viral infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human) is disclosed. One embodiment relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection or AIDS or for use in the therapeutic treatment or delaying the onset of AIDS is disclosed.
In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an HIV virus infection in an individual (e.g., a human) is disclosed. In certain embodiments, a compound of any of formula (I), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV virus infection is disclosed.
In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) in need of the treatment. In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) who is at risk of developing AIDS.
Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is for use in a method of treating an HIV viral infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human).
Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV in an individual in need thereof. In certain embodiments, the individual in need thereof is a human who has been infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but who has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk for developing AIDS. In certain embodiments, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS.
Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment or delaying the onset of AIDS.
Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.
In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof can be used as a research tool (e.g, to study the inhibition of HIV reverse transcriptase in a subject or in vitro).
Routes of Administration
One or more compounds disclosed herein which are of the Formula (I) (also referred to herein as the active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. In certain embodiments, the compounds disclosed are orally bioavailable and can be dosed orally.
Dosing Regimen
The compound, such as a compound of Formula (I), may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual's life.
The dosage or dosing frequency of a compound of Formula (I) may be adjusted over the course of the treatment, based on the judgment of the administering physician.
The compound may be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.
A compound as disclosed herein (e.g., any compound of Formula (I)) may be administered in a dosage amount of the compound of Formula I that is effective. For example, the dosage amount can be from 10 mg to 1000 mg of compound, such as 75 mg to 100 mg of the compound.
Combinations
In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is disclosed, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is disclosed, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
In certain embodiments, the present disclosure relates to a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another active ingredient for treating HIV, for use in a method of treating or preventing HIV. In one embodiment, the another active ingredient for treating HIV is selected from the group consisting of HIV protease inhibiting compounds. HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.
Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with another active ingredient for treating HIV. In one embodiment, the another active ingredient for treating HIV is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.
A compound as disclosed herein (e.g., any compound of Formula (I)) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula I (e.g., from 10 mg to 1000 mg of compound or 75 mg to 100 mg of compound).
In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are disclosed.
In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are disclosed.
In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and BRD4 inhibitors), compounds that target the HIV capsid (“capsid inhibitors”; e.g., capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1 modulators, toll like receptors modulators, IL-15 agonists), HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives) including those targeting HIV gp120 or gp41, combination drugs for HIV, HIV p17 matrix protein inhibitors, IL-13 antagonists, Peptidyl-prolyl cis-trans isomerase A modulators. Protein disulfide isomerase inhibitors. Complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors. Rev protein inhibitors. Integrin antagonists, Nucleoprotein inhibitors. Splicing factor modulators, COMM domain containing protein 1 modulators, HIV Ribonuclease H inhibitors, Retrocyclin modulators, CDK-9 inhibitors, Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators. Ubiquitin ligase inhibitors. Deoxycytidine kinase inhibitors. Cyclin dependent kinase inhibitors Proprotein convertase PC9 stimulators. ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, PI3K inhibitors, compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco). WO 2010/130034 (Boehringer Ingelheim). WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences). WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources), and other drugs for treating HIV, and combinations thereof.
In certain embodiments, the additional therapeutic is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
In certain embodiments a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors. HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
In certain embodiments, such tablets are suitable for once daily dosing. In certain embodiments, the additional therapeutic agent is selected from one or more of:
(1) Combination drugs selected from the group consisting of ATRIPLA® (efavirenz+tenofovir disoproxil fumarate+emtricitabine). COMPLERA® (EVIPLERA®, rilpivirine+tenofovir disoproxil fumarate+emtricitabine), STRIBILD® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), dolutegravir+abacavir sulfate+lamivudine, dolutegravir+abacavir sulfate+lamivudine, lamivudine+nevirapine+zidovudine, dolutegravir+rilpivirine, atazanavir sulfate+cobicistat, darunavir+cobicistat, efavirenz+lamivudine+tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate+cmtricitabine+cobicistat+elvitcgravir, Vacc-4x+romidepsin, darunavir+tenofovir alafenamide hemifumarate+emtricitabine+cobicistat, APH-0812, raltegravir+lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir), atazanavir sulfate+ritonavir, COMBIVIR® (zidovudine+lamivudine. AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC), TRIZIVIR® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC). TRUVADA® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), tenofovir+lamivudine and lamivudine+tenofovir disoproxil fumarate;
(2) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;
(3) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of delavirdine, delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine, rilpivirine, efavirenz, KM-023, VM-1500, lentinan and AIC-292; (4) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of V1DEX® and VIDEX® EC (didanosine, ddI), zidovudine, emtricitabine, didanosine, Stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir dipivoxil, and festinavir; (5) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, elvitegravir, dolutegravir and cabotegravir;
(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) selected from the group consisting of CX-05168, CX-05045 and CX-14442;
(7) HIV gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide and albuvirtide;
(8) HIV entry inhibitors selected from the group consisting of cenicriviroc;
(9) HIV gp120 inhibitors selected from the group consisting of Radha-108 (Receptol) and BMS-663068;
(10) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir (RAP-101), TBR-220 (TAK-220) and vMIP (Haimipu);
(11) CD4 attachment inhibitors selected from the group consisting of ibalizumab;
(12) CXCR4 inhibitors selected from the group consisting of plerixafor, ALT-1188, vMIP and Haimipu;
(13) Pharmacokinetic enhancers selected from the group consisting of cobicistat and ritonavir;
(14) Immune-based therapies selected from the group consisting of derma Vir, interleukin-7, lexgenleucel-T (VRX-496), plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-2 XL, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators (tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), rintatolimod and IR-103;
(15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine). CD4-derived peptide vaccines, vaccine combinations, rgp120 (A1DSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409, Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), AGS-004, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-H1V-PT1, NYVAC-H1V-PT4, DNA-HIV-PT123, Vichrepol, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR and DNA-Ad5 gag/pol/nef/nev (HVTN505);
(16) HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives) including BMS-936559, TMB-360 and those targeting HIV gp120 or gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, KD-247, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8 and VRC07;
(17) latency reversing agents selected from the group consisting of Histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; Proteasome inhibitors such as Velcade; protein kinase C (PKC) activators such as Indolactam, Prostratin, Ingenol B and DAG-lactones, Ionomycin, GSK-343, PMA, SAHA, BRIM inhibitors, IL-15, JQ1, disulfram, and amphotericin B;
(18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide;
(19) HIV maturation inhibitors selected from the group consisting of BMS-955176 and GSK-2838232;
(20) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401;
(21) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and
(22) other drugs for treating HIV selected from the group consisting of TR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide and PA-1050040 (PA-040).
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from raltegravir, Truvada® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine+tenofovir disoproxil fumarate+emtricitabine), Cobicistat. Atripla® (efavirenz+tenofovir disoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir), ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir, 1 amivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, Stavudine, indinavir, indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate. Radha-108 (Receptol), Hlviral, lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid, lamivudine+nevirapine+zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents disclosed herein in any dosage amount of the compound (e.g., from 10 mg to 1000 mg of compound, 10 mg to 500 mg, or 75 mg to 100 mg of compound) the same as if each combination of dosages were specifically and individually listed.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents disclosed herein in any dosage amount of the compound (e.g., from 10 mg to 1000 mg of compound, 10 mg to 500 mg, or 75 mg to 100 mg of compound) the same as if each combination of dosages were specifically and individually listed.
In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.
In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
Administration of HIV Combination Therapy
In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one or more additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered in two or more administrations.
Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of the one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
In certain embodiments, a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase. HIV nucleoside or nucleotide inhibitors of reverse transcriptase. HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
In certain embodiments, such tablets are suitable for once daily dosing.
HIV Combination Therapy
In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV. HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers. HIV gene therapy, HIV vaccines, and combinations thereof.
HIV Combination Drugs
Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZFVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.
Other HIV Drugs
Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1 viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, BIT-225, CYT-107, HGTV-43, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGC-007, SCY-635, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.
HIV Protease Inhibitors
Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100). T-169, and TMC-310911.
HIV Reverse Transcriptase Inhibitors
Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500.
Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddI), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, fozivudine tidoxil, lamivudine, phosphazid, Stavudine, zalcitabine, zidovudine, and KP-1461.
HIV Integrase Inhibitors
Examples of HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyiphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, and cabotegravir.
Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, T-169, and CX-14442.
HIV Entry Inhibitors
Examples of HIV entry (fusion) inhibitors include cenicriviroc. CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.
Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu).
Examples of gp41 inhibitors include albuvirtide, enfuvirtide, and sifuvirtide.
Examples of CD4 attachment inhibitors include ibalizumab.
Examples of gp120 inhibitors include Radha-108 (receptol) and BMS-663068
Examples of CXCR4 inhibitors include plerixafor, and vMIP (Haimipu).
HIV Maturation Inhibitors
Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.
Latency Reversing Agents
Examples of latency reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B, and GSK-343.
Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.
Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactones.
Capsid Inhibitors
Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, and HIV p24 capsid protein inhibitors.
Immune-Based Therapies
Examples of immune-based therapies include toll-like receptors modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir, interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; GS-9620; BMS-936559; and IR-103.
Phosphatidylinositol 3-kinase (PI3K) Inhibitors
Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.
HIV Antibodies, Bispecific Antibodies, and “Antibody-like” Therapeutic Proteins
Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include DARTs®, DUOBODIES®. BITES®, XmAbs®, TandAbs®, Fab derivatives, BMS-936559. TMB-360, and those targeting HIV gp120 or gp41.
Examples of those targeting HIV gp120 or gp41 include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G124C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, MGD-014 and VRC07.
Pharmacokinetic Enhancers
Examples of pharmacokinetic enhancers include cobicistat and ritonavir.
Additional Therapeutic Agents
Examples of additional therapeutic agents include the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences); WO 2013/091096 (Boehringer Ingelheim); and U.S. 20100143301 (Gilead Sciences).
HIV Vaccines
Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, VRC-HIV MAB060-00-AB, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TV1-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26, MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine.
HIV Combination Therapy
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir, atazanavir sulfate and ritonavir, darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir, nelfinavir mesylate; interferon; didanosine; Stavudine; indinavir, indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptal); Hlviral; lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.
In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.
A compound as disclosed herein (e.g., any compound of Formula (I)) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula (I) (e.g., from 50 mg to 1000 mg of compound).
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400.350-400.300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
Kits and Articles of Manufacture
The present disclosure relates to a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, e.g., for use in inhibiting an HIV reverse transcriptase, such as for use in treating an HIV infection or AIDS or as a research tool. The instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.
The present disclosure also relates to a pharmaceutical kit comprising one or more containers comprising a compound of any of formula (I), or a pharmaceutically acceptable salt thereof. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency for the manufacture, use or sale for human administration. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
Also disclosed are articles of manufacture comprising a unit dosage of a compound of any of formula (I), or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.
The present disclosure is also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.
Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013.)
Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography. E. Stahl (ed.). Springer-Verlag, New York, 1969.
During any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0° C. to the reflux temperature of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to formula (I).
Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.
The embodiments are also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.
Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013). Angew. Chem. Int. Ed. 2014, 53, 2-21, which is herein incorporated by reference in its entirety, provides a review of sulfur (VI) fluoride exchange, which can also be useful in the synthetic schemes.
Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.
During any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes may be run at a temperature from about 0° C. to the reflux temperature of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to formula (I).
Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.
Scheme 1 shows a representative synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.
In Scheme 1, R1, R2, R3, R4, R5, R6, R7, R8. X1. X2, X3, and Q are as defined herein. Also in Scheme 1, as discussed below, Y1a, Z1a, and Z2a are precursor moieties to forming the proper bonds and moieties in formula (I). Starting materials may be obtained from commercial sources or via well-established synthetic procedures. The synthesis of formula 1-D is discussed below in Schemes 4 and 5.
In Scheme 1, a nucleophilic substitution reaction between formula 1-A and 1-B occurs to produce a compound of formula 1-C. The amino group of formula 1-B reacts with formula 1-A to displace Y1a, which is a leaving group, such as halogen, triflate, mesylate, and tosylate. In certain instances, Y1a is halogen, such as iodo, bromo, or chloro.
With continued reference to Scheme 1, a coupling reaction between formula 1-C and 1-D occurs to produce a compound of formula (I). In certain instances, a palladium-catalyzed reaction between an aryl halide and an organoboron compound (e.g., Suzuki coupling reaction) can be used. With a Suzuki coupling reaction. Z1a in formula 1-C can be a halide, such as iodo or bromo and Z2a in formula 1-D can be a boronic acid or boronic acid ester. In certain instances, Z2a is
In certain instances, the coupling step includes a palladium catalyst, such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride.
With continued reference to Scheme 1, as an alternative coupling reaction between formula 1-C and 1-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (e.g., Stille coupling reaction) can be used to produce a compound of formula (I). With the Stille reaction, Z1a in formula 1-C can be an organotin moiety (—SnR4, where R is an alkyl group) and Z2a in formula 1-D can be a halide, such as iodo, or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0).
Scheme 2 is another representative synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.
In Scheme 2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, X3, and Q are as defined herein. Also in Scheme 2, as discussed below, Y1a, Z1a, and Z2a are precursor moieties to forming the proper bonds and moieties in formula (I). Starting materials may be obtained from commercial sources or via well-established synthetic procedures.
In Scheme 2, a nucleophilic substitution reaction between formula 2-A and 2-B occurs to produce a compound of formula 2-C. The amino group of formula 2-B reacts with formula 2-A to displace Y1a, which is a leaving group, such as halogen, triflate, mesylate, and tosylate. In certain instances, Y1a is halogen, such as iodo, bromo, or chloro.
With continued reference to Scheme 2, a coupling reaction between formula 2-C and 2-D occurs to produce formula 2-E. In certain instances, a palladium-catalyzed reaction between an aryl halide and an organoboron compound (e.g., Suzuki coupling reaction) can be used. With a Suzuki coupling reaction, Z1a in formula 2-C can be a halide, such as iodo or bromo and Z2a in formula 2-D can be a boronic acid or boronic acid ester. In certain instances, Z2a is
In certain instances, the coupling step includes a palladium catalyst, such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride.
With continued reference to Scheme 2, as an alternative coupling reaction between formula 2-C and 2-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (e.g., Stille coupling reaction) can be used to produce a compound of formula (I). With the Stille reaction, Z1a in formula 2-C can be an organotin moiety (—SnR4, where R is an alkyl group) and Z2a in formula 2-D can be a halide, such as iodo or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0).
With continued reference to Scheme 2, a coupling reaction between formula 2-D and 2-E occurs to produce a compound of formula (I). In certain instances, a coupling reaction between a stabilized phosphonate carbanion and an aldehyde (e.g., Homer-Wadsworth-Emmons reaction) can be used.
Scheme 3 is another representative synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.
In Scheme 3, R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, X3, and Q are as defined herein. Also in Scheme 3, as discussed below. Y1a, Z1a, and Z2a are precursor moieties to forming the proper bonds and moieties in formula (I). Starting materials may be obtained from commercial sources or via well-established synthetic procedures. The synthesis of formula 1-D is discussed below in Schemes 4 and 5.
With reference to Scheme 3, a coupling reaction between formula 3-A and 1-D occurs to produce formula 3-B. In certain instances, a palladium-catalyzed reaction between an aryl halide and an organoboron compound (e.g., Suzuki coupling reaction) can be used. With a Suzuki coupling reaction. Z1a in formula 3-A can be a halide, such as iodo or bromo and Z28 in formula 1-D can be a boronic acid or boronic acid ester. In certain instances, Z28 is
In certain instances, the coupling step includes a palladium catalyst, such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride or 1,1-bis(diphenylphosphino)ferrocene palladium dichloride.
With continued reference to Scheme 3, as an alternative coupling reaction between formula 3-A and 1-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (e.g., Stille coupling reaction) can be used to produce a compound of formula (I), With the Stille reaction, Z1a in formula 1-C can be an organotin moiety (—SnR4, where R is an alkyl group) and Z2a in formula 1-D can be a halide, such as iodo, or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0).
With continued reference to Scheme 3, a nucleophilic substitution reaction between formula 3-B and 3-C occurs to produce a compound of formula (I). The amino group of formula 3-C reacts with formula 3-B to displace Y1a, which is a leaving group, such as halogen, triflate, mesylate, and tosylate. In certain instances, Y1a is halogen, such as iodo, bromo, or chloro.
Scheme 4 shows a representative synthesis of formula 1-D. The methodology is compatible with a wide variety of functionalities.
In Scheme 4, R7, R8, R9, R10, and Q are as defined herein. Also in Scheme 4, as discussed below, Q1a, X1a, and X2a are precursor moieties to forming the proper bonds and moieties in formula 1-D. Starting materials may be obtained from commercial sources or via well-established synthetic procedures.
In Scheme 4, a coupling reaction between formula 4-A and 4-B occurs to produce formula 4-C. In certain instances, a palladium-catalyzed reaction between an aryl halide and an alkene compound (e.g., Heck coupling reaction) can be used. With a Heck coupling reaction, X1a in formula 4-A can be a halide, such as iodo, or bromo and X2a in formula 4-B can be hydrogen. The Heck coupling reaction can be carried out in the presence of a palladium catalyst, such as palladium(II) acetate in a combination with tri(o-tolyl)phosphine.
With continued reference to Scheme 4, Q1a in formula 4-A and 4-C is a precursor moiety to a boronic acid or boronic acid ester in formula 1-D, wherein Z2a is a boronic acid or boronic acid ester. A borylation reaction of formula 4-C occurs to produce a compound of formula 1-D. In certain instances, a cross-coupling reaction of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) with an aryl halide (e.g., Miyaura borylation reaction) can be used. With a Miyaura borylation reaction, Q1a in formula 4-C can be a halide, such as iodo, or bromo. In certain instances. Formula 4-C can react with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to provide for formula 1-D, in which Z28 is
In certain instances, the borylation step includes a palladium catalyst, such as palladium(II) acetate in a combination with dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine. Other borylation reactions can be used.
Scheme 5 shows another representative synthesis of formula 1-D. The methodology is compatible with a wide variety of functionalities.
In Scheme 5, R7, R8, R9, R10, and Q are as defined herein. Also in Scheme 5, as discussed below, Q1a and X1a are precursor moieties to forming the proper bonds and moieties in formula 1-D. Starting materials may be obtained from commercial sources or via well-established synthetic procedures.
In Scheme 5, a coupling reaction between formula 5-A and 5-B occurs to produce formula 5-C. In certain instances, a coupling reaction between a stabilized phosphonate carbanion and an aldehyde (e.g., Horner-Wadsworth-Emmons reaction) can be used. With a Horner-Wadsworth-Emmons reaction, X1a in formula 4-A can be an aldehyde or ketone (e.g., X1a is —CHO or —C(O)R9).
With continued reference to Scheme 5, Q1a in formula 5-A and 5-C is a precursor moiety to a boronic acid in formula 1-D, wherein Z28 is a boronic acid. A borylation reaction of formula 5-C occurs to produce a compound of formula 1-D. In certain instances, a cross-coupling reaction of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) with an aryl halide (e.g., Miyaura Borylation reaction) can be used. With a Miyaura Borylation reaction, Q1a in formula 5-C can be a halide, such as iodo, or bromo In certain instances, Formula 5-C can react with 4,4,4′,4′,5,5,5′5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to provide for formula 1-D, in which Z2a is
In certain instances, the borylation step includes a palladium catalyst, such as palladium(II) acetate in a combination with dicyclohexyl(2′,6′-dimethoxy-[1,1-biphenyl]-2-ylphosphine. Other borylation reactions can be used.
Accordingly, and as described in more detail herein, the present disclosure relates to a process of preparing a compound of the present disclosure, the process involving:
reacting a compound of formula:
with a compound of formula:
thereby producing a compound of formula
wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, X3, Z1a, Z28, and Q are as defined herein.
Accordingly, and as described in more detail herein, the present disclosure relates to a process of preparing a compound of the present disclosure, the process involving:
reacting a compound of formula:
with a compound of formula:
thereby producing a compound of formula
wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, X3, Y1a, and Q are as defined herein.
In certain instances, the above processes further involve the step of forming a salt of a compound of the present disclosure. Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein.
Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See. e.g., Loudon, Organic Chemistry, 5th edition. New York: Oxford University Press, 2009: Smith, March's Advanced Organic Chemistry: Reactions. Mechanisms, and Structure, 7th edition. Wiley-Interscience, 2013.
LIST OF ABBREVIATIONS AND ACRONYMS
Abbreviation—Meaning
Ac—Acetyl
B2pin2—4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane)
bs—Broad singlet
° C.—Degree Celsius
d—Doublet
DCM—Dichloromethane
dd—Doublet of doublet
DIPEA—N,N-Diisopropylethylamine
DMF—N,N-Dimethylformamide
DMSO—Dimethylsulfoxide
dppf—1,1′-Bis(diphenylphosphino)ferrocene
dtbpf—1,1′-Bis(di-tert-butylphosphino)ferrocene
EC50—Half maximal effective concentration
Equiv/eq—Equivalents
Et—Ethyl
EtOH—Ethanol
g—Grams
HPLC—High-performance liquid chromatography
hrs/h—Hours
Hz—Hertz
J—Coupling constant
LCMS—Liquid chromatography-mass spectrometry
M—Molar
m—Multiplet
m/z—mass-to-charge ratio
M+—Mass peak
Me—Methyl
mg—Milligram
MHz—Megahertz
min—Minute
mL—Milliliter
mM—Millimolar
mm—Millimeter
mmol—Millimole
mol—Mole
MS—mass spectrometry
MW—Microwave
nM—Nanomolar
NMP—N-Methyl-2-pyrrolidone
NMR—Nuclear magnetic resonance
P(oTol)3—Tri(o-tolyl)phosphine
P(r-Bu)3—Tri-tert-butylphosphine
Pd2(dba)3—Tris(dibenzylideneacetone)palladium(0)
q—Quartet
quant—Quantitative
Rf—Retention factor
RT/rt/r.t.—Room temperature
s—Singlet
sat.—Saturated
SPhos—Dicyclohexyl(2′,6′-dimethoxy-[1,1-biphenyl]-2-ylphosphine
t—Triplet
TFA—Trifluoroacetic acid
TMS—Trimethylsilyl
Tr/tr—Retention time
UV—Ultraviolet
wt.—Weight
Xantphos—(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)
δ—Chemical shift
μL—Microliter
μM—Micromolar
μmol—Micromole
The following examples are merely illustrative, and do not limit this disclosure in any way. Unless otherwise stated, preparative HPLC was performed on a Gilson HPLC system, using a 21.2×250 mm 10 micron CIS Phenomenex Gemini semi-preparative column and gradient 0-100% acetonitrile in water mobile phase with 0.1% trifluoroacetic acid at a flow rate of 20 mL/min.
Chemical names for all prepared compounds were generated using ChemBioDraw 12.0 software.
While the structures in the examples below are drawn as certain geometric isomers, a certain geometric isomer (e.g., E or Z isomer) or a ratio of the E and Z isomers may be indicated in the title and/or description of the example to represent the results of the example.
The following methods were used for the purification and characterization of certain compounds described in the following Examples.
LCMS method 1—Phenomenex Gemini-NX 3u CIS 110A, 100×2 mm 3 micron column. Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid; 0 min-7.0 min 0-100% ACN, flow rate 0.5 mL/min.
LCMS method 2—Gemini 5u CIS 110A, 50×4.60 mm 5 micron column; Acetonitrile with 0.1% acetic acid. Water with 0.1% acetic acid; Gradient: 0 min-3.5 min 5-100% ACN; flow rate 2 mL/min.
LCMS method 3—Kinctex 2.6μ CIS 100A, 50×3.00 mm column; Acetonitrile with 0.1% formic acid. Water with 0.1% formic acid; Gradient: 0 min-1.4 min 2-100% ACN, 1.4 min-1.8 min 100% ACN, 1.8 min-1.85 min 100%-2% ACN, 1.85 min-2 min 2% ACN; flow rate 1.8 mL/min.
Example 1
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 1
Step 1: Synthesis of 4-((8-bromoquinazolin-2-yl)amino)benzonitrile (Compound 1a)
A mixture of 8-bromo-2-chloroquinazoline (1.0 g, 4.10 mmol, Ark Pharm Inc, AK-27609) and 4-cyanoaniline (533 mg, 4.52 mmol, Sigma-Aldrich) in isopropanol (15 mL) was heated under reflux for 15 hours. The solid product was filtered off and washed twice with cold isopropanol (2×10 mL). The product was dried on air to afford the title compound 1a. 1H NMR (400 MHz, DMSO-4) δ 10.76 (s, 1H), 9.47 (s, 1H), 8.41 (d, J=8.8 Hz, 2H), 8.28 (dd, J=7.8.1.2 Hz, 1H), 8.06 (dd, J=7.8, 1.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.44 (t, J=7.8 Hz, 1H). HRMS: (ESI+) calculated for C15H10N4Br [M+H] 325.00834, found 325.00821. LCMS (m/z) 325.0 [M+H], Tr=4.69 min (LCMS method 1).
Step 2: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile (Compound 1b)
To a solution of 2,5-dibromo-1,3-dimethylbenzene (2640 mg, 10 mmol, Oakwood Products, Inc, —018507) in anhydrous acetonitrile (25 mL) was added palladium(II) acetate (112 mg, 0.5 mmol), acrylonitrile (531 mg, 10 mmol), tri(o-tolyl)phosphine (131 mg, 0.5 mmol) and triethylamine (4 mL, 30 mmol) then the mixture was purged with argon and heated at 110° C. for 2 hours. The reaction mixture was filtered through Celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The water layer was back extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. This was subjected to silica gel chromatography (gradient from 0-20% ethyl acetate in iso-hexanes) to afford the crude product which was treated in sonic bath with hexane (10 mL) for 10 minutes. The product precipitated out of solution and was collected by filtration. The solids were washed with cold hexane to afford compound 1b. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=16.6 Hz, 1H), 7.12 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z) no MS signal, Tr=2.78 min (LCMS method 2).
Step 3: Synthesis of (E)-3-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile (Compound 1c)
A mixture of compound 1b (391 mg, 1.66 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (630 mg, 2.48 mmol), potassium carbonate (687 mg, 5 mmol), palladium(II) acetate (19 mg, 0.08 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos, 85 mg, 0.21 mmol) in dry N,N-dimethylformamide (20 mL) was purged with argon and heated at 100° C. for 1 hour. The reaction mixture was filtered through Celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The water layer was back extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography (gradient from 0-20% ethyl acetate in iso-hexanes) to afford compound 1c. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=16.6 Hz, 1H), 7.00 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.39 (s, 6H), 1.37 (s, 12H). LCMS (m/z) 284.3 [M+H], Tr=2.85 min (LCMS method 2).
Step 4: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 1)
A mixture of compound 1a (50 mg, 0.15 mmol), compound 1c (129 mg, 0.45 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (100 mg, 0.12 mmol), potassium carbonate (64 mg, 0.45 mmol), and copper (I) acetate (19 mg, 0.15 mmol) in dry MW-dimethylformamide (5 mL) was purged with argon and heated at 100° C. for 15 hours. Solvent was removed under reduced pressure and crude mixture was subjected to silica gel chromatography (gradient from 0-30% ethyl acetate in iso-hexanes). The crude product was then re-purified on HPLC (preparative column Phenomenex Gemini 10 micron CIS, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.50 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.70-7.87 (m, 4H), 7.63 (t, J=7.8 Hz, 1H), 7.61 (s, 2H), 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=16.7 Hz, 1H), 1.94 (s, 6H). HRMS: (ESI+) calculated for C26H20N5 [M+H] 402.17132, found 402.17126. LCMS (m/z) 402.2 [M+H], Tr=4.91 min (LCMS method 1).
Example 2
(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 2
Step 1: Synthesis of (E)-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 2a)
A mixture of 8-bromo-2-chloroquinazolin-4-amine (129 mg, 0.5 mmol, Ark Pharm Inc, AK-28702), compound 1c (184 mg, 0.65 mmol), potassium phosphate tribasic (159 mg, 0.75 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (65 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide: water mixture (85:15.40 mL) under argon. The reaction was heated to 80° C. for 30 minutes. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure and the residue was treated with diethyl ether in a sonic bath.
The solid product was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 2a. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (bs, 2H), 8.28 (dd, J=8.1, 1.6 Hz, 1H), 7.66-7.52 (m, 3H), 7.43 (s, 2H), 6.46 (d, J=16.7 Hz, 1H), 1.86 (s, 6H). LCMS (m/z) 335.2 [M+H], Tr=2.48 min (LCMS method 2).
Step 2: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 2)
A mixture of compound 2a (100 mg, 0.30 mmol), 4-cyanoaniline (46 mg, 0.388 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane (4M, 7 μL, 0.03 mmol) in dry N-methyl-2-pyrrolidone (2 mL) was heated at 120° C. for 2 hours. The reaction mixture was cooled down to room temperature and triethylamine (0.1 mL, 0.72 mmol) was added. After 15 minutes, water (5 mL) was added and the solid product was filtered off and washed with water. The crude residue was taken up in a mixture of dichloromethane and diethyl ether (1:1.5 mL) and then treated in a sonic bath for 3 minutes. The solid compound was filtered off and washed with diethyl ether (5 mL) to afford the title compound 2. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.18 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (d, J=16.7 Hz, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.51 (s, 2H), 7.48 (dd, J=7.1, 1.3 Hz, 1H), 7.34 (dd, J=8.2, 7.1 Hz, 1H), 7.26 (d, J=8.9 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 1.91 (s, 6H). HRMS: (ESI+) calculated for C26H21N6 [M+H] 417.1822, found 417.1820. LCMS (m/z) 417.2 [M+H], Tr=4.68 min (LCMS method 1).
Example 3
(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methoxybenzonitrile—Compound 3
Step 1: Synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)-2-methoxybenzonitrile hydrochloride (Compound 3a)
A mixture of 8-bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol. Ark Pharm Inc. AK-28702) and 4-amino-2-methoxybenzonitrile (222 mg, 1.5 mmol, Ark Pharm Inc. AK-77827) in isopropanol (7 mL) was heated in microwave at 180° C. for 8 hours. The reaction mixture was cooled down to room temperature and the solid product was filtered off and washed with cold isopropanol and then with diethyl ether and hexane to afford the compound 3a as the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=8.1 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.42 (dd, J=8.6, 1.9 Hz, 1H), 7.37-7.04 (m, 5H), 3.99 (s, 3H). LCMS (m/z) 370.3 [M+H], Tr=2.43 min (LCMS method 2).
Step 2: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methoxybenzonitrile (Compound 3)
A mixture of compound 3a (50 mg, 0.14 mmol), compound 1c (76 mg, 0.27 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (33 mg, 0.04 mmol), potassium phosphate tribasic (86 mg, 0.41 mmol), and copper (I) acetate (2 mg, 0.01 mmol) in dry N,N-dimethylformamide (5 mL) was purged with argon and heated at 120° C. for 3 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 1 volume equivalent of hexane added and this mixture was filtered through a 3 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure and the crude mixture was subjected to silica gel chromatography (gradient from 5-50% ethyl acetate in iso-hexanes). Product was then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 3. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (bs, 1H), 7.74-7.65 (m, 2H), 7.62-7.42 (m, 5H), 7.30 (d, J=9.0 Hz, 2H), 7.26-6.95 (m, 1H), 6.53 (d, J=17.0 Hz, 1H), 3.41 (s, 3H), 1.93 (s, 6H). LCMS (m/z) 447.4 [M+H], Tr=2.39 min (LCMS method 2).
Example 4
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile—Compound 4
Step 1: Synthesis of 4-((8-bromo-6-fluoroquinazolin-2-yl)amino)benzonitrile (Compound 4a)
A mixture of 8-bromo-2-chloro-6-fluoroquinazoline (500 mg, 1.91 mmol, Ark Pharm Inc, AK-93358) and 4-aminobenzonitrile (250 mg, 2.12 mmol, Sigma-Aldrich) in dry N-methylpyrrolidone was heated in microwave at 200° C. for 5 hours. The reaction mixture was cooled down to room temperature and subjected to silica gel chromatography (gradient from 5-50% ethyl acetate in iso-hexanes). to afford the title compound 4a. 1H NMR (400 MHz. DMSO-d6) δ 10.69 (s, 1H), 9.37 (s, 1H), 8.32 (d, J=8.7 Hz, 2H), 8.26 (dd, J=8.5, 2.7 Hz, 1H), 7.86 (dd, J=8.5, 2.7 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H). LCMS (m/z) 343.0 [M+H], Tr=4.72 min (LCMS method 1).
Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile (Compound 4)
A mixture of compound 4a (50 mg, 0.14 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (40 mg, 0.16 mmol), potassium acetate (60 mg, 0.61 mmol) and [1,1′-bis(diphenylphosphinoferrocene] dichloropalladium(II), complex with dichloromethane (50 mg, 0.061 mmol) in dry MA-dimethylformamide (5 mL) was purged with argon and heated at 100° C. for 1 hour. A mixture of compound 1b (33 mg, 0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (50 mg, 0.061 mmol) and potassium carbonate (90 mg, 0.65 mmol) was added to the reaction mixture. The reaction mixture was heated to 100° C. for 5 hours, cooled down to room temperature, concentrated down under reduced pressure and subjected to silica gel chromatography (gradient from 5-50% ethyl acetate in iso-hexanes). The crude product was then re-purified on HPLC (preparative column Phenomenex Gemini 10 micron C1-8, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 4. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.92-7.86 (m, 1H), 7.82-7.76 (m, 2H), 7.72 (s, 1H), 7.68 (d, J=8.9 Hz, 2H), 7.58 (s, 2H), 7.36 (d, J=8.9 Hz, 2H), 6.60 (d, J=16.7 Hz, 1H), 1.92 (s, 6H). LCMS (m/z) 420.1 [M+H], Tr=4.85 min (LCMS method 1).
Example 5
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile—Compound 5 (mixture E/Z=4/1)
Step 1: Synthesis of 4-((8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 5a)
A mixture of compound 1a (40 mg, 0.12 mmol), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (66 mg, 0.24 mmol. Sigma-Aldrich), and potassium fluoride (24 mg, 0.4 mmol) in a tetrahydrofuran/water mixture (10:1.10 mL) was purged with argon and tris(dibenzylideneacetone)palladium(0) (68 mg, 0.07 mmol) was added followed by tri-tert-butylphosphine (36 μL, 0.14 mmol). This mixture was heated at 80° C. for 4 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography (gradient from 20-80% ethyl acetate in iso-hexanes) to afford the title compound 5a. 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.15 (s, 1H), 9.51 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.90 (d, J=6.9 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.67-7.58 (m, 1H), 7.53 (d, J=8.8 Hz, 2H). LCMS (m/z) 387.1 [M+H], Tr=4.67 min (LCMS method 1).
Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile (Compound 5) (Mixture E/Z=4/1)
Cesium carbonate (1.5 g, 4.6 mmol) was added to a solution of compound 5a (70 mg, 0.18 mmol) and diethyl (cyanomethylphosphonate (32 μL, 0.2 mmol) in dry dichloromethane (25 mL) and the solvent was slowly removed under reduced pressure at 30° C. The resulting reaction mixture was allowed to stand overnight at room temperature. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the residue was purified by HPLC (preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 5 as a mixture of E/Z isomers 4/1. 1H NMR for the E isomer (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.49 (s, 1H), 8.16-8.12 (m, 1H), 8.0 (d, J=7.3 Hz, 1H), 7.87-7.83 (m, 3H), 7.73 (d, J=8.0 Hz, 2H), 7.63-7.58 (m, 1H), 7.56-7.52 (m, 2H), 6.81 (d, J=16.7 Hz, 1H). LCMS (m/z) 410.1 [M+H], Tr=4.76 min (LCMS method 1).
Example 6
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile—Compound 6
Step 1: Synthesis of 8-bromo-2-chloro-N-(cyclopropylmethyl)quinazolin-4-amine (Compound 6a)
Cyclopropylmethanamine (95 μL, 1.1 mmol) and N-ethyldiisopropylamine (0.35 mL, 2 mmol) were added to a solution of 8-bromo-2,4-dichloroquinazoline (278 mg, 1 mmol. Ark Pharm Inc., AK-28703) in isopropanol (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solid product was filtered off and washed with water (2×5 mL) and pentane (3×5 mL) to give the title compound 6a. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.30 (dd, J=8.3 Hz, J=1.3 Hz, 1H), 8.12 (dd, J=7.7 Hz, J=1.3 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 3.41-3.35 (m, 2H), 1.23-1.11 (m, 1H), 0.52-0.45 (m, 2H), 0.34-0.28 (m, 2H). HRMS: (ESI+) calculated for C12H12N3BrCl [M+H] 311.9898, found 311.9898. LCMS (m/z) 312.0 [M+H], Tr 4.59 min (LCMS method 1).
Step 2: Synthesis of 4-((8-bromo-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile hydrochloride (Compound 6b)
A mixture of compound 6a (156 mg, 0.5 mmol) and 4-aminobenzonitrile (71 mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 180° C. for 2 hours. The reaction mixture was cooled down to room temperature and the solid product was filtered off and washed twice with cold isopropanol and then three times with pentane to afford the compound 6b as the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=7.7 Hz, 1H), 8.15-7.99 (m, 3H), 7.81 (d, J=8.4 Hz, 2H), 7.33 (t, J=7.9 Hz, 1H), 3.53-3.45 (m, 2H), 1.30-1.17 (m, 1H), 0.54-0.48 (m, 2H), 0.37-0.32 (m, 2H). HRMS: (ESI+) calculated for C19H17N5Br [M+H] 394.0662, found 394.0661. LCMS (m/z) 394.0 [M+H], Tr 4.29 min (LCMS method 1).
Step 3: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile (Compound 6)
A mixture of compound 6b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23 mmol), [1,1′-(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (37 mg, 0.05 mmol) and potassium carbonate (104 mg, 0.75 mmol) in the mixture of 1,4-dioxane and water (10:1, 5 mL) was purged with argon and heated at 100° C. for 1 hour. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20-40% ethyl acetate in iso-hexanes) to afford the title compound 6. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.39 (t, J=5.6 Hz, 1H), 8.24-8.13 (m, 2H), 7.74-7.69 (m, 2H), 7.51 (s, 2H), 7.46 (dd, J=7.2 Hz, J=1.4 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.26 (d, J=8.9 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 3.47-3.43 (m, 2H), 1.90 (s, 6H), 1.30-1.21 (m, 1H), 0.53-0.47 (m, 2H), 0.35-0.30 (m, 2H). HRMS: (ESI+) calculated for C30H27N6 [M+H] 471.2292, found 471.2292. LCMS (m/z) 471.2 [M+H], Tr 4.05 min (LCMS method 1).
Example 7
(E)-4-((4-(Butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 7
Step 1: Synthesis of 8-bromo-N-butyl-2-chloroquinazolin-4-amine (Compound 7a)
n-Butylamine (109 μL, 1.1 mmol) and N-ethyldiisopropylamine (0.35 mL, 2 mmol) were added to a solution of 8-bromo-2,4-dichloroquinazoline (278 mg, 1 mmol. Ark Pharm Inc., AK-28703) in isopropanol (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solid product was filtered off and washed with water (2×5 mL) and pentane (3×5 mL) to give the title compound 7a. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.27 (dd, J=8.3 Hz, J=1.2 Hz, 1H), 8.12 (dd, J=7.7 Hz, J=1.2 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 3.55-3.48 (m, 2H), 1.66-1.57 (m, 2H), 1.41-1.31 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). HRMS: (ESI+) calculated for C12H14N3BrCl [M+H] 314.0054, found 314.0055. LCMS (m/z) 314.0 [M+H], Tr 4.76 min (LCMS method 1).
Step 2: Synthesis of 4-((8-bromo-4-(butylamino)quinazolin-2-yl)amino)benzonitrile hydrochloride (Compound 7b)
A mixture of compound 7a (157 mg, 0.5 mmol) and 4-aminobenzonitrile (71 mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 180° C. for 2 hours. The reaction mixture was cooled down to room temperature and the solid product was filtered off and washed twice with cold isopropanol and then three times with pentane to afford the compound 7b as the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=7.8 Hz, 1H), 8.21-7.79 (m, 3H), 7.79 (d, J=8.3 Hz, 2H), 7.29 (t, J=7.8 Hz, 1H), 3.65-3.63 (m, 2H), 1.74-1.59 (m, 2H), 1.43-1.33 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). HRMS: (ESI+) calculated for C1-9H19N5Br [M+H] 396.0818, found 396.0816. LCMS (m/z) 396.1 [M+H], Tr 4.34 min (LCMS method 1).
Step 3: Synthesis of (E)-4-((4-(butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 7)
A mixture of compound 7b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (37 mg, 0.05 mmol) and potassium carbonate (104 mg, 0.75 mmol) in the mixture of 1,4-dioxane and water (10:1.5 mL) was purged with argon and heated at 100° C. for 1 hour. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20-40% ethyl acetate in iso-hexanes) to afford the title compound 7. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.25-8.16 (m, 2H), 7.78-7.69 (m, 3H), 7.51 (s, 2H), 7.46 (dd, J=7.1 Hz, J=1.3 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.27 (d, J=8.9 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 3.63-3.51 (m, 2H), 1.90 (s, 6H), 1.72-1.65 (m, 2H), 1.46-1.38 (m, 2H), 0.95 (t, J=7.4 Hz, 3H). MS-ESI+ m/z (%): 473 (100, M+H+), 495 (20, M+Na+); HRMS: (ESI+) calculated for C30H29N6 [M+H] 473.2448, found 473.2448. LCMS (m/z) 473.3 [M+H], Tr 4.14 min (LCMS method 1).
Example 8
(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile—Compound 8 (mixture E/Z=3/2)
Step 1: Synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile (Compound 8a)
A mixture of 8-bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, Ark Pharm Inc, AK-28702) and 4-aminobenzonitrile (130 mg, 1.1 mmol. Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 160° C. for 3 hours. The reaction mixture was cooled down to room temperature and the solid product was filtered off and washed with cold isopropanol and then with diethyl ether to afford the compound 2a. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.35 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H). HRMS: (ESI+) calculated for C15H11N5Br [M+H] 340.0192, found 340.0192. LCMS (m/z) 340.0 [M+H], Tr=4.06 min (LCMS method 1).
Step 2: Synthesis of 4-((4-amino-8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 8b)
A mixture of compound 8a (120 mg, 0.36 mmol), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (285 mg, 1.06 mmol, Sigma-Aldrich), and potassium fluoride (102 mg, 1.76 mmol) in a tetrahydrofuran/water mixture (10:1.30 mL) was purged with argon and tris(dibenzylideneacetone)palladium(0) (195 mg, 0.213 mmol) was added followed by tri-tert-butylphosphine (103 μL, 0.43 mmol). The mixture was heated at 80° C. for 4 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography (gradient from 20-80% ethyl acetate in iso-hexanes) to afford the title compound 8b. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.56 (s, 1H), 8.29 (dd, J=8.2 Hz, J=1.1 Hz, 2H), 7.87-7.73 (m, 6H), 7.44-7.34 (m, 3H). LCMS (m/z) 401.9 [M+H], Tr=4.28 min (LCMS method 1).
Step 3: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile (Compound 8) (Mixture E/Z=3/2)
Cesium carbonate (2.5 g, 7.69 mmol) was added to a solution of compound 8b (74 mg, 0.18 mmol) and diethyl (cyanomethylphosphonate (30 μL, 0.18 mmol) in dry dichloromethane (25 mL) and the solvent was slowly removed under reduced pressure at 30° C. The resulting reaction mixture was allowed to stand overnight at room temperature. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the residue was purified by HPLC (preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 8 as a mixture of E/Z isomers 3/2. 1H NMR for the E isomer (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.29-8.24 (m, 2H), 7.84 (d, J=2.4 Hz, 1H), 7.82-7.78 (m, 2H), 7.72 (d, J=7.3, 2H), 7.66 (d, J=7.8 Hz, 2H), 7.43-7.39 (m, 2H), 7.38-7.33 (m, 1H), 6.77 (d, J=16.7 Hz, 1H). LCMS (m/z) 424.9 [M+H], Tr=3.46 min (LCMS method 1).
Example 9
(E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile—Compound 9
Step 1: Synthesis of 5-((4-amino-8-bromoquinazolin-2-yl)amino)picolinonitrile (Compound 9a)
A mixture of 8-bromo-2-chloroquinazolin-4-amine (500 mg, 1.9 mmol, Ark Pharm Inc, AK-28702) and 5-aminopicolinonitrile (253 mg, 2.1 mmol, Ark Pharm Inc, AK-26123) in isopropanol (10 mL) was heated under argon in microwave at 180° C. for 8 hours. The reaction mixture was cooled down to room temperature and the solid product was filtered off and washed with cold isopropanol and then with diethyl ether and hexane to afford the compound 9a. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.35 (dd, J=2.6, 0.7 Hz, 1H), 8.85 (dd, J=8.7, 2.6 Hz, 1H), 8.17 (dd, J=8.2, 1.3 Hz, 1H), 8.03 (dd, J=7.6, 1.3 Hz, 1H), 7.95-7.91 (m, 2H), 7.23-7.10 (m, 2H). LCMS (m/z) 343.2 [M+H], Tr=2.31 min (LCMS method 2).
Step 2: Synthesis of (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile (Compound 9)
Compound 9a (150 mg, 0.44 mmol), compound 1c (498 mg, 1.76 mmol), potassium phosphate tribasic (560 mg, 2.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (57 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide: water mixture (85:15.25 mL) under argon. The reaction was heated at 90° C. for 1 hour. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated. The water layer was washed with additional ethyl acetate. Combined organics were washed twice with brine and dried over magnesium sulfate. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 0-40% ethyl acetate and methanol (4/1) in iso-hexanes). Solvents were removed under reduced pressure and the solid residue was treated with the mixture of hexane/diethyl ether (5:1) in the sonic bath for 5 minutes, filtered off and washed with hexane to afford the title compound 9. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.24-8.15 (m, 2H), 7.72 (d, J=16.7 Hz, 1H), 7.49 (d, J=7.6 Hz, 3H), 7.40-7.30 (m, 2H), 6.51 (d, J=16.7 Hz, 1H), 1.90 (s, 6H). LCMS (m/z) 418.3 [M+H], Tr=2.47 min (LCMS method 2).
Example 10
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound 10
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (Compound 10)
Compound 2a (820 mg, 2.45 mmol), 6-aminonicotinonitrile (875 mg, 7.35 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (2.53 g, 19.6 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (142 mg, 0.25 mmol) and palladium (II) acetate (55 mg, 0.25 mmol) were combined under argon in N-methyl-2-pyrrolidone (40 mL). The reaction was heated at 120° C. in a sealed vessel for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.05 volume equivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether/dichloromethane mixture (1:1) in the sonic bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 10. 1H NMR (400 MHz, DMSO-4) δ 9.58 (s, 1H), 8.57 (dd, J=2.4, 0.8 Hz, 1H), 8.20 (dd, J=8.3, 1.4 Hz, 1H), 7.95 (dd, J=9.0, 0.8 Hz, 1H), 7.73 (d, J=16.7 Hz, 1H), 7.55-7.51 (m, 3H), 7.44-7.36 (m, 2H), 6.53 (d, J=16.7 Hz, 1H), 1.90 (s, 6H). LCMS (m/z) 418.3 [M+H], Tr=1.82 min (LCMS method 2).
Example 11
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazine-3-carbonitrile—Compound 11
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazine-3-carbonitrile (Compound 11)
Compound 2a (20 mg, 0.06 mmol), 6-aminopyridazine-3-carbonitrile (22 mg, 0.18 mmol. Matrix Scientific, 112287), N,N-diisopropylethylamine (62 mg, 0.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (2 mL). The reaction was heated at 120° C. in a sealed vessel for 1 hour. The reaction mixture was cooled down to room temperature and purified by HPLC reverse phase chromatography (0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 11. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (bs, 1H), 8.09 (bs, 1H), 7.78-7.39 (m, 6H), 6.54 (d, J=16.7 Hz, 1H), 1.93 (s, 6H). LCMS (m/z) 419.3 [M+H], Tr=2.03 min (LCMS method 2).
Example 12
(E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile—Compound 12
Synthesis of (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile (Compound 12)
Compound 2a (20 mg, 0.06 mmol), 5-aminopyrazine-2-carbonitrile (22 mg, 0.18 mmol. Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (62 mg, 0.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in a sealed vessel for 3 hours. The reaction mixture was cooled down to room temperature and purified by reverse phase chromatography (0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 12. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (bs, 1H), 8.36 (bs, 1H), 7.85-7.28 (m, 6H), 6.59 (d, J=15.6 Hz, 1H), 1.94 (s, 6H). LCMS (m/z) 419.3 [M+H], Tr=1.89 min (LCMS method 2).
Example 13
(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound 13
Step 1: Synthesis of (E)-3-(4-(2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 13a)
A mixture of 8-bromo-2-chloroquinazoline (500 mg, 2.05 mmol, Ark Pharm Inc, AK-27609), compound 1c (776 mg, 2.67 mmol), potassium phosphate tribasic (633 mg, 3.08 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (134 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide: water mixture (85:15.10 mL) under argon. The reaction was heated to 50° C. for 2 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional hexane/ethyl acetate mixture (1/1). Combined organics were concentrated down under reduced pressure and the residue was treated with diethyl ether in a sonic bath. The solid product was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 13a. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.30 (dd, J=7.1.2.5 Hz, 1H), 7.99-7.84 (m, 2H), 7.66 (d, J=16.7 Hz, 1H), 7.49 (s, 2H), 6.50 (d, J=16.7 Hz, 1H), 1.85 (s, 6H). LCMS (m/z) 320.1 [M+H], Tr=1.40 min (LCMS method 3).
Step 2: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (Compound 13)
Compound 13a (508 mg, 1.60 mmol), 6-aminonicotinonitrile (567 mg, 4.77 mmol. Ark Pharm Inc, AK-32349), ACV-diisopropylethylamine (1.64 g, 12.71 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) were combined under argon in N-methyl-2-pyrrolidone (10 mL). The reaction was heated at 80° C. in a sealed vessel for 30 minutes. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional hexane/ethyl acetate mixture (1/1). Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonic bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 13. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.52 (s, 1H), 8.66 (dd, J=2.3, 0.9 Hz, 1H), 8.10 (dd, J=8.0, 1.4 Hz, 1H), 7.92 (dd, J=8.9, 0.9 Hz, 1H), 7.85-7.70 (m, 2H), 7.65 (dd, J=8.1, 7.1 Hz, 1H), 7.57-7.48 (m, 3H), 6.56 (d, J=16.7 Hz, 1H), 1.89 (s, 6H). LCMS (m/z) 403.2 [M+H], Tr=1.48 min (LCMS method 3).
Example 14
(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile—Compound 14
Step 1: (E)-3-(4-(2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 14a)
A mixture of compound 1c (100 mg, 0.35 mmol), 8-bromo-2-chloro-6-fluoroquinazoline (100 mg, 0.38 mmol, Ark Pharm Inc. AK-93358), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg, 0.08 mmol) and potassium phosphate tribasic monohydrate (200 mg, 0.77 mmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) was heated under argon at 80° C. for 30 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography This was subjected to silica gel chromatography (gradient from 0-100% ethyl acetate in iso-hexanes) to afford compound 14a. LCMS (m/z) 337.9 [M+H], Tr=4.52 min (LCMS method 1).
Step 2: Synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile (Compound 14)
Compound 14aa (100 mg, 0.30 mmol), 6-aminonicotinonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (0.5 mL, 2.86 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (180 mg, 0.31 mmol) and palladium (II) acetate (40 mg, 0.18 mmol) were combined under argon in N-methyl-2-pyrrolidone (3 mL). The reaction was heated at 100° C. in a sealed vessel for 1 hour. The reaction mixture was cooled down to room temperature and directly purified by silica gel chromatography (gradient from 60-100% ethyl acetate in iso-hexanes and then gradient from 0-20% methanol in ethyl acetate) to afford the title compound 14. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.77 (dd, J=2.3, 0.8 Hz, 1H), 8.08-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.87 (d, J=16.7 Hz, 1H), 7.68 (s, 2H), 7.65-7.60 (m, 1H), 7.60-7.53 (m, 1H), 7.36 (d, J=8.2, Hz, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.01 (s, 6H). LCMS (m/z) 420.9 [M+H], Tr=4.62 min (LCMS method 1).
Example 15
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2,4-dimethylnicotinonitrile—Compound 15
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2,4-dimethylnicotinonitrile (Compound 15)
Compound 2a (20 mg, 0.06 mmol), 6-amino-2,4-dimethylnicotinonitrile (26 mg, 0.18 mmol, Key Organics Ltd, 1X-0933), N,N-diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in a sealed vessel for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonic bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 15. 1H NMR (400 MHz. DMSO-d6) δ 9.56 (bs, 1H), 9.29 (bs, 1H), 8.44 (d, J=8.0 Hz, 1H), 7.99-7.47 (m, 5H), 7.41-7.10 (m, 1H), 6.55 (d, J=16.7 Hz, 1H), 2.41 (bs, 3H), 1.96 (s, 6H), 1.62 (bs, 3H). LCMS (m/z) 446.4 [M+H], Tr=1.19 min (LCMS method 3).
Example 16
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methylnicotinonitrile—Compound 16
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methylnicotinonitrile (Compound 16)
Compound 2a (20 mg, 0.06 mmol), 6-amino-2-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-78835), N,N-diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in a sealed vessel for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonic bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 16. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.55 (s, 1H), 9.10 (s, 1H), 8.46 (dd, J=8.3, 1.3 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.89-7.73 (m, 3H), 7.69 (s, 2H), 7.32 (d, J=2.2 Hz, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.37 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 432.4 [M+H], Tr=1.15 min (LCMS method 3).
Example 17
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-5-methylnicotinonitrile—Compound 17
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-5-methylnicotinonitrile (Compound 17)
Compound 2a (20 mg, 0.06 mmol), 6-amino-5-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-25043), N,N-diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in a sealed vessel for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonic bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 17. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.55 (s, 1H), 9.10 (s, 1H), 8.46 (dd, J=8.3, 1.3 Hz, 1H), 8.25-8.13 (m, 1H), 7.91-7.72 (m, 3H), 7.69 (s, 2H), 7.35-7.29 (m, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.37 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 432.4 [M+H], Tr=1.19 min (LCMS method 3).
Example 18
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile—Compound 18
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile (Compound 18)
Compound 2a (20 mg, 0.06 mmol), 6-amino-4-methylnicotinonitrile (24 mg, 0.18 mmol. Ark Pharm Inc, AK-80125), N,N-diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in a sealed vessel for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonic bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 18. 1H NMR (400 MHz. DMSO-d6) δ 11.97 (bs, 1H), 9.55 (bs, 1H), 9.32 (bs, 1H), 8.48-8.37 (m, 1H), 7.90-7.62 (m, 5H), 7.52-7.43 (m, 1H), 7.32-7.23 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 2.45 (s, 3H), 1.96 (s, 6H). LCMS (m/z) 432.3 [M+H], Tr=1.25 min (LCMS method 3).
Example 19
(E)-4-((4-Amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 19
Step 1: Synthesis of 2-amino-3-bromo-5-chlorobenzoic acid (Compound 19a)
A mixture of 2-amino-5-chlorobenzoic acid (5 g, 29 mmol, Ark Pharm Inc, AK-26989) and N-bromosuccinimide (5.4 g, 30 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 mL) and product was extracted with diethylether (400 mL). The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated down under reduced pressure to afford the title compound 19a. LCMS (m/z) 250.0 [M+H], Tr=4.05 min (LCMS method 1).
Step 2: Synthesis of 8-bromo-6-chloroquinazoline-2,4(1H,3H)-dione (Compound 19b)
A mixture of compound 19a (5.3 g, 21 mmol) and urea (30 g, 500 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled down, diluted with methanol (100 mL) and the product was filtered off. The solid was washed with water (50 mL) and methanol (50 mL) to afford the title compound 19b. LCMS (m/z) 275.0 [M+H], Tr=3.32 min (LCMS method 1).
Step 3: Synthesis of 8-bromo-2,6-dichloroquinazolin-4-amine (Compound 19c)
A mixture of compound 19b (5.3 g, 21 mmol), phosphorus(V) oxychloride (15 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into water (200 mL) and the product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (50 mL) and stirred at room temperature for 14 hours. The solid product was filtered off to afford the title compound 19c. 1H NMR (400 MHz, DMSO-4) δ 8.65 (s, 2H), 8.47 (d, J=2.2 Hz, 1H), 8.25 (d, 7=2.2 Hz, 1H). LCMS (m/z) 291.9 [M+H], Tr=3.86 min (LCMS method 1).
Step 4: Synthesis of (E)-3-(4-(4-amino-2,6-dichloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 19d)
A mixture of compound 19c (146 mg, 0.5 mmol), compound 1c (170 mg, 0.6 mmol), potassium phosphate tribasic monohydrate (230 mg, 1 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 5.5 mL) under argon and this mixture was stirred at 80° C. for 30 minutes. The product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in iso-hexanes) to afford the title compound 19d. LCMS (m/z) 369.0 [M+H], Tr=4.30 (LCMS method 1).
Step 5: Synthesis of (E)-4-((4-amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 19)
A mixture of compound 19d (85 mg, 0.23 mmol), 4-aminobenzonitrile (33 mg, 0.28 mmol. Sigma-Aldrich), palladium(II) acetate (10 mg, 0.046 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (27 mg, 0.046 mmol) was dissolved in N-methyl-2-pyrrolidone (2 mL) under argon. MN-Diisopropylethylamine (174 μL, 1 mmol) was then added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel flash chromatography (gradient from 40-60% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep pre-packed column, gradient 5-100%, acetonitrile in water) to afford the title compound 19. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 7.74 (d, J=16.7 Hz, 1H), 7.66 (d, J=8.9 Hz, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.52 (s, 2H), 7.40-7.35 (m, 2H), 7.26 (d, J=8.9 Hz, 2H), 6.55 (d, J=16.7 Hz, 1H), 1.93 (s, 6H). LCMS (m/z) 451.2 [M+H], Tr=4.25 min (LCMS method 1).
Example 20
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile—Compound 20
Step 1: Synthesis of 2-amino-3-bromo-5-fluorobenzoic acid (Compound 20a)
A mixture of 2-amino-5-fluorobenzoic acid (10 g, 65 mmol, Ark Pharm Inc, AK-35193) and N-bromosuccinimide (12 g, 67 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (500 mL), the solid product was filtered off and washed with water to afford the title compound 20a. LCMS (m/z) 233.7 [M+H], Tr=3.75 min (LCMS method 1).
Step 2: Synthesis of 8-bromo-6-fluoroquinazoline-2,4(1H,3H)-dione (Compound 20b)
A mixture of compound 20a (12 g, 51 mmol) and urea (20 g, 333 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled down and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) to afford the title compound 20b. LCMS (m/z) 259.0 [M+H], Tr=3.23 min (LCMS method 1).
Step 3: Synthesis of 8-bromo-2-chloro-6-fluoroquinazolin-4-amine (Compound 20c)
A mixture of compound 20b (3 g, 20 mmol), phosphorus(V) oxychloride (20 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was evaporated to dryness and the solid residue was suspended in water. The solid product was filtered off to afford the title compound 20c. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.46 (s, 1H), 8.19 (dd, J=8.3, 2.7 Hz, 1H), 8.13 (dd, J=9.2, 2.7 Hz, 1H). LCMS (m/z) 275.7 [M+H], Tr=3.74 min (LCMS method 1).
Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 20d)
A mixture of compound 20c (276 mg, 1 mmol), compound 1c (340 mg, 1.2 mmol), potassium phosphate tribasic monohydrate (460 mg, 2 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture of MM-dimethylformamide and water (10:1, 11 mL) under argon and this mixture was stirred at 80° C. for 30 minutes. The product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in iso-hexanes) to afford the title compound 20d. LCMS (m/z) 352.9 [M+H], Tr=4.12 min (LCMS method 1).
Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile (Compound 20)
A mixture of compound 20d (176 mg, 0.5 mmol), 6-aminonicotinonitrile (178 mg, 1.5 mmol, Ark Pharm Inc. AK-32349), palladium(II) acetate (22 mg, 0.1 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) under argon. N,N-Diisopropylethylamine (348 μL, 2 mmol) was then added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 20 as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (bs, 1H), 9.46 (bs, 1H), 8.40-8.20 (m, 2H), 8.02-7.84 (m, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.69 (s, 2H), 7.51 (bs, 1H), 7.42 (bs, 1H), 6.69 (d, J=16.6 Hz, 1H), 1.98 (s, 6H). LCMS (m/z) 435.8 [M+H], Tr=3.45 min (LCMS method 1).
Example 21
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amino)nicotinonitrile—Compound 21
Step 1: Synthesis of 2-amino-3-bromo-5-methylbenzoic acid (Compound 21a)
A mixture of 2-amino-5-methylbenzoic acid (10 g, 66 mmol, Ark Pharm, Inc AK-34555) and N-bromosuccinimide (12 g, 67 mmol) in ACV-dimethylformamide (100 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered off and washed with water to afford the title compound 21a. LCMS (m/z) 229.80 [M+H], Tr=3.87 min (LCMS method 1).
Step 2: Synthesis of 8-bromo-6-methylquinazoline-2,4(1H,3H)-dione (Compound 21b)
A mixture of compound 21a (5 g, 22 mmol) and urea (30 g, 500 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to afford the title compound 21b. LCMS (m/z) 254.7 [M+H], Tr=3.19 min (LCMS method 1).
Step 3: Synthesis of 8-bromo-2-chloro-6-methylquinazolin-4-amine (Compound 21c)
A mixture of compound 21b (5 g, 20 mmol), phosphorus(V) oxychloride (15 mL) and ACV-dimethylformamide (3 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room temperature for 14 hours. The solid product was filtered off to afford the title compound 21c. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 8.06 (d, J=1.7 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 2.42 (s, 3H). LCMS (m/z) 271.8 [M+H], Tr=3.65 min (LCMS method 1).
Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-methylquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 21d)
A mixture of compound 21c (273 mg, 1 mmol), compound 1c (340 mg, 1.2 mmol), potassium phosphate tribasic monohydrate (460 mg, 2 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture of MM-dimethylformamide and water (10:1, 5.5 mL) under argon and this reaction mixture was stirred at 80° C. for 30 minutes. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso-hexanes) to afford the title compound 21d. LCMS (m/z) 348.9 [M+H], Tr=4.17 min (LCMS method 1).
Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amino)nicotinonitrile (Compound 21)
A mixture of compound 21d (175 mg, 0.5 mmol), 6-aminonicotinonitrile (298 mg, 2.5 mmol, Ark Pharm Inc. AK-32349), palladium(II) acetate (23 mg, 0.1 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) under argon. N,N-Diisopropylethylamine (435 μL, 2.5 mmol) was then added via syringe and the reaction mixture was stirred at 110° C. for 6 hours. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 21 as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.31 (s, 1H), 8.33-8.24 (m, 2H), 7.82 (d, J=16.7 Hz, 1H), 7.77-7.66 (m, 3H), 7.58-7.50 (m, 1H), 7.45-7.36 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 2.54 (s, 3H), 1.96 (s, 6H). LCMS (m/z) 432.0 [M+H], Tr=3.56 min (LCMS method 1).
Example 22
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile—Compound 22
Step 1: Synthesis of 2-amino-3-bromo-5-nitrobenzoic acid (Compound 22a)
A mixture of 2-amino-5-nitrobenzoic acid (5 g, 27 mmol, Sigma-Aldrich) and N-bromosuccinimide (6 g, 34 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered off and washed with water to afford the title compound 22a. LCMS (m/z) 261.03 [M+H], Tr=3.70 min (LCMS method 1).
Step 2: Synthesis of 8-bromo-6-nitroquinazoline-2,4(1H,3H)-dione (Compound 22b)
A mixture of compound 22a (5 g, 22 mmol) and urea (20 g, 333 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to afford the title compound 22b. LCMS (m/z) 286.2 [M+H], Tr=3.21 min (LCMS method 1).
Step 3: Synthesis of 8-bromo-2-chloro-6-nitroquinazolin-4-amine (Compound 22c)
A mixture of compound 22b (5 g, 17 mmol), phosphorus(V) oxychloride (15 mL) and N,N-dimethylformamide (4 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated down under reduced pressure and water was added. The solid product was filtered off to afford the title compound 22c. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J=2.4 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H). LCMS (m/z) 303.0 [M+H], Tr=3.97 min (LCMS method 1).
Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-nitroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 22d)
A mixture of compound 22c (152 mg, 0.5 mmol), compound 1c (170 mg, 0.6 mmol), potassium phosphate tribasic monohydrate (230 mg, 1 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (33 mg, 0.05 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 5.5 mL) under argon and this reaction mixture was stirred at 80° C. for 7 hours. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso-hexanes) to afford the title compound 22d. LCMS (m/z) 379.9 [M+H], Tr=4.40 min (LCMS method 1).
Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile (Compound 22)
A mixture of compound 22d (110 mg, 0.29 mmol), 6-aminonicotinonitrile (171 mg, 1.45 mmol. Ark Pharm Inc. AK-32349), palladium(II) acetate (13 mg, 0.06 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (34 mg, 0.06 mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) under argon. N,N-Diisopropylethylamine (514 μL, 2.95 mmol) was then added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 22 as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (bs, 2H), 7.80 (d, J=16.7 Hz, 1H), 7.77-7.50 (m, 7H), 7.48 (bs, 1H), 6.53 (d, J=16.7 Hz, 1H), 1.97 (s, 6H). LCMS (m/z) 463.0 [M+H], Tr=3.98 min (LCMS method 1).
Example 23
(E)-6-((4,6-Diamino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound 23
Synthesis of (E)-6-((4,6-diamino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (Compound 23)
Compound 22 (20 mg, 0.043 mmol) was dissolved in the methanol-acetic acid mixture (10:1.2 mL), iron dust (20 mg, 0.358 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 24 hours. The product was isolated by silica gel chromatography (gradient from 10-30% methanol in ethyl acetate) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 23 as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.04 (s, 1H), 8.26-8.21 (m, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.83-7.74 (m, 1H), 7.68 (s, 2H), 7.51 (s, 1H), 7.38-7.32 (m, 1H), 7.11 (s, 1H), 6.69 (d, J=16.6 Hz, 1H), 1.98 (s, 6H). LCMS (m/z) 433.1 [M+H], Tr=3.68 min (LCMS method 1).
Example 24
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl)amino)nicotinonitrile—Compound 24
Step 1: Synthesis of 2-amino-3-bromo-5-methoxybenzoic acid (Compound 24a)
A mixture of 2-amino-5-methoxybenzoic acid (3.95 g, 23.6 mmol, Sigma-Aldrich) and N-bromosuccinimide (4.2 g, 23.6 mmol) in N,N-dimethylformamide (80 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 mL) and the solid product was filtered off and washed with water to afford the title compound 24a. LCMS (m/z) 245.8 [M+H], Tr=4.06 min (LCMS method 1).
Step 2: Synthesis of 8-bromo-6-methoxyquinazoline-2,4(1H,3H)-dione (Compound 24b)
A mixture of compound 24a (2.19 g, 8.9 mmol) and urea (12 g, 200 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered off and washed with water (50 mL) to afford the title compound 24b.
Step 3: Synthesis of 8-bromo-2-chloro-6-methoxyquinazolin-4-amine (Compound 24c)
A mixture of compound 24b (2.45 g, 9 mmol), phosphorus(V) oxychloride (10 mL) and N,N-dimethylformamide (5 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated down under reduced pressure and water (20 mL) was added. The solid product was filtered off to afford the title compound 24c. LCMS (m/z) 287.7 [M+H], Tr=4.33 min (LCMS method 1).
Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 24d)
A mixture of compound 24c (30 mg, 0.1 mmol), compound 1c (34 mg, 0.12 mmol), potassium phosphate tribasic monohydrate (46 mg, 0.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (13 mg, 0.02 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 2 mL) under argon and this reaction mixture was stirred at 80° C. for 30 minutes. The product was isolated by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) to afford the title compound 24d. LCMS (m/z) 364.9 [M+H], Tr=4.65 min (LCMS method 1).
Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl)amino)nicotinonitrile (Compound 24)
A mixture of compound 24d (15 mg, 0.041 mmol), 6-aminonicotinonitrile (24 mg, 0.21 mmol. Ark Pharm Inc, AK-32349), palladium(II) acetate (4 mg, 0.016 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (10 mg, 0.016 mmol) was dissolved in A-methyl-2-pyrrolidone (1 mL) under argon. N,N-Diisopropylethylamine (37 μL, 0.21 mmol) was then added via syringe and the reaction mixture was stirred at 100° C. for 2 hours. The product was isolated by silica gel chromatography (gradient from 60-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 24 as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 13.52 (bs, 1H), 11.99 (bs, 1H), 9.46 (bs, 1H), 9.26 (bs, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.83 (d, J=16.7 Hz, 1H), 7.70 (s, 2H), 7.62-7.48 (m, 2H), 7.42-7.36 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 3.95 (s, 3H), 1.98 (s, 6H). LCMS (m/z) 448.0 [M+H], Tr=3.95 min (LCMS method 1).
Example 25
(E)-4-((4-Amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 25
Step 1: Synthesis of 2-amino-5-bromo-3-iodobenzoic acid (Compound 25a)
A mixture of 2-amino-5-bromobenzoic acid (1 g, 4.6 mmol, Sigma-Aldrich) and N-iodosuccinimide (1.9 g, 8.4 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 48 hours. The reaction mixture was poured into water (100 mL). The solid product was filtered off and washed with water to afford the title compound 25a. LCMS (m/z) 341.9 [M+H], Tr=4.53 min (LCMS method 1).
Step 2: Synthesis of 6-bromo-8-iodoquinazoline-2,4(1H/3H)-dione (Compound 25b)
A mixture of compound 25a (1.2 g, 3.5 mmol) and urea (10 g, 166 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to afford the title compound 25b.
Step 3: Synthesis of 6-bromo-2-chloro-8-iodoquinazolin-4-amine (Compound 25c)
A mixture of compound 25b (5.33 g, 14.5 mmol), phosphorus(V) oxychloride (30 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated down under reduced pressure and subjected to silica gel column chromatography (gradient from 10-50% ethyl acetate in iso-hexanes) to afford the title compound 25c. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.78 (bs, 2H). LCMS (m/z) 383.9 [M+H], Tr=5.98 min (LCMS method 1).
Step 4: Synthesis of (E)-3-(4-(4-amino-6-bromo-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 25d)
A mixture of compound 25c (120 mg, 0.31 mmol), compound 1c (106 mg, 0.37 mmol), potassium phosphate tribasic monohydrate (143 mg, 0.62 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (40 mg, 0.062 mmol) was dissolved in a mixture of N,N-dimethyl formamide and water (10:1.3 mL) under argon and this reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of saturated ammonium chloride and the product was isolated by silica gel chromatography (gradient from 30-60% ethyl acetate in iso-hexanes) to afford the title compound 25d. LCMS (m/z) 412.8 [M+H], Tr=4.62 min (LCMS method 1).
Step 5: Synthesis of (E)-4-((4-amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 25)
A mixture of compound 25d (55 mg, 0.13 mmol) and 4-aminobenzonitrile (20 mg, 0.17 mmol, Sigma-Aldrich) in isopropanol (2 mL) was heated under microwave conditions at 170° C. for 30 minutes. The reaction mixture was concentrated down under reduced pressure and purified by silica gel column chromatography (gradient from 0-100% ethyl acetate in iso-hexanes) to afford the title compound 25. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.47 (d, J=2.2 Hz, 1H), 7.75 (d, J=16.7 Hz, 1H), 7.68-7.63 (m, 3H), 7.52 (s, 2H), 7.32-7.21 (m, 2H), 6.56 (d, J=16.7 Hz, 1H), 1.92 (s, 6H). LCMS (m/z) 495.1 [M+H], Tr=4.58 min (LCMS method 1).
Example 26
(E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2-carbonitrile—Compound 26
Synthesis (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2-carbonitrile (Compound 26)
Compound 20d (92 mg, 0.21 mmol), 5-aminopyrazine-2-carbonitrile (60 mg, 0.50 mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (174 μL, 1.0 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24 mg, 0.042 mmol) and palladium (II) acetate (9 mg, 0.042 mmol) were combined under argon in W-methyl-2-pyrrolidone (2 mL). The reaction was heated at 100° C. in a sealed vessel for 7 hours. The reaction mixture was cooled down to room temperature, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 26. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.20 (s, 1H), 7.74 (d, J=16.7 Hz, 1H), 7.77-7.60 (m, 2H), 7.57 (s, 2H), 6.56 (d, J=16.7 Hz, 1H), 1.94 (s, 6H). LCMS (m/z) 436.9 [M+H], Tr=3.59 min (LCMS method 1).
Example 27
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3-carbonitrile—Compound 27
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3-carbonitrile (Compound 27)
Compound 20d (92 mg, 0.21 mmol), 6-aminopyridazine-3-carbonitrile (60 mg, 0.50 mmol, Matrix Scientific, 112287), N,N-diisopropylethylamine (174 μL, 1.0 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24 mg, 0.042 mmol) and palladium (II) acetate (9 mg, 0.042 mmol) were combined under argon in N-methyl-2-pyrrolidone (2 mL). The reaction was heated at 100° C. in a sealed vessel for 7 hours. The reaction mixture was cooled down to room temperature, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 27. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (bs, 1H), 8.06 (bs, 1H), 7.73 (d, J=16.7 Hz, 1H), 7.71-7.58 (m, 2H), 7.54 (s, 2H), 6.55 (d, J=16.7 Hz, 1H), 1.93 (s, 6H). LCMS (m/z) 436.9 [M+H], Tr=3.73 min (LCMS method 1).
Example 28
(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)benzonitrile—Compound 28
Step 1: Synthesis of 8-bromo-5-methoxyquinazoline-2,4(1H,3H)-dione (Compound 28a)
A mixture of 2-amino-3-bromo-6-methoxybenzoic acid (2 g, 8.1 mmol, Ark Pharm Inc, AK137474) and urea (12 g, 200 mmol) was heated at 200° C. for 2 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered off and washed with water (50 mL) to afford the title compound 28a.
Step 2: synthesis 8-bromo-2-chloro-5-methoxyquinazolin-4-amine (Compound 28b)
A mixture of compound 28a (4.67 g, 17 mmol), phosphorus(V) oxychloride (20 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated down under reduced pressure and the solid residue was subjected to extraction with acetone. The acetone solution was concentrated down under reduced pressure to afford the title compound 28b. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.26 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 3.98 (s, 3H). LCMS (m/z) 288.1 [M+H], Tr=3.74 min (LCMS method 1).
Step 3: Synthesis of (E)-3-(4-(4-amino-2-chloro-5-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 28c)
A mixture of compound 28b (100 mg, 0.35 mmol), compound 1c (118 mg, 0.42 mmol), potassium phosphate tribasic monohydrate (159 mg, 0.69 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (23 mg, 0.035 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 5 mL) under argon and this reaction mixture was stirred at 80° C. for 30 minutes. The product was isolated by silica gel chromatography (gradient from 60-100% ethyl acetate in iso-hexanes) to afford the title compound 28c. LCMS (m/z) 364.9 [M+H], Tr=4.38 min (LCMS method 1).
Step 4: Synthesis of (E)-4-((4-amino-8-(4-(2-cyano vinyl)-2,6-dimethyl phenyl)-5-methoxyquinazolin-2-yl)amino)benzonitrile (Compound 28)
A mixture of compound 28c (37 mg, 0.1 mmol), 4-aminobenzonitrile (60 mg, 0.5 mmol, Sigma-Aldrich), palladium(II) acetate (4 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12 mg, 0.02 mmol) was dissolved in N-methyl-2-pyrrolidone (2 mL) under argon. N,N-Diisopropylethylamine (87 μL, 0.5 mmol) was then added via syringe and the reaction mixture was stirred at 110° C. for 6 hours. The product was isolated by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 28 as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.65 (m, 3H), 7.71 (d, J=16.7 Hz, 1H), 7.58-7.45 (m, 4H), 7.07 (s, 1H), 6.55 (d, J=16.7 Hz, 1H), 4.07 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 447.0 [M+H], Tr=3.85 min (LCMS method 1).
Example 29
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)nicotinonitrile—Compound 29
Synthesis (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)nicotinonitrile (Compound 29)
Compound 28c (37 mg, 0.1 mmol), 6-aminonicotinonitrile (60 mg, 0.5 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (87 μL, 0.5 mmol). (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12 mg, 0.02 mmol) and palladium (II) acetate (4 mg, 0.02 mmol) were combined under argon in A-methyl-2-pyrrolidone (2 mL). The reaction was heated at 110° C. in a sealed vessel for 6 hours. The reaction mixture was cooled down to room temperature, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 29. 1H NMR (400 MHz, DMSO-d6) δ 13.31 (bs, 1H), 11.92 (bs, 1H), 9.49 (s, 1H), 9.09 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.82 (d, J=16.7 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.68 (s, 2H), 7.55-7.40 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 6.69 (d, J=16.7 Hz, 1H), 4.13 (s, 3H), 1.97 (s, 6H). LCMS (m/z) 448.0 [M+H], Tr=3.60 min (LCMS method 1).
Example 30
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile—Compound 30
Step 1: Synthesis of 8-bromo-2-chloro-N-methylquinazolin-4-amine (Compound 30a)
8-Bromo-2,4-dichloroquinazoline (556 mg, 2 mmol. Ark Pharm Inc., AK-28703) was dissolved in 6 mL of 20% solution of methylamine in ethanol and the reaction was stirred at room temperature for 15 minutes. Volatiles were removed under reduced pressure and the solid residue was suspended in water. The solid product was filtered off and washed with water (3×5 mL) and pentane (3×5 mL) to give the title compound 30a. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=4.7 Hz, 1H), 8.19 (dd, J=8.3 Hz, J=1.2 Hz, 1H), 8.11 (dd, 7=7.7 Hz, J=1.2 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 3.00 (d, J=4.3 Hz, 3H). HRMS: (ESI+) calculated for C9H8N3BrCl [M+H] 271.9585, found 271.9585. LCMS (m/z) 272.0 [M+H], Tr 3.80 min (LCMS method 1).
Step 2: Synthesis of (E)-3-(4-(2-chloro-4-(methylamino)quinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 30b)
A mixture of compound 30a (110 mg, 0.4 mmol), compound 1c (147 mg, 0.52 mmol), potassium phosphate tribasic monohydrate (138 mg, 0.6 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (26 mg, 0.04 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (85:15, 5 mL) under argon and this reaction mixture was stirred at 80° C. for 20 minutes. The reaction mixture was concentrated down under reduced pressure and the product was isolated by silica gel chromatography (gradient from 50-80% ethyl acetate in iso-hexanes) to afford the title compound 30b. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=4.4 Hz, 1H), 8.25 (dd, J=8.2 Hz, J=1.5 Hz, 1H), 7.67-7.58 (m, 2H), 7.53 (dd, 7=7.2 Hz, J=1.5 Hz, 1H), 7.43 (s, 2H), 6.46 (d, J=16.7 Hz, 1H), 3.01 (d, J=4.4 Hz, 3H), 1.85 (s, 6H). HRMS: (ESI+) calculated for C20H18N4Cl [M+H] 349.1215, found 349.1216. LCMS (m/z) 349.1 [M+H], Tr 4.51 min (LCMS method 1).
Step 3: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile (Compound 30)
A mixture of compound 30b (52 mg, 0.15 mmol), 4-aminobenzonitrile (90 mg, 0.75 mmol, Sigma-Aldrich), palladium(II) acetate (20 mg, 0.064 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon. N,N-Diisopropylethylamine (150 μL, 0.85 mmol) was then added via syringe and the reaction mixture was stirred at 110° C. for 3 hours. The reaction mixture was concentrated down under reduced pressure and the product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%, acetonitrile in water) to afford the title compound 30. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.77-7.70 (m, 3H), 7.51 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 3.06 (d, J=4.3 Hz, 3H), 1.90 (s, 6H). HRMS: (ESI+) calculated for C27H23N6 [M+H] 431.1979, found 431.1977. LCMS (m/z) 431.2 [M+H], Tr 3.67 min (LCMS method 1).
Example 31
(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)nicotinonitrile—Compound 31
Synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)nicotinonitrile (Compound 31)
A mixture of compound 30b (52 mg, 0.15 mmol), 6-aminonicotinonitrile (90 mg, 0.75 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20 mg, 0.064 mmol) and (9,9-dimethyl-97f-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon. N,N-Diisopropylethylamine (150 μL, 0.85 mmol) was then added via syringe and the reaction mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated down under reduced pressure and the product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%, acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of the title compound 31. 1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 12.28 (s, 1H), 10.13 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.88-7.80 (m, 2H), 7.80-7.72 (m, 1H), 7.71 (s, 2H), 7.59-7.49 (m, 1H), 7.46-7.41 (m, 1H), 6.70 (d, J=16.7 Hz, 1H), 3.21 (d, J=4.4 Hz, 3H), 1.96 (s, 6H). HRMS: (ESI+) calculated for C26H22N7 [M+H] 432.1931, found 432.1929. LCMS (m/z) 432.2 [M+H], Tr 3.53 min (LCMS method 1).
Example 32
(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 32
Step 1: Synthesis of 4-((4-amino-8-(trimethylstannyl)quinazolin-2-yl)amino)benzonitrile (Compound 32a)
To a mixture of 8a (1000 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) in dry dioxane (5 mL) was added hexamethylditin (1 mL, 4.82 mmol) under argon. The reaction mixture was heated to 100° C. for 14 hours under argon, then cooled down to room temperature and directly purified by silica gel chromatography (gradient from 25-50% ethyl acetate in iso-hexanes) to afford the title compound 32a. 1H NMR (400 MHz, DMSO-4) δ 9.42 (s, 1H), 8.08-8.18 (m, 3H), 7.73 (d, J=9.9 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 7.51 (bs, 2H), 7.20-7.28 (m, 1H), 0.36 (s, 9H). LCMS (m/z) 424.0 [M−H], Tr=4.84 min (LCMS method 1).
Step 2: Synthesis of (E)-3-(4-bromo-3,5-dimethoxyphenyl)acrylonitrile (Compound 32b)
To a solution of 4-bromo-3,5-dimethoxybenzaldehyde (24.5 g, 100 mmol, Ark Pharm Inc., AK-34641) and diethylcyanomethyl phosphonate (18.6 g, 105 mmol) in anhydrous 2-methyltetrahydrofuran (400 mL) was slowly added potassium t-butoxide (12.3 g, 110 mmol) at 0° C. under argon. The reaction mixture was vigorously stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over MgSO4 and, filtered through a 3 cm layer of silica gel which was washed with additional ethyl acetate. The combined organics were concentrated down under reduced pressure and the solid residue was treated in sonic bath with hexane/diethyl ether mixture (1/3) for 3 minutes. The solid product was filtered off and washed with hexane to afford the title compound 32b. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=16.7 Hz, 1H), 7.06 (s, 2H), 6.65 (d, J=16.7 Hz, 1H), 3.87 (s, 6H). LCMS (m/z) no MS signal, Tr 2.50 min (LCMS method 2).
Step 3: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 32)
A mixture of compound 32a (20 mg, 0.047 mmol), compound 32b (20 mg, 0.075 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C. for 2 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%, acetonitrile in water with 0.1% TFA) to afford the TFA salt of the title compound 32. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (bs, 1H), 9.72-9.53 (m, 2H), 7.88-7.83 (m, 2H), 7.77 (d, J=16.7 Hz, 1H), 7.71 (d, J=7.8 Hz, 2H), 7.58 (bs, 1H), 7.54 (bs, 1H), 7.41-7.34 (m, 1H), 7.16 (s, 2H), 6.76 (d, J=16.7 Hz, 1H), 3.72 (s, 6H). LCMS (m/z) 449.0 [M+H], Tr=3.48 min (LCMS method 1).
Example 33
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 33
Step 1: Synthesis of 4-((8-(trimethylstannyl)quinazolin-2-yl)amino)benzonitrile (Compound 33a)
To a mixture of 1a (1000 mg, 3.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) in dry dioxane (5 mL) was added hexamethylditin (1 mL, 4.82 mmol) under argon. The reaction mixture was heated to 110° C. for 4 hours under argon, then cooled down to room temperature and directly purified by silica gel chromatography (gradient from 0-30% ethyl acetate in iso-hexanes) to afford the title compound 33a. 1H NMR (400 MHz. DMSO-d6) δ 10.53 (s, 1H), 9.47 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.31-8.24 (m, 2H), 8.09-8.02 (m, 1H), 7.90-7.85 (m, 2H), 7.60-7.51 (m, 1H), 0.05 (s, 9H). LCMS (m/z) 409.0 [M+H], Tr=5.54 min (LCMS method 1).
Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 33)
A mixture of compound 33a (20 mg, 0.048 mmol), compound 32b (20 mg, 0.075 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C. for 2 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 0-50% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%, acetonitrile in water with 0.1% TFA) to afford the TFA salt of the title compound 33. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.40 (s, 1H), 7.96 (dd, J=8.1, 1.4 Hz, 1H), 7.78-7.85 (m, 3H), 7.71 (dd, J=7.2, 1.4 Hz, 1H), 7.44-7.54 (m, 3H), 7.21 (s, 2H), 6.77 (d, J=16.7 Hz, 1H), 3.62 (s, 6H). LCMS (m/z) 433.98 [M+H], Tr=4.39 min (LCMS method 1).
Example 34
(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile—Compound 34
Step 1: Synthesis of 8-bromo-2-chloroquinazolin-4(3H)-one (Compound 34a)
Aqueous sodium hydroxide (30 mL, 0.2 M, 6 mmol) was added into a solution of 8-bromo-2,4-dichloroquinazoline (556 mg, 2 mmol. Ark Pharm Inc., AK-28703) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 0.5 hour. Then the reaction mixture was acidified with glacial acetic acid to pH=5 and concentrated down under reduced pressure. Water was added and the solid product was filtered off and washed with water (3×20 ml) to afford the title compound 34a. 1H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.42-7.51 (m, 1H). HRMS: (ESI+) calculated for C8H4ON2BrClNa [M+Na] 280.9088, found 280.9089. LCMS (m/z) 259.0 [M+H], Tr 3.58 min (LCMS method 1).
Step 2: Synthesis of (E)-3-(4-(2-chloro-4-oxo-3,4-dihydroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 34b)
A mixture of compound 34a (74 mg, 0.28 mmol), compound 1c (120 mg, 0.42 mmol), potassium phosphate tribasic monohydrate (200 mg, 0.87 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (30 mg, 0.05 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 3.3 mL) under argon and this mixture was stirred at 80° C. for 2 hours. The product was isolated by silica gel chromatography (gradient from 0-100% ethyl acetate in iso-hexanes) to afford the title compound 34b. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (bs, 1H), 8.16 (dd, J=7.7, 1.8 Hz, 1H), 7.67-7.51 (m, 3H), 7.43 (s, 2H), 6.46 (d, J=16.7 Hz, 1H), 1.88 (s, 6H). LCMS (m/z) 336.1 [M+H], Tr=4.24 (LCMS method 1).
Step 3: Synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile (Compound 34)
A mixture of compound 34b (80 mg, 0.24 mmol), 6-aminonicotinonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (100 mg, 0.17 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon. N,N-Diisopropylethylamine (1 mL, 5.7 mmol) was then added via syringe and the reaction mixture was stirred at 100° C. for 1 hour. The product was isolated by silica gel flash chromatography (gradient from 0-100% ethyl acetate in iso-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep pre-packed column, gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 34. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (bs, 1H), 10.26 (bs, 1H), 8.74 (bs, 1H), 8.10 (dd, J=7.8, 1.6 Hz, 1H), 7.94-7.81 (m, 1H), 7.69 (d, J=16.7 Hz, 1H), 7.59-7.36 (m, 5H), 6.51 (d, J=16.7 Hz, 1H), 1.94 (s, 6H). LCMS (m/z) 418.9 [M+H], Tr=4.11 min (LCMS method 1).
Example 35
(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 35
Step 1: Synthesis of (E)-3-(4-bromo-3,5-diethylphenyl)acrylonitrile (Compound 35a)
To a solution of 2,5-dibromo-1,3-diethylbenzene (2920 mg, 10 mmol, Oakwood Products, Inc, —034265) in anhydrous acetonitrile (25 mL) was added palladium(II) acetate (224 mg, 1 mmol), acrylonitrile (1060 mg, 20 mmol), tri(o-tolylphosphine (913 mg, 3 mmol) and triethylamine (4 mL, 30 mmol) then the mixture was purged with argon and heated at 70° C. for 3 hours. The reaction mixture was filtered through Celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The water layer was back extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. This was subjected to silica gel chromatography (gradient from 0-20% ethyl acetate in iso-hexanes) to afford the title compound 35a. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=16.6 Hz, 1H), 7.12 (s, 2H), 5.86 (d, J=16.6 Hz, 1H), 2.79 (q, J=7.5 Hz, 4H), 1.22 (t, J=7.5 Hz, 6H). LCMS (m/z) no MS signal, Tr=3.07 min (LCMS method 2).
Step 2: Synthesis of (E)-3-(3,5-diethyl-4-(4A5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile (Compound 35b)
A mixture of compound 35a (300 mg, 1.14 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (432 mg, 1.70 mmol), potassium carbonate (471 mg, 3.4 mmol), palladium(II) acetate (13 mg, 0.06 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos, 58 mg, 0.14 mmol) in dry MW-dimethylformamide (20 mL) was purged with argon and heated at 100° C. for 2 hour. The reaction mixture was filtered through Celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The water layer was back extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography (gradient from 0-15% ethyl acetate in iso-hexanes) to afford compound 35b. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=16.6 Hz, 1H), 7.04 (s, 2H), 5.85 (d, J=16.6 Hz, 1H), 2.67 (q, J=7.6 Hz, 4H), 1.38 (s, 12H), 1.20 (t, J=7.6 Hz, 6H). LCMS (m/z) no MS signal, Tr=3.07 min (LCMS method 2).
Step 3: Synthesis of (E)-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5-diethylphenyl)acrylonitrile (Compound 35c)
A mixture of 8-bromo-2-chloroquinazolin-4-amine (90 mg, 0.35 mmol, Ark Pharm Inc, AK-28702), compound 35b (130 mg, 0.42 mmol), potassium phosphate tribasic (96 mg, 0.45 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (23 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide: water mixture (80:20, 5 mL) under argon. The reaction was heated at 80° C. for 60 minutes. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 1 volume equivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure and the residue was treated with hexane in a sonic bath. The solid product was filtered off and washed twice with hexane to afford the title compound 35c. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (bs, 2H), 8.29 (dd, J=7.2.2.5 Hz, 1H), 7.67 (d, J=16.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.46 (s, 2H), 6.52 (d, J=16.7 Hz, 1H), 2.22-2.01 (m, 4H), 0.91 (t, J=7.5 Hz, 6H). LCMS (m/z) 363.3 [M+H], Tr=2.68 min (LCMS method 2).
Step 4: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 35)
A mixture of compound 35c (40 mg, 0.11 mmol), 4-cyanoaniline (18 mg, 0.154 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane (4M, 3 μL, 0.011 mmol) in dry N-methyl-2-pyrrolidone (1 mL) was heated under argon at 120° C. for 12 hours. The reaction mixture was cooled down to room temperature and purified directly by HPLC reverse phase chromatography (gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 35. 1H NMR (400 MHz, DMSO-d6) δ 10.57-9.84 (m, 1H), 9.82-8.84 (m, 2H), 8.27 (bs, 1H), 7.86-7.22 (m, 7H), 6.62 (d, J=16.8 Hz, 1H), 2.40-1.98 (m, 4H), 0.94 (t, J=7.2 Hz, 6H). LCMS (m/z) 445.4 [M+H], Tr=2.59 min (LCMS method 2).
Example 36
(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound 36
Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (Compound 36)
Compound 35c (40 mg, 0.11 mmol), 6-aminonicotinonitrile (53 mg, 0.44 mmol. Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (28 mg, 0.22 mmol) and [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (9 mg, 0.011 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in a sealed vessel for 4 hours. The reaction mixture was cooled down to room temperature and purified directly by HPLC reverse phase chromatography (gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 36. 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs, 1H), 12.09 (bs, 1H), 9.62 (bs, 1H), 9.38 (bs, 1H), 8.46 (d, 7=8.2 Hz, 1H), 8.37-8.15 (m, 1H), 7.94-7.83 (m, 2H), 7.80-7.66 (m, 3H), 7.56-7.27 (m, 2H), 6.76 (d, J=16.7 Hz, 1H), 2.40-2.01 (m, 4H), 0.94 (t, J=7.5 Hz, 6H). LCMS (m/z) 446.4 [M+H], Tr=1.98 min (LCMS method 2).
Example 37
(E)-1-(2-((4-Cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-4-yl)urea—Compound 37
Synthesis of (E)-1-(2-((4-cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-4-yl)urea (Compound 37)
Compound 2 (42 mg, 0.10 mmol) was suspended in dry dichloromethane (2 mL), and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) was added to the suspension followed by dropwise addition of phosgene (0.5 mL, 20% solution in toluene). The mixture was stirred at 50° C. for 1 hour. Another portion of N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and phosgene (0.2 mL, 20% solution in toluene) was added to the reaction mixture and this mixture was stirred at 50° C. for another 1 hour. The mixture was cooled down to room temperature and saturated aqueous ammonia (1 mL) was added. Volatiles were removed under reduced pressure and the crude residue was purified by HPLC using gradient from 50-100% acetonitrile in water (HPLC preparative column Phenomenex Gemini 10u. C18, 250×21.2 mm, 10 mL/min) to afford the title compound 37. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (bs, 1H), 8.26-8.07 (m, 1H), 7.78-7.65 (m, 3H), 7.62-7.45 (m, 3H), 7.44-7.30 (m, 3H), 7.29-7.16 (m, 3H), 6.43 (d, J=16.7 Hz, 1H), 1.81 (s, 6H). LCMS (m/z) 460.3 [M+H], Tr=3.98 min (LCMS method 1).
Example 38
(E)-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 38
Step 1: Synthesis of 4-bromo-3,5-dimethylbenzoic acid (Compound 38a)
4-Bromo-3,5-dimethylbenzonitrile (630 mg, 3 mmol, Ark Pharm Inc. AK-44760) was dissolved in ethanol (1 mL), and 8M sodium hydroxide solution (5 mL) was added and this reaction mixture was stirred in a sealed vessel at 120° C. for 12 hours. The reaction mixture was diluted with water (100 mL) and washed with diethylether (2×50 mL), aqueous layer was acidified with concentrated hydrochloric acid (to pH=3) and extracted with diethylether (2×100 mL). Combined organic layers were dried over sodium sulfate and concentrated down under reduced pressure to afford the title compound 38a. NMR (600 MHz, DMSO-d6) δ 7.72 (s, 2H), 2.41 (s, 6H).
Step 2: Synthesis of 1-(4-bromo-3,5-dimethylphenyl)ethanone (Compound 38b)
Compound 38a (100 mg, 0.44 mmol) was suspended in dry 1,4-dioxane (5 mL) and methyllithium (0.8 mL, 1.6 M solution in diethyl ether) was added dropwise under argon. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by addition of methanol (10 mL) and concentrated down under reduced pressure. The solid residue was extracted with ethyl acetate (3×10 mL). Combined organic solutions were concentrated down under reduced pressure to afford the title compound 38b. LCMS (m/z) 227.0 [M+H], Tr=4.65 min (LCMS method 1).
Step 3: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)but-2-enenitrile and (Z)-3-(4-bromo-3,5-dimethylphenyl)but-2-enenitrile (Compound 38c and compound 38d)
Compound 38b (95 mg, 0.42 mmol) and diethyl (cyanomethyl)phosphonate (70 μL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Cesium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated down under reduced pressure at 30° C. The resulting solid was allowed to stand at room temperature for 4 hours. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using gradient from 0-10% ethyl acetate in iso-hexanes to afford the title compound 38c LCMS (m/z) 250.0 [M+H], Tr=5.01 min (LCMS method 1); and the title compound 38d LCMS (m/z) 250.0 [M+H], Tr=4.48 min (LCMS method 1).
Step 4: Synthesis of (E)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 38)
A mixture of compound 32a (20 mg, 0.047 mmol), compound 38c (20 mg, 0.080 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C. for 14 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then re-purified on HPLC (preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 38. 1H NMR (600 MHz, DMSO-d6) δ 8.23 (bs, 1H), 7.83-7.72 (m, 2H), 7.60-7.29 (m, 7H), 6.17 (q, J=1.0 Hz, 1H), 2.52-2.51 (m, 3H), 1.96 (s, 6H). LCMS (m/z) 430.9 [M+H], Tr=3.83 min (LCMS method 1).
Example 39
(Z)-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 39
Synthesis of (Z)-4-((4-amino-8-(4-(l-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 39)
A mixture of compound 32a (20 mg, 0.047 mmol), compound 38d (18 mg, 0.072 mmol) and bis(tri-re/7-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C. for 14 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then re-purified on HPLC (preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 38. 1H NMR (600 MHz, DMSO-4) δ 8.22 (bs, 1H), 7.84-7.71 (m, 4H), 7.62-7.29 (m, 5H), 5.89-5.79 (m, 1H), 2.36 (d, J=1.5 Hz, 3H), 1.97 (s, 6H). LCMS (m/z) 430.9 [M+H], Tr=3.76 min (LCMS method 1).
Example 40
4-((4-Amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound 40 (mixture E/Z=1/1)
Step 1: Synthesis of 4-bromo-3,5-dimethylbenzaldehyde (Compound 40a)
A mixture of 4-bromo-3,5-dimethylbenzonitrile (2 g, 9.57 mmol, Ark Pharm Inc. AK-44760) in dichloromethane (25 mL) was cooled to −62° C. A solution of diisobutylaluminum hydride (1M in dichloromethane, 11 mL) was added dropwise and the reaction was left to reach room temperature during 2 hours. After that, 5% aqueous solution of hydrochloric acid (10 mL) was added and the reaction mixture was heated to reflux for 30 minutes. Then, the reaction mixture was diluted with dichloromethane, washed with brine. The organic layer was dried over calcium chloride. The solvent was removed under reduced pressure and the crude product was subjected to silica gel chromatography (gradient from 0-10% ethyl acetate in iso-hexanes) to afford the title compound 40a. 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.57 (s, 2H), 2.50 (s, 6H). HRMS: (TOP CI+) calculated for C9H10BrO [M+H] 212.9915, found 212.9913. LCMS (m/z) 213.0 [M+H], Tr=4.59 min (LCMS method 1).
Step 2: Synthesis of 3-(4-bromo-3,5-dimethylphenyl)-2-methylacrylonitrile (compound 40b) mixture E/Z=1/1
Compound 40a (100 mg, 0.47 mmol) and diethyl (1-cyanoethyl)phosphonate (70 μL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Cesium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated down under reduced pressure at 30° C. The resulting solid was allowed to stand at room temperature for 4 hours. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using gradient from 0-10% ethyl acetate in iso-hexanes to afford the title compound 40b as a 1:1 mixture of E/Z isomers. LCMS (m/z) 250.0 [M+H], Tr=5.07 and 5.10 min (LCMS method 1).
Step 4: Synthesis of 4-((4-amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (Compound 40) mixture E/Z=1/1
A mixture of compound 32a (20 mg, 0.047 mmol), compound 40b (20 mg, 0.080 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C. for 8 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iso-hexanes) and then re-purified on HPLC (preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 40 as a 1:1 mixture of E/Z isomers. 1H NMR (600 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.82-7.74 (m, 2H), 7.64-7.23 (m, 7H), 2.23-2.19 (m, 3H), 1.96 (s, 6H). LCMS (m/z) 430.8 [M+H], Tr=3.86 min (LCMS method 1).
Example 41
(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile—Compound 41
Step 1: Synthesis of 4-((8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile (Compound 41a)
A mixture of compound 34a (260 mg, 1 mmol) and 4-aminobenzonitrile (130 mg, 1.1 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 130° C. for 30 minutes. The reaction mixture was cooled down to room temperature and diethyl ether (10 mL) was added. The solid product was filtered off and washed with diethyl ether (3×20 mL) to afford the title compound 41a. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (bs, 1H), 9.41 (bs, 1H), 8.11 (d, J=8.8 Hz, 2H), 8.04-7.96 (m, 2H), 7.80 (d, J=8.8 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H). HRMS: (ESI+) calculated for C15H10ON4Br [M+H] 341.0033, found 341.0033. LCMS (m/z) 341.1 [M+H], Tr 4.52 min (LCMS method 1).
Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile (Compound 41)
A mixture of compound 41a (68 mg, 0.2 mmol), compound 1c (85 mg, 0.3 mmol), potassium phosphate tribasic (92 mg, 0.4 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide: water mixture (85:15.40 mL) under argon. The reaction was heated to 80° C. for 3 hours. The reaction mixture was concentrated down under reduced pressure and the residue was purified by silica gel chromatography (gradient from 50-80% ethyl acetate in iso-hexanes) and then repurified by HPLC reverse phase chromatography (gradient 5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA salt of compound 41. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (bs, 1H), 9.15 (bs, 1H), 8.05 (dd, J=7.9, 1.6 Hz, 1H), 7.75 (d, J=16.7 Hz, 1H), 7.57 (dd, J=7.3, 1.6 Hz, 1H), 7.53 (s, 2H), 7.48-7.29 (m, 6H), 6.56 (d, J=16.7 Hz, 1H), 1.93 (s, 6H). LCMS (m/z) 418.3 [M+H], Tr=2.72 min (LCMS method 2).
Example 42
Alternative synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile—Compound 1b
Alternative synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile (compound 1b)
To a solution of diethyl cyanomethylphosphonate (266 mg, 1.5 mmol) in tetrahydrofuran (10 mL) was added potassium t-butoxide (168 mg, 1.5 mmol) at 0° C. with stirring for 30 minutes. After that, compound 40a (212 mg, 1 mmol) in tetrahydrofuran (10 mL) was added dropwise into the reaction mixture at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water. Ethyl acetate was added and the organic layer was washed with brine, dried over anhydrous calcium chloride and concentrated down under reduced pressure. The residue was purified by silica gel column chromatography (gradient from 0-20% ethyl acetate in iso-hexanes) to afford the title compound 1b. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=16.6 Hz, 1H), 7.12 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z) no MS signal, Tr=2.78 min (LCMS method 2).
Example 43
Alternative synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile—Compound 8a
Step 1: Synthesis of 3-bromo-2-((triphenylphosphoranylidene)amino)benzonitrile (Compound 43a)
A solution of triphenylphosphine (10.65 g, 40.6 mmol) in dichloromethane (200 mL) was treated slowly with bromine (6.49 g, 40.6 mmol) at 0° C. for 5 minutes. Then triethylamine (8.22 g, 81.2 mmol) was added followed by addition of 2-amino-3-bromobenzonitrile (4.00 g, 20.3 mmol, Abblis, AB1000095). Then, the ice bath was removed and the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was poured onto water and extracted two times with dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. Solvent was removed under reduced pressure and the residue was subjected to silica gel chromatography (gradient from 0-30% ethyl acetate in iso-hexanes) to afford the title compound 43a. 1H NMR (400 MHz, DMSO-4) δ 7.80-7.70 (m, 6H), 7.66 (dt, 7=7.9, 1.4 Hz, 1H), 7.64-7.58 (m, 3H), 7.57-7.47 (m, 6H), 7.40 (dt, J=7.7, 1.5 Hz, 1H), 6.64 (td, J=7.8.1.5 Hz, 1H). LCMS (m/z) 457.1 [M+H], Tr=2.99 min (LCMS method 2).
Step 2: alternative synthesis 4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile (Compound 8a)
To a solution of compound 43a (500 mg, 1.09 mmol) in 2-methyltetrahydrofuran (10 mL) was added 4-isocyanatobenzonitrile (173 mg, 1.20 mmol, Sigma-Aldrich) at 0° C. and the reaction mixture was stirred at 0° C. for 30 minutes, 2M ammonia in isopropanol (3.3 mL, 6.6 mmol) was added and the reaction mixture was heated to reflux for 3 hours then concentrated down under reduced pressure. The residue was purified by silica gel chromatography (gradient from 0-40% ethyl acetate in iso-hexanes) to afford the title compound 8a. 1H NMR (400 MHz. DMSO-d6) δ 9.74 (s, 1H), 8.35 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H),7.71 (d, J=8.8 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H). LCMS (m/z) 340.0 [M+H], Tr=4.06 min (LCMS method 1).
BIOLOGICAL EXAMPLES
Example A
High Throughput Screening of Anti-HIV-1 RT (Reverse Transcriptase)
Compounds were screened in a miniaturized, high throughput cytopathic effect assay for activity against HIV-1 HBX2 (wild type) and HIV-1 reverse transcriptase mutants K103N and Y181C. In Tables 1 and 2 below, “w.t.” refers to results of the tested compounds run with the wildtype 1 and “w.t. assay 2” refers results of the tested compounds run with the wildtype on the same day as the testing of the compounds with the mutants. Thus, “w.t. assay 2” was run under the same conditions as the testing of the compounds with the mutants and provides a direct comparison with the results from the testing with the mutants.
Ten-point serial dilutions of compounds with half-log step size were generated in DMSO. AZT (5 μM) was used as the positive control and DMSO as the negative control. The Echo acoustic dispenser was used to deliver 200 nL of serially diluted compound into sterile 384 well tissue culture assay plates. Two million MT-4 cells were incubated with each of the 3 viruses at MOI of 0.0005 in separate 1 mL infection tubes for 1 hour at 37° C. The cells were diluted in cell culture medium (RPMI+10% FBS) to 50.000 cells/mL. The infected cells were added to 384 well assay plates containing serially dilute compounds. Assay plates were incubated for 5 days in a humidified incubator set at 37° C. and 5% CO2. To measure the cytopathic effect of HIV, 40 μL Cell TiterGlo was added to each well and the resulting luminescence signal is read with the Envision plate reader (Perkin Elmer). Data were normalized to positive and negative controls in each plate and expressed as % CPE Protection. EC50 values were defined as the compound concentration that caused a 50% decrease in luminescence signal, and were calculated by non-linear regression using Pipeline Pilot software by applying a four parameter fit equation (Accelrys, San Diego, Calif.). Results are disclosed in Table 1.
TABLE 1
MT4
EC50
MT4 EC50 (nM) against
(nM)
w.t.
FC against
against
assay
mutant
Compound ID
w.t.
2*
K103N
Y181C
K103N
Y181C
1
3.0
6.2
8.8
17.8
1.4
2.9
2
3.7
3.6
4.0
10.9
1.1
3.0
3
NA
12.9
12.0
50.2
0.9
3.9
4
9.2
9.8
19.1
47.0
2.0
4.8
5
1.3
1.5
2.5
12.0
1.7
8.2
6
99.3
82.6
81.1
469.5
1.0
5.7
7
122.2
116.8
130.5
>500
1.1
>4.3
8
2.7
2.8
3.7
21.7
1.3
7.8
9
3.4
3.2
3.5
10.8
1.1
3.4
10
2.8
3.0
2.9
29.3
1.0
9.8
11
4.7
4.2
5.2
126.4
1.2
29.8
12
1.8
1.8
1.7
12.5
0.9
6.9
13
3.2
4.3
5.9
27.4
1.4
6.4
14
8.1
12.7
15.1
121.9
1.2
9.6
15
22.6
33.2
72.2
179.5
2.2
5.4
16
6.3
7.5
12.5
42.6
1.7
5.7
17
229.1
189.9
150.8
>500
0.8
>2.6
18
21.9
13.1
12.1
112.3
0.9
8.6
19
27.5
29.0
30.3
79.7
1.0
2.7
20
7.0
6.6
7.1
69.9
1.1
10.5
21
10.1
10.6
10.8
187.0
1.0
17.6
22
69.3
87.5
101.4
>500
1.2
>5.7
23
8.7
NA
NA
NA
NA
NA
24
27.8
27.8
32.5
478.5
1.2
17.2
25
39.1
28.3
44.1
159.8
1.6
5.6
26
2.7
2.0
2.4
27.2
1.2
13.5
27
6.3
3.8
5.3
399.7
1.4
105.9
28
11.4
9.1
14.3
57.2
1.6
6.3
29
22.1
18.6
33.4
>500
1.8
>26.9
30
15.9
13.0
17.0
55.6
1.3
4.3
31
10.5
8.6
17.6
432.5
2.1
50.5
32
1.9
1.3
1.5
10.5
1.2
8.3
33
2.1
1.5
3.2
12.3
2.1
7.9
34
2.4
3.0
3.2
11.3
1.0
3.7
35
12.8
16.8
16.9
38.6
1.0
2.3
36
7.7
10.5
10.1
87.3
1.0
8.3
37
4.7
6.8
7.8
22.1
1.2
3.3
38
6.0
7.9
7.0
18.6
0.9
2.4
39
5.9
8.9
111
27.2
14
3.0
40
6.8
9.9
16.3
36.1
1.7
3.7
(mixture of
isomers)
41
6.3
9.5
15.7
32.8
1.6
3.4
*w.t. assay 2 were run on the same day as the assays with K103N and Y181C mutants.
The high-throughput screening was also run for nevirapine (“NPV”), rilpivirinc (“RPV”), and efavirenz (“EFV”). Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #N391275). Rilpivirinc was obtained from Key Organics Ltd. (Camelford, Cornwall, United Kingdom; Catalogue #KE-0036). Efavirenz was obtained from Toronto Research Chemicals. Inc. (Toronto, Canada; Catalogue #E425000). The results are shown below in Table 2.
TABLE 2
MT4
EC50
(nM)
MT4 EC50 (nM) against
against
w.t.
FC against mutant
Compound
w.t.
assay 2*
K103N
Y181C
K103N
Y181C
Nevirapine
65.0
ND
ND
ND
ND
ND
(“NVP”)
Rilpivirine
0.9
1.3
1.5
3.8
1.2
3.1
(“RPV”)
Efavirenz
1.3
1.6
46.4
3.8
28.9
2.3
(“EFV”)
*w.t. assay 2 were run on the same day as the assays with K103N and Y181C mutants.
ND: not determined
It is understood that EC50 may be evaluated by techniques known in the art. In one embodiment, the compounds exhibit an EC50 of less than about 3000 nM in the wild-type or any of the HIV RT mutants, as measured by the method disclosed in the “high throughput screening of anti-HIV mutants K103N and Y181C” assay section discussed above. In one embodiment, the compounds exhibit an EC50 of less than about 1000 nM, 500 nM, 400 nM, 300 nM, 250 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM, or 1 nM in the wild-type or any of the HIV RT mutants (e.g., K103N, Y181C).
Example B
Resistance Profile Against HIV-1 RT (Reverse Transcriptase) Mutants
Compounds were tested for antiviral activity against a panel of NNRTI resistant viruses. A panel of 8 clonal site-directed mutant viruses representing the major resistance development pathways against rilpivirine (“RPV”), efavirenz (“EFV”), and nevirapine (“NVP”), containing both single and double mutations within HIV-1 reverse transcriptase was employed. Further details and background can be found in Janssen et al, J. Med. Chem, 2005, 48, 1901-1909; Das et al., Proc. Nat. Acad. Sci., 2008, vol., 105, no. 5, 1466-1471; and Kuroda et al., Nature Chemistry, 2013. DOI: 10.1038/NCHEM.1559. Retention of full antiviral potency against the K103N mutation relative to the wild type virus was considered especially desirable as this mutation is present in a minor subset of treatment-naïve patients (1.4%). HIV-1 recombinant strains encoding reverse transcriptase mutations K103N. Y181C, Y188L, G190A, K103N/Y181C, L1001/Y181C, E138K or E138K/M184V were constructed by site-directed mutagenesis. Wild-type and mutant viruses were prepared by transfecting infectious proviral HXB2-based cDNA clones into MT-2 cells and harvesting the cell supernatants. MT-2 cells were infected with wild-type and mutant HIV-1 strains at a multiplicity of infection (MOI) of 0.005 by gentle mixing for 3 hours at 37° C. and then added at a density of 16,667 cells per well in 50 μL complete RPMI cell culture media (containing 10% fetal bovine serum (FBS) and 10% penicillin-streptomycin) to 96-well plates containing 50 μL of a 3-fold serial dilution of test compounds in RPMI medium. After 5 days of incubation at 37° C. in a humidified incubator in the presence of 5% CO2, 100 μL of Cell Titer-Glo™ Reagent (Promega Biosciences, Inc., Madison, Wis.) was added to each well and the relative light units (RLU) measured on an Envision plate reader. The virus-induced cytopathic effect was determined as a percentage of the RLU measurements from samples with fully suppressed virus replication after subtracting the signal from untreated (DMSO) controls. The EC50 value was defined as the compound concentration inducing a 50% decrease in virus replication. Data analysis for the antiviral activity observed in MT-2 cells was performed using XL-Fit™ software (IDBS, Guildford, Surrey, UK) to calculate EC50 from an 8-point dose-response curve using the following equation:
y
=
M
-
(
M
-
H
)
×
EC
50
n
(
EC
50
n
+
x
n
)
where y=virus inhibition, x=drug concentration, M=maximum inhibition. H=minimum inhibition and n=Hill coefficient. EC50 values (mean±standard deviation) were calculated from at least three independent experiments performed in triplicate. The level of resistance was calculated as a ratio of the mean EC50 for each mutant/WT virus. Results are disclosed in FIG. 1 and in Tables 3 and 4 below.
TABLE 3
Biology resistance panel-low throughput fold change (FC)
Com-
L100I/
K103N/
E138K/
pound
K103N
Y181C
Y181C
Y181C
Y188L
G190A
M184V
1
1.3
5.7
6.9
14.8
15.2
0.6
ND
2
0.9
4.0
1.6
4.1
10.0
1.6
5.0
3
1.0
3.4
1.0
3.4
13.7
ND
ND
4
1.4
4.9
5.4
12.8
16.9
ND
ND
5
1.6
15.4
18.9
208.0
174.0
ND
ND
9
1.0
5.7
4.0
14.7
11.4
ND
ND
10
0.9
11.9
3.8
19.9
53.6
ND
ND
11
2.1
154.0
85.0
157.0
161.0
ND
ND
34
1.4
3.4
1.7
12.4
18.7
ND
4.2
ND: not determined
The resistance profile against HIV-1 RT mutants was also run for nevirapine (“NPV”), rilpivirine (“RPV”), and efavirenz (“EFV”). Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto. Canada: Catalogue #N391275). Rilpivirine was obtained from Key Organics Ltd. (Camelford, Cornwall, United Kingdom; Catalogue #KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #E425000). The results are shown below in Table 4.
TABLE 4
Biology resistance panel-low throughput fold change (FC)
Com-
L100I/
K103N/
E138K/
pound
K103N
Y181C
Y181C
Y181C
Y188L
G190A
M184V
Nevira-
87.0
>229
>229
ND
>229
183.0
ND
pine
(“NVP”)
Rilpivi-
1.0
4.6
18.1
7.7
22.8
0.8
3.0
rine
(“RPV”)
Efavir-
48.1
3.6
>200
83.5
132.5
14.8
ND
enz
(“EFV”)
ND: not determined
Example C
hERG Assay
Cells:
AVFVA's CHO cell line, which stably expresses hERG channels, was used for the study. Cells were cultured in DMEM/F12 containing 10% FBS, 1% penicillin/streptomycin and 500 μg/ml G418. Before testing, cells were harvested using Accumax (Innovative Cell Technologies).
Solutions:
For electrophysiological recordings, the following solutions were used:
External Solution: 2 mM CaCl2; 2 mM MgCl2; 4 mM KCl; 150 mM NaCl; 10 mM Glucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5M NaOH.)
Internal Solution: 140 mM KCl: 10 mM MgCl2; 6 mM EGTA; 5 mM HEPES-Na; 5 mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with 1M KOH).
Electrophysiology:
Whole cell recordings were performed using PX 7000A (Axon Instruments) with AVIVA's SealChip™ technology. Cells were voltage clamped at a holding potential of −80 mV. The hERG current was then activated by a depolarizing step to −50 mV for 300 ms. This first step at −50 mV was used as a baseline for measuring peak amplitude of the tail current. Next, a voltage step to +20 mV was applied for 5 s to activate the channels. Finally, a step back to −50 mV for 5 s removed activation and the deactivating tail current was recorded.
Test Article Handling and Dilutions:
All test articles were prepared from 10 mM DMSO stock solutions. Solutions were mixed by sonication for 20 min, followed by vigorous vortexing. Prior to testing, compounds were diluted to test concentrations in glass vials using External Solution. Dilutions were prepared no longer than 20 min prior to use.
Electrophysiology Procedures
After achieving whole cell configuration, cells were monitored for 90 s to assess stability and then washed with External Solution for 66 s. The voltage protocol was then applied to the cells every 12 s throughout the procedure. Only stable cells with recording parameters above threshold were allowed to enter the drug addition procedure.
External solution containing 0.1% DMSO (vehicle) was applied to the cells to establish a baseline. After allowing the current to stabilize for 3 to 10 min, test articles were applied. Test article solutions were added to cells in 4 separate additions. Cells were kept in test solution until effect of the test article reached steady state, to a maximum of 12 min. Next, 1 μM cisapride (positive control) was added. Finally, washout with External Solution was performed until the recovery current reached steady state.
Data Analysis
Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments) and Origin (OriginLab Corporation) software. Results are disclosed in Table 5. The greater than values in Table 5 indicate the maximum achievable concentration in the assay (e.g., compounds achieving their solubility limit).
TABLE 5
Compound No.
hERG (μM)
2
>1
9
>3
10
>3
11
>3
12
>3
13
1.3
34
>3
The hERG assay was also run for rilpivirine (“RPV”). The result was 0.5 μM.
The specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present disclosure.
The Examples disclosed herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.
All references, including publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure.
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16718311
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gilead sciences, inc.
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USA
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B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
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|
|
Apr 20th, 2022 02:27PM
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Apr 20th, 2022 02:27PM
|
Gilead
|
Health Care
|
Pharmaceuticals & Biotechnology
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|
nasdaq:gild
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Gilead
|
Aug 28th, 2018 12:00AM
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Dec 28th, 2016 12:00AM
|
https://www.uspto.gov?id=US10059677-20180828
|
Process for preparing phosphatidylinositol 3-kinase inhibitors and intermediates thereof
|
A process for the synthesis of benzoxazinone containing compounds which may be useful precursors for synthesizing compounds for the treatment of cancer, is hereby disclosed.
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10059677
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1. A process for synthesizing a compound of formula 8:
or a salt thereof, comprising
step a) combining a compound of formula 9
or a salt thereof,
and a compound of formula 10
wherein the compound of formula 8 or a salt thereof is synthesized.
2. The process of claim 1, wherein step a) further comprises a step of combining a dehydrating agent.
3. The process of claim 2, wherein the dehydrating agent is diphenylphosphite, triphenylphosphite, N,N′-dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, or 1,1′-carbonyldiimidazole.
4. The process of claim 1, wherein step a) further comprises a base selected from the group consisting of pyridine, 4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, and N,N-diisopropylethylamine.
5. The process of claim 1, wherein step a) further comprises a solvent selected from the group consisting of pyridine, toluene, tetrahydrofuran, acetonitrile and 2-MeTHF.
6. The process of claim 1, wherein step a) is performed at a temperature between 0 and 45 degrees Celsius.
7. A process for synthesizing a compound of formula 15:
or a salt thereof, comprising
step a) combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 15 or a salt thereof is synthesized.
8. The process claim 7, wherein step a) further comprises a step of combining a dehydrating agent.
9. The process of claim 8, wherein the dehydrating agent is diphenylphosphite, triphenylphosphite, N,N′-dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, or 1,1′-carbonyldiimidazole.
10. The process of claim 7, wherein step a) further comprises a step of combining a base selected from the group consisting of pyridine, 4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, and N,N-diisopropylethylamine.
11. The process of claim 7, wherein step a) further comprises combining a solvent selected from the group consisting of pyridine, toluene, tetrahydrofuran, acetonitrile and 2-MeTHF.
12. The process of claim 7, wherein step a) is performed at a temperature between 0 and 45 degrees Celsius.
13. A compound of formula 8:
or a salt thereof.
14. A compound of formula 15:
or a salt thereof.
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14
|
CROSS REFERENCE TO RELATED APPLICATION
The present application is a divisional of U.S. patent application Ser. No. 14/575,670, filed Dec. 18, 2014, which claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/919,548, filed Dec. 20, 2013, the disclosure of both of which are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
The present disclosure relates generally to the synthesis or preparation of certain phosphatidylinositol 3-kinase (PI3K) inhibitors and their synthetic intermediates. Inhibitors of PI3K, such as quinazoline-purinyl containing compounds, may be useful in treating PI3K-mediated disorders such as cancer. There is a need to have alternative processes in making such PI3K inhibitors.
BRIEF SUMMARY OF THE INVENTION
The present disclosure provides a process of making certain PI3K inhibitors and compound intermediates thereof.
In one embodiment, the application discloses processes for synthesizing a compound of formula
or a salt thereof.
In another embodiment, the application discloses processes for synthesizing a compound of formula II:
or a salt thereof.
In an alternative embodiment, the application discloses processes for synthesizing a compound of formula III:
or a salt thereof.
In one embodiment, the application discloses a process for synthesizing a compound of formula
or a salt thereof, comprising step a) combining a compound of formula 2:
or a salt thereof, and a compound of formula 3:
wherein the compound of formula 1 or a salt thereof is synthesized, wherein R1 is halo; R2 is selected from the group consisting of H and optionally substituted C1-C8 alkyl; and R3 and R4 are each independently selected from the group consisting of hydrogen, an amino protective group and an optionally substituted purinyl group.
In a further embodiment the process further comprises step b) combining the compound of formula 1 or a salt thereof; and
a compound of formula 22:
wherein n is 0-5; and each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein a compound of formula 4:
or a salt thereof is synthesized.
In yet a further embodiment, the process further comprises step c) combining the compound of formula 4 or a salt thereof, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized;
step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
or a salt thereof is synthesized; and if R6 is an amino protective group, step e) further combining the compound of formula 7 or a salt thereof; and one or more reagents, wherein the one or more reagents are used to remove the amino protective group, wherein a compound of formula I:
or a salt thereof is synthesized.
In one embodiment, the present application discloses a process for synthesizing a compound of formula 8:
or a salt thereof, comprising step a) combining a compound of formula 9
or a salt thereof,
and a compound of formula 10
wherein the compound of formula 8 or a salt thereof is synthesized.
In a further embodiment, the process further comprises step b) combining the compound of formula 8 or a salt thereof and aniline, wherein a compound of formula 11:
or a salt thereof is synthesized.
In yet a further embodiment, the process further comprises step c) combining the compound of formula 11 or a salt thereof and an acid, wherein a compound of formula 12:
or a salt thereof is synthesized; step d) combining the compound of formula 12 or a salt thereof and a compound of formula 13
wherein a compound of formula 14:
or a salt thereof is synthesized; and
step e) combining the compound of formula 14 or a salt thereof and an acid, wherein a compound of formula II:
or a salt thereof is synthesized.
In an alternative embodiment, the application discloses a process for synthesizing a compound of formula 15:
or a salt thereof, comprising step a) combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 15 or a salt thereof is synthesized.
In a further embodiment, the process further comprises step b) combining the compound of formula 15 or a salt thereof and aniline, wherein a compound of formula 17:
or a salt thereof is synthesized.
In yet a further embodiment, the process further comprises step c) combining the compound of formula 17 or a salt and an acid thereof, wherein a compound of formula 18:
or a salt thereof is synthesized;
step d) combining the compound of formula 18 or a salt thereof and a compound of formula 13
wherein a compound of formula (19):
or a salt thereof is synthesized; and
step e) combining the compound of formula 19 or a salt thereof and an acid, wherein the compound of formula III:
or a salt thereof is synthesized.
In some embodiments, the application discloses the intermediate compounds formed from the processes disclosed herein. In some embodiments, the application discloses compounds selected from the group consisting of
and salts thereof. In certain embodiments, compounds of formula (8), (15), (14), (19), (20), and (21), are disclosed. In certain embodiments, pharmaceutically acceptable salts of the compounds of formula (8), (15), (14), (19), (20), and (21), are disclosed.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term “about” includes and describes the value or parameter per se. For example, “about x” includes and describes “x” per se. In certain embodiment, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−1-10%. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−5%. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−10%.
The term “between” includes and describes the value or parameter per se. For example, “between x and y” includes and describes “x” and “y” per se.
The term “and/or” includes subject matter in the alternative as well as subject matter in combination. For instance, “x, and/or y”, includes “x or y” and “x and y”.
The term “alkyl” as used herein refers to a straight or branched chain, saturated hydrocarbon having the indicated number of carbon atoms. For example, (C1-C8)alkyl is meant to include, but is not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein throughout.
The term “substituted alkyl” refers to: 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, in some embodiments, having from 1 to 20 carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbon atoms). This term is exemplified by groups such as methylene(—CH2—), ethylene (—CH2CH2—), the propylene isomers (e.g., —CH2CH2CH2— and —CH(CH3)CH2—), and the like.
The term “substituted alkylene” refers to an alkylene group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.
The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
The term “aralkyloxy” refers to the group —O-aralkyl. “Optionally substituted aralkyloxy” refers to an optionally substituted aralkyl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, and the like.
The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3 carbon-carbon double bonds. In some embodiments, alkenyl groups include ethenyl (or vinyl, i.e. —CH═CH2), 1-propylene (or allyl, i.e. —CH2CH═CH2), isopropylene (—C(CH3)═CH2), and the like.
The term “substituted alkenyl” refers to an alkenyl group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.
The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups include ethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH3), and the like.
The term “substituted alkynyl” refers to an alkynyl group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.
The term “hydroxy” or “hydroxyl” refers to a group —OH.
The term “alkoxy” refers to the group R—O—, where R is alkyl; and includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.
The term “substituted alkoxy” refers to the group R—O—, where R is substituted alkyl, where substituted alkyl, substituted alkenyl and substituted alkynyl are as defined herein.
The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like or multiple ring structures such as adamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to which is fused an aryl group, for example indanyl, and the like, provided that the point of attachment is through the cyclic alkyl group.
The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings and having at least one double bond and in some embodiments, from 1 to 2 double bonds.
The terms “substituted cycloalkyl” and “substituted cycloalkenyl” refer to cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents (in some embodiments, 1, 2 or 3substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “aryl” refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl and anthryl). In some embodiments, aryls include phenyl, fluorenyl, naphthyl, anthryl, and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5 substituents (in some embodiments, 1, 2 or 3substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “substituted purinyl” refers to a purinyl having 1, 2, 3, 4, or 5 substituents (in some embodiments 1, 2, or 3 substituents), each independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, purinyl is substituted with 1, 2, or 3 substituents selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2.
The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to a monoradical saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms, and from 1 to 10 heteroatoms or 1 to 4 heteroatoms within the ring, each heteroatom independently selected from the group consisting of nitrogen, sulfur, phosphorus, and oxygen.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Examples of heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.
The term “heteroaryl” refers to a group comprising single or multiple rings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. The term “heteroaryl” is generic to the terms “aromatic heteroaryl” and “partially saturated heteroaryl”. The term “aromatic heteroaryl” refers to a heteroaryl in which at least one ring is aromatic, regardless of the point of attachment. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline, pteridine. The term “partially saturated heteroaryl” refers to a heteroaryl having a structure equivalent to an underlying aromatic heteroaryl which has had one or more double bonds in an aromatic ring of the underlying aromatic heteroaryl saturated. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, 2-oxo-1,2-dihydropyridin-4-yl, and the like.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole or benzothienyl). Examples of nitrogen heterocyclyls and heteroaryls include, but are not limited to pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy nitrogen containing heteroaryl compounds.
The term “substituted amino” refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or —C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “aminocarbonyl” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “thiol” refers to the group —SH.
The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
A “substituted” group includes embodiments in which a monoradical substituent is bound to a single atom of the substituted group (e.g. forming a branch), and also includes embodiments in which the substituent may be a diradical bridging group bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.
Where a given group (moiety) is described herein as being attached to a second group and the site of attachment is not explicit, the given group may be attached at any available site of the given group to any available site of the second group. For example, an “alkyl-substituted phenyl”, where the attachment sites are not explicit, may have any available site of the alkyl group attached to any available site of the phenyl group. In this regard, an “available site” is a site of the group at which a hydrogen of the group may be replaced with a substituent.
A compound of a given formula is intended to encompass the compounds of the disclosure, and the salts, esters, isomers, tautomers, solvates, isotopes, hydrates, and prodrugs of such compounds. Additionally, the compounds of the disclosure may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given formula depends upon the number of asymmetric centers present (there are 2″ stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present disclosure, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. Compounds of the present disclosure include separable rotational isomers, or atropisomers.
“Isomers” are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers and diastereomers.
“Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term“(±)” is used to designate a racemic mixture where appropriate.
“Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the Cahn Ingold Prelog R S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (−) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.
“Tautomers” are structural isomers resulting from the migration of an atom or a functional group within the same organic molecule and lead to a change in one or more of its structural skeleton, electronic density distribution, and chemical properties. It is understood that compounds disclosed herein includes tautomeric forms although not necessarily explicitly shown. In one example, purine may be represented by any of the following tautomers:
Accordingly, a reference to any one of the purine tautomers includes the other tautomeric forms.
The term “amino protective group” is well understood by the person skilled in synthetic organic chemistry as a moiety that can be selectively installed onto and removed from a suitable amine functional group. Amino protective groups, and methods for using them, are described in the authoritative treatise on the subject, P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition (Wiley, 2006). In some embodiments, the amino protective group is selected from the group consisting of a carbamate, an amide, and a sulfonamide. In some embodiments, the amino protective group is a benzyl group, or a Schiff base.
Non-limiting examples of carbamate based amino protective groups include methyl carbamate, 9-fluoroenylmethyl carbamate (FMOC), 2,2,2-trichloroethyl carbamate, 2-trimethylsilylethyl carbamate, 1,1-dimethylpropynyl carbamate, 1-methyl-1-phenethyl carbamate, 1-methyl-1-(4-biphenylyl)ethyl carbamate, 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2-cyanoethyl carbamate, t-butyl carbamate, cyclobutyl carbamate, 1-methylcyclobutyl carbamate, 1-adamantyl carbamate, vinyl carbamate, allyl carbamate, cinnamyl carbamate, 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, 4,5-diphenyl-3-oxazolin-2-one, benzyl carbamate, p-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 5-benzisoxazolylmethyl carbamate, 9-anthrylmethyl carbamate, diphenylmethyl carbamate, isonicotinyl carbamate, and S-benzyl carbamate, N—(N′-phenylaminothiocarbonyl) derivative. In one embodiment, the amino protective group is selected from the group consisting methyl carbamate, t-butyl carbamate, vinyl carbamate, and allyl carbamate. In another embodiment, the amino protective group is selected from the group consisting of t-butyl carbamate (BOC) and 9-fluoroenylmethyl carbamate (FMOC).
Non-limiting examples of amide based amino protective groups include N-formyl, N-acetyl, N-chloracetyl, N-trichloroacetyl, N-trifluoroacetyl, N-o-nitrophenylacetyl, N-o-nitrophoxyacetyl, N-acetoacetyl, N-3-phenylpropionyl, N-3-(p-hydroxyphenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-4-chorobutyryl, N-o-nitrocinnamoyl, N-picolinoyl, N—(N′-acetylmethionyl), N-benzoyl, N-phthaloyl, and N-dithiasuccinoyl. In one embodiment, the amino protective group is selected from the group consisting of N-formyl, N-acetyl, N-chloracetyl, N-trichloroacetyl, N-trifluoroacetyl, and N-acetoacetyl.
Other non-limiting examples of amino protective groups include N-allyl, N-phenacyl, N-3-acetoxypropyl, quaternary ammonium salts, N-methyoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl, N-tetrahydropyranyl, N-2,4-dinitrophenyl, N-benzyl, N-o-nitrobenzyl, N-di(p-methoxyphenyl)methyl, N-triphenylmethyl, N-(p-methyoxyphenyl)diphenylmethyl, N-diphenyl-4-pyridylmethyl, N-2-picolyl N′-oxide, N,N′-isopropylidene, N-salicylidene, N-(5,-dimethyl-3-oxo-1-cyclohexenyl), N-nitro, N-oxide, N-diphenylphosphinyl, N-dimetylthiophosphinyl, N-dimethylthiophosphinyl, N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4,6-trimethylbenzenesulfonyl, N-toluenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N-phenyacylsulfonyl. In one embodiment, the amino protective group is selected from the group consisting of N-allyl, N-phenacyl, N-3-acetoxypropyl, quaternary ammonium salts, N-methyoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl, and N-tetrahydropyranyl. In one embodiment, the amino protective group is N-tetrahydropyranyl.
If there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure controls. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold, wedged, or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereo isomers of it.
The term “solvate” refers to a complex formed by the combining of a compound of any formula as disclosed herein, and a solvent.
The term “hydrate” refers to the complex formed by the combining of a compound of any formula disclosed herein, and water.
Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
In certain embodiments, the isotopically labeled compound is a compound of formula 6. In other embodiments, the isotopically labeled compound is a compound of formula 6, wherein X is a halogen and R6 is an amino protective group. In another embodiment, the isotopically labeled compound is a compound of formula 6, wherein X is CI and R6 is THF or THP.
The disclosure also includes compounds of any formula disclosed herein, in which from 1 to “n” hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and may thus be useful for increasing the half-life of a compound of any formula described herein, for instance formula II or formula III, when administered to a mammal. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacal. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent in a compound of any formula disclosed herein. Similarly, in certain embodiments, tritium (i.e., 3H) is also regarded as a substituent in a compound of any formula disclosed herein. In certain embodiments, 14C is regarded as a substituent in a compound of any formula disclosed herein.
The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Base addition salts can be prepared from inorganic and organic bases. Salts derived from in organic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Further salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkylamines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroarylamines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. In the general structure N(Rx)(Ry)(Rz), mono-substituted amines have 2 of the three substituents on nitrogen (Rx, Ry and Rz) as hydrogen; di-substituted amines have 1 of the three substituents on nitrogen (Rx, Ry and Rz) as hydrogen; and tri-substituted amines have none of the three substituents on nitrogen (Rx, Ry and Rz) as hydrogen. Rx, Ry and Rz may be selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl and the like. The abovementioned amines refer to the compounds wherein either one, two or three substituents on the nitrogen are as listed in the name. For example, the term “cycloalkenyl amine” refers to cycloalkenyl-NH2, wherein “cycloalkenyl” is as defined herein. The term “diheteroarylamine” refers to NH(heteroaryl)2, wherein “heteroaryl” is as defined herein and so on.
Acid addition salts may be prepared from inorganic and organic acids. Acid addition salts may be prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
In some embodiments, a salt is a “pharmaceutically acceptable salt”. A pharmaceutically acceptable salt of a given compound, for instance a compound of Formula I, II, or III, refers to salts that retain the biological effectiveness and properties of a given compound, and which are not biologically or otherwise undesirable. See: P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts: Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2nd revise Edition (May 16, 2011). In certain embodiments, a pharmaceutically acceptable salt of a given compound, for instance a compound of any of Formula I, II, or III, or a compound of any of formula 1-21, refers to that a salt form which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
Compounds described herein may be presented in the form of chemical structures or names. The compounds shown below in Table A are named using ChemBioDraw Ultra 12.0 and it should be understood that other names may be used to identify compounds of the same structure. Other compounds or radicals may be named with common names, or systematic or non-systematic names. The compounds may also be named using other nomenclature systems and symbols that are commonly recognized in the art of chemistry including, for example, Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). The naming and numbering of the compounds of the present disclosure is illustrated with the compounds shown in Table A below.
TABLE A
(8)
(9)
(10)
(11)
(12)
(14)
(II)
(15)
(16)
(10a)
(17)
(18)
(19)
(III)
Processes
In some embodiments, the application discloses a process for synthesizing a compound of formula 1:
or a salt thereof, comprising step a) combining a compound of formula 2:
or a salt thereof,
and a compound of formula 3:
wherein the compound of formula 1 or a salt thereof is synthesized,
wherein R1 is halo;
R2 is selected from the group consisting of H, and optionally substituted C1-C8 alkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen, an amino protective group and an optionally substituted purinyl group.
In some embodiments, the application discloses a process for synthesizing a compound of formula 1:
comprising step a) combining a compound of formula 2:
and a compound of formula 3:
wherein the compound of formula 1 is synthesized,
wherein R1 is halo;
R2 is selected from the group consisting of H, and optionally substituted C1-C8 alkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen, an amino protective group and an optionally substituted purinyl group.
In some embodiments, R1 is F or Cl. In some embodiments, R1 is F. In some embodiments, R2 is selected from the group consisting of methyl, ethyl or propyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is unsubstituted C1-C8 alkyl. In some embodiments, R2 is unsubstituted. In some embodiments, R3 is H and R4 is an amino protective group. In some embodiments, R3 is H and R4 is a carbamate. In some embodiments, R3 is H and R4 is an optionally substituted purinyl group. In some embodiments, R1 is F or Cl; R2 is selected from the group consisting of methyl, ethyl or propyl; R3 is H and R4 is an amino protective group. In some embodiments, R1 is F or Cl; R2 is selected from the group consisting of methyl, ethyl or propyl; R3 is H and R4 is an optionally substituted purinyl group. In some embodiments, the amino protective group is selected from the group consisting of t-butyl carbamate, tetrahydropyranyl, alkylsilyl, benzyl, an optionally substituted purinyl group, and alkoxymethyl. In other embodiments, the amino protective group is carbamate. In some embodiments, the amino protective group is t-butyl carbamate (BOC) or 9-fluoroenylmethyl carbamate (FMOC). In some embodiments, the amino protective group is BOC. In some embodiments, when R4 is purinyl, the purinyl group has 0, 1, 2, 3, 4, or 5 substituents, each independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, the purinyl group has 0, 1, 2, or 3 of the above list of substituents. In some embodiments, the purinyl group has 0, 1, 2, or 3 substituents selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2. In some embodiments, the purinyl group is has with 0, 1 or 2 substituents selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2. In some embodiments, the purinyl group has 1 substituent selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2. In some embodiments, the purinyl group is unsubstituted.
In some embodiments, step a) further comprises a step of combining a dehydrating agent. In some embodiments, step a) (i.e., combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof) is performed in the presence of a dehydrating agent. Non-limiting examples of the dehydrating agent include DPP (diphenylphosphite), TPP (triphenylphosphite), DCC (N,N′-dicyclohexylcarbodiimide), EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), and CDI (1,1′-carbonyldiimidazole). In some embodiments, the dehydrating agent is DPP (diphenylphosphite), TPP (triphenylphosphite), DCC (N,N′-dicyclohexylcarbodiimide), EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), CDI (1,1′-carbonyldiimidazole), or a mixture thereof. In some embodiments, the dehydrating agent is DPP. In some embodiments, step a) further comprises combining DPP. In some embodiments, step a) is performed in the presence of DPP.
In some embodiments, the dehydrating reagent is combined with a compound of formula 2 and a compound of formula 3, wherein the amount of the dehydrating reagent is in at least 2, 2.5, 3, 3.5, or 4 molar equivalents with respect to a compound of formula 2. In one embodiment, at least 2 molar equivalents of the dehydrating reagent with respect to the compound of formula 2 is combined with the compound of formula 2 and a compound of formula 3. In a another embodiment, at least 2 molar equivalents of the DPP (diphenylphosphite) with respect to the compound of formula 2 is combined with the compound of formula 2 and a compound of formula 3. In a yet another embodiment, at least 2 molar equivalents of the DPP (diphenylphosphite) with respect to the compound of formula 9 is combined with the compound of formula 9 and a compound of formula 10. In a further embodiment, at least 2 molar equivalents of the DPP (diphenylphosphite) with respect to the compound of formula 16 is combined with the compound of formula 16 and a compound of formula 10a.
In some embodiments, step a) further comprises a step of combining a base. In some embodiments, step a) (i.e., combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof) is performed in the presence of a base. Non-limiting examples of the base includes pyridine, 4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, and N,N-diisopropylethylamine. In some embodiments, the base is pyridine, 4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, N,N-diisopropylethylamine, or a mixture thereof. In some embodiments, the base is pyridine.
In some embodiments, step a) further comprises a solvent selected from the group consisting of pyridine, toluene, tetrahydrofuran, acetonitrile and 2-MeTHF. In some embodiments, step a) further comprises a solvent selected from the group consisting of pyridine, toluene, tetrahydrofuran, acetonitrile, 2-MeTHF, and a mixture thereof.
In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent, a base, a solvent, or a mixture thereof. In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent. In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent and a base. In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent, a base, and a solvent.
In some embodiments, step a) is performed at a temperature between 0 and 45 degrees Celsius, between 15 and 40 degrees Celsius, or between 20 and 30 degrees Celsius. In some embodiments, step a) is performed at a temperature below 45 degrees Celsius.
In some embodiments, the process further comprises step b) combining the compound of formula 1 or a salt thereof and
a compound of formula 22:
wherein n is 0-5; and each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein a compound of formula 4:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step b) combining the compound of formula 1; and a compound of formula 22:
wherein n is 0-5; and each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein a compound of formula 4:
is synthesized.
In some embodiments, the compound of formula 22 is a substituted aniline. In some embodiments n is 1-5, and in other embodiments, n is 1-3. In some embodiments n is 0-3. In some embodiments n is 0, 1, or 2. In some embodiments n is 0. In some embodiments, each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, each R5 is independently C1-C4-alkyl or halo. In other embodiments, n is 1, 2, or 3; and R5 is selected from a group consisting of alkyl and halo. In some embodiments, n is 1, 2, or 3; and each R5 is independently selected from a group consisting of C1-C4-alkyl or halo. In yet other embodiments, n is 1, 2, or 3; and R5 is selected from a group consisting of methyl, F, and Cl. In some embodiments, n is 1, 2, or 3; and each R5 is independently selected from a group consisting of methyl, F, and Cl. In some embodiments, the compound of formula 22 is 2,6-difluoroaniline.
In some embodiments, step b) is performed at a temperature between 0 and 80 degrees Celsius; between 20 and 70 degrees Celsius; between 40 and 60 degrees Celsius; or between 45 and 55 degrees Celsius.
In some embodiments, the process further comprises step c) combining the compound of formula 4 or a salt thereof, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
two or more reagents, wherein one of the one or more reagents is used to remove the amino protective group and wherein another of the one or more reagents is an acid; wherein a compound of formula 5:
or a salt thereof is synthesized.
In some embodiments, the acid is hydrochloric acid.
In some embodiments, the process further comprises step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4 or a salt thereof, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized; and
step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized; and
step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
is synthesized.
In some embodiments, the compound of formula (5) is a salt. In some embodiments, the compound of formula (5) is an HCl salt.
In some embodiments, the compound of formula (7) is a salt. In some embodiments, the compound of formula (7) is an HCl salt.
In some embodiments, X is halogen. In other embodiments, X is Cl or Br. In other embodiments, X is Cl.
In some embodiments, step c) further comprises combining a solvent selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, n-propanol THF, water, and toluene. In some embodiments, step c) is performed in the presence of a solvent selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, n-propanol THF, water, toluene and mixtures thereof.
In some embodiments, step c) comprises combining one or more reagents for the deprotection of amino protective groups. For instance, if the amino protective group is an alkoxymethyl or a carbamate, such as a t-butyl carbamate or Fmoc, then the one or more reagents is an acid. In further embodiments, the acid is a mineral acid. Non-limiting examples of mineral acids include hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), and perchloric acid (HClO4). In some embodiments, the reagent is hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), perchloric acid (HClO4), or a mixture thereof. In other embodiments, the acid is trifluoroacetic acid (TFA). In another example, if the amino protective group is an alkyl silyl group, the one or more reagents are tetra-n-butylammonium fluoride (TBAF) and/or trifluoroacetic acid (TFA). In yet another example, if the amino protective group is benzyl, then the one or more reagents are Pd/C and H2.
In some embodiments, step c) is performed at a temperature between 0 and 70 degrees Celsius; between 20 and 60 degrees Celsius; or between 35 and 50 degrees Celsius.
In some embodiments, the compound of formula 5 is synthesized as the free base, whereas in other embodiments, the compound of formula 5 is synthesized as a salt. In one embodiment, the compound of formula 5 is the salt of the compound of formula 12. In another embodiment, the compound of formula 12 is synthesized as the HCl salt. In yet other embodiments, the compound of formula 12 is synthesized as free base. In additional embodiments, the compound of formula 5 is the free base of the compound of formula 18. In some other embodiments, the compound of formula 5 is the salt of the compound of formula 18. By way of example, preparation of the salt can be followed by a neutralization step to synthesize the free base.
The choice of synthesizing either a salt or free base form may depend on the materials physical properties. In one embodiment, for stability reasons and manufacturing reasons, such as ease of handling, the compound of formula 12 is synthesized and/or isolated as the salt. In another example, the compound of formula 18 is synthesized and/or isolated as the free base, which is sufficiently stable and easy to handle.
In some embodiments, the compound of formula 5 or a salt thereof is crystallized from one or more solvents independently selected from the group comprising water, methanol, ethanol, isopropanol, n-propanol, concentrated NH4OH, acetonitrile, MTBE (tert-butyl methyl ether), DCM (dichloromethane), EtOAc (ethyl acetate), iPrOAc (isopropylacetate), toluene, 2-Me-THF, DIPE (diisopropylether), heptane and heptanes. In some embodiments, the compound of formula 5 or a salt thereof is crystallized from one or more solvents selected from the group consisting of water, NH4OH, acetonitrile, isopropanol, toluene, and mixtures thereof. In one embodiment, the one or more solvents are i) water, NH4OH, and acetonitrile; or ii) isopropanol and toluene.
In some embodiments, step d) comprises a step of combining a base selected from the group consisting of triethylamine, pyridine, Hunig's base, and a carbonate base. In some embodiments, step d) comprises a step of combining a base selected from the group consisting of triethylamine, pyridine, Hunig's base, a carbonate base, and combinations thereof.
In some embodiments, step d) further comprises combining a solvent selected from the group consisting of water, an alcoholic solvent, and combinations thereof.
In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a base or a solvent. In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a base. In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a solvent. In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a base and a solvent.
In some embodiments, step d) is performed at a temperature between 35 and 110 degrees Celsius; between 40 and 90 degrees Celsius; between 50 and 80 degrees Celsius; or between 60 and 90 degrees Celsius.
In some embodiments, the compound of formula 7 or a salt thereof is crystallized from one or more solvents selected from the group consisting of alcohol and water. In other embodiments, the one or more solvents are i) methanol and water; ii) ethanol and water; iii) propanol and water; or iv) isopropanol and water.
In some embodiments, the compound of formula 6 is an unprotected purinyl compound, wherein R6 is hydrogen. In alternative embodiments, the compound of formula 6 is a protected purinyl compound wherein R6 is an amino protecting group. Use of the protected purinyl compound, such as the compound of formula 13, to synthesize a compound of formula 7 or a salt thereof has been observed to proceed faster, with less dipurine adducts, and at a higher yield compared to use of an unprotected purinyl compound.
In one embodiment, if R6 is an amino protective group, the process further comprises step e) combining the compound of formula 7, or a salt thereof, and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group, wherein a compound of formula I:
or a salt thereof is synthesized. In one embodiment, R6 is an amino protective group.
In one embodiment, if R6 is an amino protective group, the process further comprises step e) combining the compound of formula 7, or a salt thereof, and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group, wherein a compound of formula I:
is synthesized.
As noted above, in certain embodiments, step e) comprises combining one or more reagents for the deprotection of amino protective groups. For instance, if the amino protective group is an alkoxymethyl or a carbamate, such as a t-butyl carbamate or Fmoc, then the one or more reagents is an acid. In further embodiments, the acid is a mineral acid. Non-limiting examples of mineral acids include hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), and perchloric acid (HClO4). In some embodiments, the reagent is hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), perchloric acid (HClO4), or a mixture thereof. In other embodiments, the acid is trifluoroacetic acid (TFA). In another example, if the amino protective group is an alkyl silyl group, the one or more reagents are tetra-n-butylammonium fluoride (TBAF) and/or trifluoroacetic acid (TFA). In yet another example, if the amino protective group is benzyl, then the one or more reagents are Pd/C and H2.
In yet further embodiments R6 is THP (tetrahydropyranyl). In some embodiments, R6 is THP and the one or more reagents used to remove the amino protective group is an acid. It has been discovered that non-aqueous acidic reaction conditions help avoid undesirable reactions such as degradation and formation of ring-opening side products. In some embodiments, the acid is generated in situ. In some embodiments, removal of the THP protective group proceeds to completion or near completion in the absence of water. In one embodiment, removal of the THP protective group proceeds to completion or near completion under anhydrous conditions. In another embodiment, removal of the THP protective group proceeds to completion or near completion with less than 0.5% water present. In a further embodiment, the acid is generated in situ. For example, ethanol and acetyl chloride may be used to generate HCl in situ. In some embodiments, step e) comprises an acid selected from the group consisting of a mineral acid, TFA and a Lewis acid. In some embodiments the acid is HCl. In another embodiment, R6 is methyl 2-trimethylsilylethyl ether (SEM) and the one or more reagents used to remove the protective group is a fluoride ion.
Deprotection is considered near completion when at least 90%, 95%, 97%, 98%, 99%, 99.5% or 99.9% of the protected material is deprotected.
In some embodiments, step e) is performed at a temperature between 30 and 70 degrees Celsius; between 40 and 60 degrees Celsius; or between 25 and 50 degrees Celsius.
In some embodiments, the compound of formula I or a salt thereof is crystallized from one or more solvents selected from the group comprising water, ethanol, methanol, isopropanol, n-propanol and acetone. In other embodiments, the one or more solvents are i) water; ii) ethanol; iii) acetone; iv) water and ethanol; or v) water, ethanol and acetone.
In some of the foregoing embodiments, the compound of formula 1 is
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 1 is
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 1 is
In some of the foregoing embodiments, the compound of formula 2 is
In some of the foregoing embodiments, the compound of formula 3 is
In some of the foregoing embodiments, the compound of formula 4 is
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 4 is
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 4 is
In some of the foregoing embodiments, the compound of formula 5 is
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 5 is
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 5 is
In some of the foregoing embodiments, the compound of formula 6 is
In some of the foregoing embodiments, the compound of formula 7 is
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 7 is
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 7 is
In some of the foregoing embodiments, the compound of formula I is
or a salt thereof.
In some of the foregoing embodiments, the compound of formula I is
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula I is
The processes described herein provide an efficient synthesis. In addition, the processes reduce or minimize certain process steps and/or side products, such as racemization of chiral centers during deprotection conditions. Furthermore, the processes disclosed herein may be suitable for various purposes, such as one or more of laboratory, industrial, commercial, non-commercial, manufacturing, non-manufacturing, regulatory, non-regulatory, medical, non-medical, pharmaceutical, and experimental uses.
By way of example, the processes of the present application may be suitable for making compounds of the formulas disclosed herein, in the amounts of 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1 g, 5 g, 10 g, 50 g, 100 g, 250 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100 kg, 250 kg, 500 kg, 750 kg, 1000 kg, 2500 kg, and 5000 kg, in a single batch. In addition, the processes of the present application may be suitable for making compounds in the amounts between 1-100 mg, 1-500 mg, 1-1000 mg, 1-100 g, 1-500 g, 1-1000 g, 10-1000 kg, 500-1000 kg, 1000-2000 kg, 1000-5000 kg, and more than 5000 kg in a single batch. Additionally, the processes of the present application may be suitable for making compound in the amounts of at least ling, 100 mg, 1 g, 10 g, 100 g, 1 kg, 10 kg, 100 kg, 1000 kg, 2500 kg, and 5000 kg, in a single batch. Also, the processes described herein may be used for making compounds in single or multiple batches, or in continuous/semi-continuous processes. In some embodiments, the process is a batch process. In some embodiments, the process is a continuous process. In some other embodiments, the process is a semi-continuous process.
By way of example, the processes of the present application may utilize at least about 1 mmol, 10 mmol, 100 mmol, 1 mol, 5 mol, 10 mol, 20 mol, 50 mol, or 100 mol of at least one starting material. The starting material includes any of the starting or intermediate compounds disclosed herein, a salt thereof, or a reagent.
Compounds
In some embodiments, the application discloses the compound of formula 1:
or a salt thereof, wherein R1 is selected from the group consisting of halo and optionally substituted C1-C8 alkyl; R2 is selected from the group consisting of H and optionally substituted C1-C8 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In some embodiments, R1 is selected from the group consisting of halo and C1-C8 alkyl. In some embodiments, R1 is halo. In some embodiments, R2 is selected from the group consisting of H and C1-C8 alkyl. In some embodiments, R2 is C1-C8 alkyl. In some embodiments, R2 is C1-C4 alkyl. In some embodiments, R1 is selected from the group consisting of halo and C1-C8 alkyl; R2 is selected from the group consisting of H and C1-C8 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In some embodiments, R1 is halo; R2 is C1-C8 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In some embodiments, R1 is halo; R2 is C1-C4 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In further embodiments, R3 is an amino protective group and R4 is an optionally substituted purinyl group. In further embodiments, R3 and R4 are amino protective groups. In further embodiments, R3 is an amino protective group and R4 is a purinyl group.
In some embodiments, the application discloses the compound of formula 1:
or a salt thereof; and wherein the compound of formula 1 or a salt thereof is synthesized by a process comprising
step a) combining a compound of formula 2:
or a salt thereof,
and a compound of formula 3:
wherein the compound of formula 1 or a salt thereof is synthesized,
wherein R1 is halo;
R2 is selected from the group consisting of H, and optionally substituted C1-C8 alkyl; and
R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In other embodiments, R1, R2, R3 and R4 are as defined above for the compound of formula 1.
In some embodiments, the application discloses the compound of formula 8:
or a salt thereof, wherein the compound of formula 8 or a salt thereof is synthesized by the process comprising combining a compound of formula 9:
or a salt thereof,
and a compound of formula 10:
wherein the compound of formula 8 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 14:
or a salt thereof, wherein the compound of formula 14 or a salt thereof is synthesized by a process comprising combining a compound of formula 12:
or a salt thereof, and
a compound of formula 13:
wherein the compound of formula 14 is synthesized. In further embodiments, the process further comprises combining a compound of formula 11:
or a salt thereof, and
an acid, wherein the compound of formula 12 or a salt thereof is synthesized. In some embodiments, the process comprises combining a compound of formula 11:
and
an acid, wherein the compound of formula 12 or a salt thereof is synthesized. In yet further embodiments, the process further comprises combining a compound of formula 8:
or a salt thereof, and
aniline, wherein the compound of formula 11 is synthesized. In yet another embodiment, the process further comprises combining compound of formula 9:
or a salt thereof,
and a compound of formula 10:
wherein the compound of formula 8 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 15:
or a salt thereof, wherein the compound of formula 15 or a salt thereof is synthesized by a process comprising combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 15 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 15a:
or a salt thereof, wherein the compound of formula 15a or a salt thereof is synthesized by a process comprising combining a compound of formula 16:
or a salt thereof,
wherein BB is halo, and a compound of formula 10a:
wherein AA is an amino protective group and wherein the compound of formula 15 or a salt thereof is synthesized. In some embodiments, BB is F. In some embodiments, the amino protective group is selected from the group consisting of t-butyl carbamate, tetrahydropyranyl, alkylsilyl, benzyl, an optionally substituted purinyl group, and alkoxymethyl. In other embodiments, the amino protective group is carbamate. In some embodiments, the amino protective group is t-butyl carbamate (BOC) or 9-fluoroenylmethyl carbamate (FMOC). In some embodiments, AA is t-butyl carbamate (BOC).
In some embodiments, the application discloses a compound of formula 19:
or a salt thereof, wherein the compound of formula 19 or a salt thereof is synthesized by a process comprising combining a compound of formula 18:
or a salt thereof, and
a compound of formula 13:
wherein a compound of formula 19 or a salt thereof is synthesized. In further embodiments, the process further comprises combining a compound of formula 17:
or a salt thereof, and
an acid, wherein the compound of formula 18 or a salt thereof is synthesized. In some embodiments, the process further comprises combining a compound of formula 17:
and
an acid, wherein the compound of formula 18 or a salt thereof is synthesized. In yet further embodiments, the process further comprises combining a compound of formula 15:
or a salt thereof, and
aniline, wherein the compound of formula 17 is synthesized. In yet another embodiment, the process further comprises combining compound of formula 16:
or a salt thereof,
and a compound of formula 10:
wherein the compound of formula 15 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 20:
or a salt thereof, wherein the compound of formula 20 or a salt thereof is synthesized by a process comprising combining a compound of formula 9:
and
a compound of formula 10:
wherein the compound of formula 20 or a salt thereof is synthesized. In some embodiments, the process further comprises synthesizing a compound of formula 8:
or a salt thereof. In some embodiments, the compound of formula 8 or a salt thereof ring-opens to form the compound of formula 20 or a salt thereof. In some embodiments, the compound of formula 20 is an intermediate that is formed during the preparation of the compound of formula 8.
A compound of formula 21:
or a salt thereof, wherein the compound of formula 21 or a salt thereof is synthesized by a process comprising
combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 21 or a salt thereof is synthesized. In some embodiments, the process further comprises synthesizing a compound of formula 15:
or a salt thereof. In some embodiments, the compound of formula 15 or a salt thereof ring-opens to form the compound of formula 21 or a salt thereof. In some embodiments, the compound of formula 21 is an intermediate that is formed during the preparation of the compound of formula 15.
By way of example, the compositions of the present application may comprise at least 2000 kg, 1000 kg, 750 kg, 500 kg, 250 kg, 100 kg, 10 kg, 1 kg, 0.5 kg, 50 g, 5 g, or 0.5 g of a compound of a formula disclosed herein or a salt thereof. In some embodiments, compositions may comprise a multi-kilogram amount of a compound of a formula disclosed herein or salt thereof. In other embodiments, compositions of the present disclosure may comprise at least about 1 mmol, 10 mmol, 100 mmol, 1 mol, 5 mol, 10 mol, 20 mol, 50 mol, or 100 mol of a compound of a formula disclosed herein or a salt thereof. In addition to a compound of a formula disclosed herein or a salt thereof, composition may further comprise solvents, reagents, or combinations thereof. In another aspect, compositions may consist essentially of a compound of a formula disclosed herein or a salt thereof.
By way of example, the resulting compounds from the processes described herein may be used in a pharmaceutical composition. In another embodiment, provided is a pharmaceutical composition comprising a resulting compound from the processes disclosed herein or a salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
EXAMPLES
Example 1. Synthesis of a Compound of Formula 17
A compound of formula 16 (1.0 kg, 1.0 eq), a compound of formula 10 (1.5 kg, 1.2 eq) and pyridine (3.0 kg) were added to reactor A. The mixture was agitated at 19 to 25° C. and diphenylphosphite (6.1 kg, 4.0 eq) was added to the mixture over at least 2 h while maintaining the internal temperature at less than about 35° C. The reaction mixture was adjusted to 19 to 25° C. and agitated until the reaction was deemed complete by HPLC analysis (1-3 h). Aniline (0.7 kg, 1.2 eq) was added over a minimum of 1 h while maintaining the internal temperature at less than about 40° C. The reaction mixture was then adjusted to 45 to 55° C. and agitated until the reaction is deemed complete. The reaction mixture was cooled to 19 to 25° C. and toluene (13 kg) was added followed by a prepared 1M HCl solution (10 kg) while maintaining the internal temperature at less than about 30° C. The biphasic mixture was agitated at about 22° C. for at least 30 minutes and then allowed to settle. The aqueous layer was separated and discarded. A second portion of 1M HCl (10 kg) was added to the organic layer in reactor A. The biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The aqueous layer was separated and discarded. A compound of formula 17 was carried forward to the next step as a stock solution in toluene.
Example 2. Synthesis of a Compound of Formula 18
To the stock solution of a compound of formula 17 in toluene was added acetonitrile (8.4 kg) and concentrated HCl (2.2 kg) while maintaining the internal temperature at no more than 30° C. The reaction mixture was adjusted to 19 to 25° C. and agitated until the reaction was deemed complete. Water (5 kg) was added and the biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor B (product was in the aqueous layer). Water (10 kg) was then added to the organic layer in reactor A. The biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor B (combining with the first aqueous phase). Toluene (4 kg) was added to the combined aqueous layers in reactor B and the biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor A. Toluene (4 kg) was added to reactor A and the biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor B. The aqueous phase was then partially concentrated under vacuum to 18 L to remove toluene and reduce acetonitrile levels to no more than 3.5%. The aqueous phase was then transferred, in portions, to reactor B containing water (5 kg), ammonium hydroxide (6.5 kg, 8.0 eq) and acetonitrile (0.8 kg) while maintaining the internal temperature at no more than 19 to 25° C. The resulting slurry was agitated at 19 to 25° C. for ca 1 h before filtering. The filter cake was rinsed with water (3 kg) and then dried under vacuum at no more than 50° C. to afford 18. 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J=8.4, 2.2 Hz, 1H), 7.71 (dd, J=9.2, 5.0 Hz, 1H), 7.55-7.45 (m, 4H), 7.27 (d, J=6.4 Hz, 2H), 3.69 (q, J=6.4 Hz, 1H), 2.01 (s, 2H), 1.27 (d, J=6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 162.3, 161.9, 160.5, 159.8, 144.4, 136.6, 130.3, 130.2, 129.9, 129.0, 128.9, 128.4, 123.4, 123.2, 122.3, 122.2, 112.1, 111.9, 48.7, 23.7 (signal splitting due to fluorine results in additional peaks).
Example 3. Synthesis of a Compound of Formula 19
A compound of formula 18 (1.0 kg, 1 eq), a compound of formula 13 (0.9 kg, 1.1 eq), triethylamine (0.5 kg, 1.5 eq), water (4 kg) and EtOH (2 kg) were added to reactor A. The mixture was adjusted to 75 to 85° C. and agitated until the reaction was deemed complete. The mixture was then adjusted to 19 to 25° C. and agitated for ca 1 h before filtering. The isolated compound of formula 19 solid was rinsed with water (2 kg) and heptanes (2×3 kg) and then dried under vacuum. 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J=2 Hz, 1H), 8.00 (bs, 1H), 7.89 (dd, J=8.8, 3.0 Hz, 1H), 7.73 (m, 1H), 7.59 (m, 3H), 7.48 (m, 2H), 7.35 (m, 1H), 6.68 (m, 1H), 5.69 (dd, J=10.0, 3.0 Hz, 1H), 5.24 (bs, 1H), 4.16 (dd, J=11.6, 2.0 Hz, 1H), 3.77 (tt, J=11.2, 1.4 Hz, 1H), 2.06 (m, 3H), 1.75 (m, 3H), 1.47 (d, J=6.8 Hz, 3H).
Example 4. Synthesis of a Compound of Formula III
To reactor A was added a compound of formula 19 followed by EtOH (4.2 kg). Acetyl chloride (0.33 kg, 1.2 eq) was then added slowly while maintaining the internal temperature at less than about 40° C. The mixture was then adjusted to 19 to 25° C. and agitated until the reaction was deemed complete. After adjusting the temperature to 5 to 15° C., 0.84 kg of a prepared 4.5% sodium carbonate solution was added to the reaction mixture followed by water (1 kg) while maintaining the internal temperature at 5 to 15° C. To reactor B was added 5.44 kg of a prepared 4.5% sodium carbonate solution and the contents were warmed to 65 to 75° C. Approximately 20% of the solution held in reactor A was then transferred to the aqueous solution in reactor B while keeping the internal temperature at 65 to 75° C. The mixture was aged for about 30 minutes until a slurry was formed. The remaining solution from reactor A was transferred to reactor B over a period of about 1 h while maintaining the internal temperature at 65 to 75° C. The slurry was agitated at 65 to 75° C. for 1 to 5 h until a thick slurry was formed. The contents were then adjusted to 19 to 25° C. over about 1 h and agitated about 1 h before filtering. The wet cake was rinsed with water (10 kg) and then dried under vacuum at about 65° C. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.98 (br, 1H), 7.90 (dd, J=8.4, 2.8 Hz, 1H), 7.74 (dd, J=8.8, 5.2 Hz, 1H), 7.65-7.57 (m 3H), 7.51-7.45 (m, 2H), 7.37 (m, 1H), 6.84 (bd, J=8.8 Hz, 1H), 5.27 (br, 1H), 1.75 (br, 1H), 1.50 (d, J=6.8 Hz, 3H). 19F NMR (400 MHz, CDCl3): δ −111.11 (referenced to TFA at −76.5 ppm).
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15392198
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Aug 14th, 2018 12:00AM
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Nov 17th, 2017 12:00AM
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https://www.uspto.gov?id=US10047060-20180814
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Process methods for phosphatidylinositol 3-kinase inhibitors
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A process for the synthesis of quinazolinone containing compounds which may be useful for the treatment of cancer, is hereby disclosed. In addition, compound intermediates relating to these processes are also disclosed.
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10047060
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1. A compound of formula 20:
or a salt thereof.
2. A compound of formula 21:
or a salt thereof.
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2
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a divisional of U.S. patent application Ser. No. 15/392,198, filed Dec. 28, 2016, which is a divisional of U.S. patent application Ser. No. 14/575,670, filed Dec. 18, 2014, now U.S. Pat. No. 9,567,337, issued Feb. 14, 2017, which claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/919,548, filed Dec. 20, 2013, the disclosures of which are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
The present disclosure relates generally to the synthesis or preparation of certain phosphatidylinositol 3-kinase (PI3K) inhibitors and their synthetic intermediates. Inhibitors of PI3K, such as quinazoline-purinyl containing compounds, may be useful in treating PI3K-mediated disorders such as cancer. There is a need to have alternative processes in making such PI3K inhibitors.
BRIEF SUMMARY OF THE INVENTION
The present disclosure provides a process of making certain PI3K inhibitors and compound intermediates thereof.
In one embodiment, the application discloses processes for synthesizing a compound of formula I:
or a salt thereof.
In another embodiment, the application discloses processes for synthesizing a compound of formula II:
or a salt thereof.
In an alternative embodiment, the application discloses processes for synthesizing a compound of formula III:
or a salt thereof.
S In one embodiment, the application discloses a process for synthesizing a compound of formula 1:
or a salt thereof, comprising step a) combining a compound of formula 2:
or a salt thereof,
and a compound of formula 3:
wherein the compound of formula 1 or a salt thereof is synthesized, wherein R1 is halo; R2 is selected from the group consisting of H and optionally substituted C1-C8 alkyl; and R3 and R4 are each independently selected from the group consisting of hydrogen, an amino protective group and an optionally substituted purinyl group.
In a further embodiment the process further comprises step b) combining the compound of formula 1 or a salt thereof; and
a compound of formula 22:
wherein n is 0-5; and each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and wherein a compound of formula 4:
or a salt thereof is synthesized.
In yet a further embodiment, the process further comprises step c) combining the compound of formula 4 or a salt thereof, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized;
step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
or a salt thereof is synthesized; and if R6 is an amino protective group, step e) further combining the compound of formula 7 or a salt thereof; and one or more reagents, wherein the one or more reagents are used to remove the amino protective group, wherein a compound of formula I:
or a salt thereof is synthesized.
In one embodiment, the present application discloses a process for synthesizing a compound of formula 8:
or a salt thereof, comprising step a) combining a compound of formula 9
or a salt thereof,
and a compound of formula 10
wherein the compound of formula 8 or a salt thereof is synthesized.
In a further embodiment, the process further comprises step b) combining the compound of formula 8 or a salt thereof and aniline, wherein a compound of formula 11:
or a salt thereof is synthesized.
In yet a further embodiment, the process further comprises step c) combining the compound of formula 11 or a salt thereof and an acid, wherein a compound of formula 12:
or a salt thereof is synthesized; step d) combining the compound of formula 12 or a salt thereof and a compound of formula 13
wherein a compound of formula 14:
or a salt thereof is synthesized; and
step e) combining the compound of formula 14 or a salt thereof and an acid, wherein a compound of formula II:
or a salt thereof is synthesized.
In an alternative embodiment, the application discloses a process for synthesizing a compound of formula 15:
or a salt thereof, comprising step a) combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 15 or a salt thereof is synthesized.
In a further embodiment, the process further comprises step b) combining the compound of formula 15 or a salt thereof and aniline, wherein a compound of formula 17:
or a salt thereof is synthesized.
In yet a further embodiment, the process further comprises step c) combining the compound of formula 17 or a salt and an acid thereof, wherein a compound of formula 18:
or a salt thereof is synthesized;
step d) combining the compound of formula 18 or a salt thereof and a compound of formula 13
wherein a compound of formula (19):
or a salt thereof is synthesized; and
step e) combining the compound of formula 19 or a salt thereof and an acid, wherein the compound of formula III:
or a salt thereof is synthesized.
In some embodiments, the application discloses the intermediate compounds formed from the processes disclosed herein. In some embodiments, the application discloses compounds selected from the group consisting of
(8)
(15)
(14)
(19)
(20)
(21)
and salts thereof. In certain embodiments, compounds of formula (8), (15). (14), (19), (20), and (21), are disclosed. In certain embodiments, pharmaceutically acceptable salts of the compounds of formula (8), (15), (14), (19), (20), and (21), are disclosed.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term “about” includes and describes the value or parameter per se. For example, “about x” includes and describes “x” per se. In certain embodiment, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−1-10%. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−5%. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−10%.
The term “between” includes and describes the value or parameter per se. For example, “between x and y” includes and describes “x” and “y” per se.
The term “and/or” includes subject matter in the alternative as well as subject matter in combination. For instance, “x, and/or y”, includes “x or y” and “x and y”.
The term “alkyl” as used herein refers to a straight or branched chain, saturated hydrocarbon having the indicated number of carbon atoms. For example, (C1-C8)alkyl is meant to include, but is not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein throughout.
The term “substituted alkyl” refers to: 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, in some embodiments, having from 1 to 20 carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbon atoms). This term is exemplified by groups such as methylene(—CH2—), ethylene (—CH2CH2—), the propylene isomers (e.g., —CH2CH2CH2— and —CH(CH3)CH2—), and the like.
The term “substituted alkylene” refers to an alkylene group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.
The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
The term “aralkyloxy” refers to the group —O-aralkyl. “Optionally substituted aralkyloxy” refers to an optionally substituted aralkyl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, and the like.
The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3 carbon-carbon double bonds. In some embodiments, alkenyl groups include ethenyl (or vinyl, i.e. —CH═CH2), 1-propylene (or allyl, i.e. —CH2CH═CH2), isopropylene (—C(CH3)═CH2, and the like.
The term “substituted alkenyl” refers to an alkenyl group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.
The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3 carbon-carbon triple bonds. In some embodiments, alkynyl groups include ethynyl (—C—CH), propargyl (or propynyl, i.e. —C≡CCH3), and the like.
The term “substituted alkynyl” refers to an alkynyl group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.
The term “hydroxy” or “hydroxyl” refers to a group —OH.
The term “alkoxy” refers to the group R—O—, where R is alkyl; and includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.
The term “substituted alkoxy” refers to the group R—O—, where R is substituted alkyl, where substituted alkyl, substituted alkenyl and substituted alkynyl are as defined herein.
The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like or multiple ring structures such as adamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to which is fused an aryl group, for example indanyl, and the like, provided that the point of attachment is through the cyclic alkyl group.
The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings and having at least one double bond and in some embodiments, from 1 to 2 double bonds.
The terms “substituted cycloalkyl” and “substituted cycloalkenyl” refer to cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents (in some embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “aryl” refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl and anthryl). In some embodiments, aryls include phenyl, fluorenyl, naphthyl, anthryl, and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5 substituents (in some embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “substituted purinyl” refers to a purinyl having 1, 2, 3, 4, or 5 substituents (in some embodiments 1, 2, or 3 substituents), each independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, purinyl is substituted with 1, 2, or 3 substituents selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2.
The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to a monoradical saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms, and from 1 to 10 heteroatoms or 1 to 4 heteroatoms within the ring, each heteroatom independently selected from the group consisting of nitrogen, sulfur, phosphorus, and oxygen.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Examples of heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.
The term “heteroaryl” refers to a group comprising single or multiple rings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. The term “heteroaryl” is generic to the terms “aromatic heteroaryl” and “partially saturated heteroaryl”. The term “aromatic heteroaryl” refers to a heteroaryl in which at least one ring is aromatic, regardless of the point of attachment. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline, pteridine. The term “partially saturated heteroaryl” refers to a heteroaryl having a structure equivalent to an underlying aromatic heteroaryl which has had one or more double bonds in an aromatic ring of the underlying aromatic heteroaryl saturated. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, 2-oxo-1,2-dihydropyridin-4-yl, and the like.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole or benzothienyl). Examples of nitrogen heterocyclyls and heteroaryls include, but are not limited to pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy nitrogen containing heteroaryl compounds.
The term “substituted amino” refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or —C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “aminocarbonyl” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term “thiol” refers to the group —SH.
The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
A “substituted” group includes embodiments in which a monoradical substituent is bound to a single atom of the substituted group (e.g. forming a branch), and also includes embodiments in which the substituent may be a diradical bridging group bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.
Where a given group (moiety) is described herein as being attached to a second group and the site of attachment is not explicit, the given group may be attached at any available site of the given group to any available site of the second group. For example, an “alkyl-substituted phenyl”, where the attachment sites are not explicit, may have any available site of the alkyl group attached to any available site of the phenyl group. In this regard, an “available site” is a site of the group at which a hydrogen of the group may be replaced with a substituent.
A compound of a given formula is intended to encompass the compounds of the disclosure, and the salts, esters, isomers, tautomers, solvates, isotopes, hydrates, and prodrugs of such compounds. Additionally, the compounds of the disclosure may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given formula depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present disclosure, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. Compounds of the present disclosure include separable rotational isomers, or atropisomers.
“Isomers” are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers and diastereomers.
“Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate.
“Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the Cahn Ingold Prelog R S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (−) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.
“Tautomers” are structural isomers resulting from the migration of an atom or a functional group within the same organic molecule and lead to a change in one or more of its structural skeleton, electronic density distribution, and chemical properties. It is understood that compounds disclosed herein includes tautomeric forms although not necessarily explicitly shown. In one example, purine may be represented by any of the following tautomers:
Accordingly, a reference to any one of the purine tautomers includes the other tautomeric forms.
The term “amino protective group” is well understood by the person skilled in synthetic organic chemistry as a moiety that can be selectively installed onto and removed from a suitable amine functional group. Amino protective groups, and methods for using them, are described in the authoritative treatise on the subject, P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition (Wiley, 2006). In some embodiments, the amino protective group is selected from the group consisting of a carbamate, an amide, and a sulfonamide. In some embodiments, the amino protective group is a benzyl group, or a Schiff base.
Non-limiting examples of carbamate based amino protective groups include methyl carbamate, 9-fluoroenylmethyl carbamate (FMOC), 2,2,2-trichloroethyl carbamate, 2-trimethylsilylethyl carbamate, 1,1-dimethylpropynyl carbamate, 1-methyl-1-phenethyle carbamate, 1-methyl-1-(4-biphenylyl)ethyl carbamate, 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2-cyanoethyl carbamate, t-butyl carbamate, cyclobutyl carbamate, I-methylcyclobutyl carbamate, 1-adamantyl carbamate, vinyl carbamate, allyl carbamate, cinnamyl carbamate, 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, 4,5-diphenyl-3-oxazolin-2-one, benzyl carbamate, p-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 5-benzisoxazolylmethyl carbamate, 9-anthrylmethyl carbamate, diphenylmethyl carbamate, isonicotinyl carbamate, and S-benzyl carbamate, N—(N′-phenylaminothiocarbonyl) derivative. In one embodiment, the amino protective group is selected from the group consisting methyl carbamate, t-butyl carbamate, vinyl carbamate, and allyl carbamate. In another embodiment, the amino protective group is selected from the group consisting of t-butyl carbamate (BOC) and 9-fluoroenylmethyl carbamate (FMOC).
Non-limiting examples of amide based amino protective groups include N-formyl, N-acetyl, N-chloracetyl, N-trichloroacetyl, N-trifluoroacetyl, N-o-nitrophenylacetyl, N-o-nitrophoxyacetyl, N-acetoacetyl, N-3-phenylpropionyl, N-3-(p-hydroxyphenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-4-chlorobutyryl, N-o-nitrocinnamoyl, N-picolinoyl, N—(N′-acetylmethionyl), N-benzoyl, N-phthaloyl, and N-dithiasuccinoyl. In one embodiment, the amino protective group is selected from the group consisting of N-formyl, N-acetyl, N-chloracetyl, N-trichloroacetyl, N-trifluoroacetyl, and N-acetoacetyl.
Other non-limiting examples of amino protective groups include N-allyl, N-phenacyl, N-3-acetoxypropyl, quaternary ammonium salts, N-methyoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl, N-tetrahydropyranyl, N-2,4-dinitrophenyl, N-benzyl, N-o-nitrobenzyl, N-di(p-methoxyphenyl)methyl, N-triphenylmethyl, N-(p-methyoxyphenyl)diphenylmethyl, N-diphenyl-4-pyridylmethyl, N-2-picolyl N′-oxide, N,N′-isopropylidene, N-salicylidene, N-(5,-dimethyl-3-oxo-1-cyclohexenyl), N-nitro, N-oxide, N-diphenylphosphinyl, N-dimetylthiophosphinyl, N-dimethylthiophosphinyl, N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4,6-trimethylbenzenesulfonyl, N-toluenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N-phenyacylsulfonyl. In one embodiment, the amino protective group is selected from the group consisting of N-allyl, N-phenacyl, N-3-acetoxypropyl, quaternary ammonium salts, N-methyoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl, and N-tetrahydropyranyl. In one embodiment, the amino protective group is N-tetrahydropyranyl.
If there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure controls. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold, wedged, or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereo isomers of it.
The term “solvate” refers to a complex formed by the combining of a compound of any formula as disclosed herein, and a solvent.
The term “hydrate” refers to the complex formed by the combining of a compound of any formula disclosed herein, and water.
Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
In certain embodiments, the isotopically labeled compound is a compound of formula 6. In other embodiments, the isotopically labeled compound is a compound of formula 6, wherein X is a halogen and R6 is an amino protective group. In another embodiment, the isotopically labeled compound is a compound of formula 6, wherein X is Cl and R6 is THF or THP.
The disclosure also includes compounds of any formula disclosed herein, in which from 1 to “n” hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and may thus be useful for increasing the half-life of a compound of any formula described herein, for instance formula II or formula III, when administered to a mammal. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacal. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent in a compound of any formula disclosed herein. Similarly, in certain embodiments, tritium (i.e., 3H) is also regarded as a substituent in a compound of any formula disclosed herein. In certain embodiments, 14C is regarded as a substituent in a compound of any formula disclosed herein.
The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Base addition salts can be prepared from inorganic and organic bases. Salts derived from in organic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Further salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkylamines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroarylamines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. In the general structure N(Rx)(Ry)(Rz), mono-substituted amines have 2 of the three substituents on nitrogen (Rx, Ry and Rz) as hydrogen; di-substituted amines have 1 of the three substituents on nitrogen (Rx, Ry and Rz) as hydrogen; and tri-substituted amines have none of the three substituents on nitrogen (Rx, Ry and Rz as hydrogen. Rx, Ry and Rz may be selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl and the like. The abovementioned amines refer to the compounds wherein either one, two or three substituents on the nitrogen are as listed in the name. For example, the term “cycloalkenyl amine” refers to cycloalkenyl-NH2, wherein “cycloalkenyl” is as defined herein. The term “diheteroarylamine” refers to NH(heteroaryl)2, wherein “heteroaryl” is as defined herein and so on.
Acid addition salts may be prepared from inorganic and organic acids. Acid addition salts may be prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
In some embodiments, a salt is a “pharmaceutically acceptable salt”. A pharmaceutically acceptable salt of a given compound, for instance a compound of Formula I, II, or III, refers to salts that retain the biological effectiveness and properties of a given compound, and which are not biologically or otherwise undesirable. See: P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts: Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2nd revise Edition (May 16, 2011). In certain embodiments, a pharmaceutically acceptable salt of a given compound, for instance a compound of any of Formula I, II, or III, or a compound of any of formula 1-21, refers to that a salt form which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
Compounds described herein may be presented in the form of chemical structures or names. The compounds shown below in Table A are named using ChemBioDraw Ultra 12.0 and it should be understood that other names may be used to identify compounds of the same structure. Other compounds or radicals may be named with common names, or systematic or non-systematic names. The compounds may also be named using other nomenclature systems and symbols that are commonly recognized in the art of chemistry including, for example, Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). The naming and numbering of the compounds of the present disclosure is illustrated with the compounds shown in Table A below.
TABLE A
(8)
(S)-tert-butyl (1-(5-fluoro-4-oxo-4H-
benzo[d][1,3]oxazin-2-yl)propyl)carbamate
(9)
2-amino-6-fluorobenzoic acid
(10)
(S)-2-((tert-butoxycarbonyl)amino)butanoic acid
(10a)
(S)-2-((tert-butoxycarbonyl)amino)propanoic acid
(11)
(S)-tert-butyl (1-(5-fluoro-4-oxo-3-phenyl-
3,4-dihydroquinazolin-2-yl)propyl)carbamate
(12)
(S)-2-(1-aminopropyl)-5-fluoro-3-
phenylquinazolin-4(3H)-one
(14)
5-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-
2H-pyran-2-yl)-9H-purin-6-
yl)amino)propyl)quinazolin-4(3H)-one
(15)
(S)-tert-butyl (1-(6-fluoro-4-oxo-4H-
benzo[d][1,3]oxazin-2-yl)ethyl)carbamate
(16)
2-amino-5-fluorobenzoic acid
(17)
(S)-tert-butyl (1-(6-fluoro-4-oxo-3-phenyl-3,4-
dihydroquinazolin-2-yl)ethyl)carbamate
(18)
(S)-2-(1-aminoethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one
(19)
6-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-
9H-purin-6-yl)amino)ethyl)quinazolin-4(3H)-one
(II)
(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-
fluoro-3-phenylquinazolin-4(3H)-one
(III)
(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-
3-phenylquinazolin-4(3H)-one
Processes
In some embodiments, the application discloses a process for synthesizing a compound of formula 1:
or a salt thereof, comprising step a) combining a compound of formula 2:
or a salt thereof,
and a compound of formula 3:
wherein the compound of formula 1 or a salt thereof is synthesized,
wherein R1 is halo;
R2 is selected from the group consisting of H, and optionally substituted C1-C8 alkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen, an amino protective group and an optionally substituted purinyl group.
In some embodiments, the application discloses a process for synthesizing a compound of formula 1:
comprising step a) combining a compound of formula 2:
and a compound of formula 3:
wherein the compound of formula 1 is synthesized,
wherein R1 is halo;
R2 is selected from the group consisting of H, and optionally substituted C1-C8 alkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen, an amino protective group and an optionally substituted purinyl group.
In some embodiments, R1 is F or Cl. In some embodiments, R1 is F. In some embodiments, R2 is selected from the group consisting of methyl, ethyl or propyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is unsubstituted C1-C8 alkyl. In some embodiments, R2 is unsubstituted. In some embodiments, R3 is H and R4 is an amino protective group. In some embodiments, R3 is H and R4 is a carbamate. In some embodiments, R3 is H and R4 is an optionally substituted purinyl group. In some embodiments, R1 is F or Cl; R2 is selected from the group consisting of methyl, ethyl or propyl; R3 is H and R4 is an amino protective group. In some embodiments, R1 is F or Cl; R2 is selected from the group consisting of methyl, ethyl or propyl; R3 is H and R4 is an optionally substituted purinyl group. In some embodiments, the amino protective group is selected from the group consisting of t-butyl carbamate, tetrahydropyranyl, alkylsilyl, benzyl, an optionally substituted purinyl group, and alkoxymethyl. In other embodiments, the amino protective group is carbamate. In some embodiments, the amino protective group is t-butyl carbamate (BOC) or 9-fluoroenylmethyl carbamate (FMOC). In some embodiments, the amino protective group is BOC. In some embodiments, when R4 is purinyl, the purinyl group has 0, 1, 2, 3, 4, or 5 substituents, each independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, the purinyl group has 0, 1, 2, or 3 of the above list of substituents. In some embodiments, the purinyl group has 0, 1, 2, or 3 substituents selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2. In some embodiments, the purinyl group is has with 0, 1 or 2 substituents selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2. In some embodiments, the purinyl group has 1 substituent selected from the group consisting of methyl, ethyl, propyl, NH2, and N(CH3)2. In some embodiments, the purinyl group is unsubstituted.
In some embodiments, step a) further comprises a step of combining a dehydrating agent. In some embodiments, step a) (i.e., combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof) is performed in the presence of a dehydrating agent. Non-limiting examples of the dehydrating agent include DPP (diphenylphosphite), TPP (triphenylphosphite), DCC (N,N′-dicyclohexylcarbodiimide), EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), and CDI (1,1′-carbonyldiimidazole). In some embodiments, the dehydrating agent is DPP (diphenylphosphite), TPP (triphenylphosphite), DCC (N,N′-dicyclohexylcarbodiimide), EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), CDI (1,1′-carbonyldiimidazole), or a mixture thereof. In some embodiments, the dehydrating agent is DPP. In some embodiments, step a) further comprises combining DPP. In some embodiments, step a) is performed in the presence of DPP.
In some embodiments, the dehydrating reagent is combined with a compound of formula 2 and a compound of formula 3, wherein the amount of the dehydrating reagent is in at least 2, 2.5, 3, 3.5, or 4 molar equivalents with respect to a compound of formula 2. In one embodiment, at least 2 molar equivalents of the dehydrating reagent with respect to the compound of formula 2 is combined with the compound of formula 2 and a compound of formula 3. In a another embodiment, at least 2 molar equivalents of the DPP (diphenylphosphite) with respect to the compound of formula 2 is combined with the compound of formula 2 and a compound of formula 3. In a yet another embodiment, at least 2 molar equivalents of the DPP (diphenylphosphite) with respect to the compound of formula 9 is combined with the compound of formula 9 and a compound of formula 10. In a further embodiment, at least 2 molar equivalents of the DPP (diphenylphosphite) with respect to the compound of formula 16 is combined with the compound of formula 16 and a compound of formula 10a.
In some embodiments, step a) further comprises a step of combining a base. In some embodiments, step a) (i.e., combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof) is performed in the presence of a base. Non-limiting examples of the base includes pyridine, 4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, and N,N-diisopropylethylamine. In some embodiments, the base is pyridine, 4-dimethylaminopyridine, triethylamine, isopropylethylamine, imidazole, DABCO, DBU, 2,6-lutidine, N,N-diisopropylethylamine, or a mixture thereof. In some embodiments, the base is pyridine.
In some embodiments, step a) further comprises a solvent selected from the group consisting of pyridine, toluene, tetrahydrofuran, acetonitrile and 2-MeTHF. In some embodiments, step a) further comprises a solvent selected from the group consisting of pyridine, toluene, tetrahydrofuran, acetonitrile, 2-MeTHF, and a mixture thereof.
In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent, a base, a solvent, or a mixture thereof. In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent. In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent and a base. In some embodiments, step a) includes combining a compound of formula 2 or a salt thereof and a compound of formula 3 or a salt thereof with a dehydrating agent, a base, and a solvent.
In some embodiments, step a) is performed at a temperature between 0 and 45 degrees Celsius, between 15 and 40 degrees Celsius, or between 20 and 30 degrees Celsius. In some embodiments, step a) is performed at a temperature below 45 degrees Celsius.
In some embodiments, the process further comprises step b) combining the compound of formula 1 or a salt thereof; and
a compound of formula 22:
wherein n is 0-5; and each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and wherein a compound of formula 4:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step b) combining the compound of formula 1; and a compound of formula 22:
wherein n is 0-5; and each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein a compound of formula 4:
is synthesized.
In some embodiments, the compound of formula 22 is a substituted aniline. In some embodiments n is 1-5, and in other embodiments, n is 1-3. In some embodiments n is 0-3. In some embodiments n is 0, 1, or 2. In some embodiments n is 0. In some embodiments, each R5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, nitro, thiol, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, each R5 is independently C1-C4-alkyl or halo. In other embodiments, n is 1, 2, or 3; and R5 is selected from a group consisting of alkyl and halo. In some embodiments, n is 1, 2, or 3; and each R5 is independently selected from a group consisting of C1-C4-alkyl or halo. In yet other embodiments, n is 1, 2, or 3; and R5 is selected from a group consisting of methyl, F, and Cl. In some embodiments, n is 1, 2, or 3; and each R5 is independently selected from a group consisting of methyl, F, and Cl. In some embodiments, the compound of formula 22 is 2,6-difluoroaniline.
In some embodiments, step b) is performed at a temperature between 0 and 80 degrees Celsius; between 20 and 70 degrees Celsius; between 40 and 60 degrees Celsius; or between 45 and 55 degrees Celsius.
In some embodiments, the process further comprises step c) combining the compound of formula 4 or a salt thereof, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
two or more reagents, wherein one of the one or more reagents is used to remove the amino protective group and wherein another of the one or more reagents is an acid; wherein a compound of formula 5:
or a salt thereof is synthesized.
In some embodiments, the acid is hydrochloric acid.
In some embodiments, the process further comprises step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4 or a salt thereof, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized; and
step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
or a salt thereof is synthesized.
In some embodiments, the process further comprises step c) combining the compound of formula 4, wherein at least one of R3 and R4 of the compound of formula 4 is an amino protective group; and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group; wherein a compound of formula 5:
or a salt thereof is synthesized; and
step d) combining the compound of formula 5 or a salt thereof and a compound of formula 6:
wherein X is selected from the group consisting of halogen, mesyl, mesylate, tosyl and tosylate; and
R6 is hydrogen or an amino protective group; wherein a compound of formula 7:
is synthesized.
In some embodiments, the compound of formula (5) is a salt. In some embodiments, the compound of formula (5) is an HCl salt.
In some embodiments, the compound of formula (7) is a salt. In some embodiments, the compound of formula (7) is an HCl salt.
In some embodiments, X is halogen. In other embodiments, X is Cl or Br. In other embodiments, X is Cl.
In some embodiments, step c) further comprises combining a solvent selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, n-propanol THF, water, and toluene. In some embodiments, step c) is performed in the presence of a solvent selected from the group consisting of acetonitrile, methanol, ethanol, isopropanol, n-propanol THF, water, toluene and mixtures thereof.
In some embodiments, step c) comprises combining one or more reagents for the deprotection of amino protective groups. For instance, if the amino protective group is an alkoxymethyl or a carbamate, such as a t-butyl carbamate or Fmoc, then the one or more reagents is an acid. In further embodiments, the acid is a mineral acid. Non-limiting examples of mineral acids include hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), and perchloric acid (HClO4). In some embodiments, the reagent is hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), perchloric acid (HClO4), or a mixture thereof. In other embodiments, the acid is trifluoroacetic acid (TFA). In another example, if the amino protective group is an alkyl silyl group, the one or more reagents are tetra-n-butylammonium fluoride (TBAF) and/or trifluoroacetic acid (TFA). In yet another example, if the amino protective group is benzyl, then the one or more reagents are Pd/C and H2.
In some embodiments, step c) is performed at a temperature between 0 and 70 degrees Celsius; between 20 and 60 degrees Celsius; or between 35 and 50 degrees Celsius.
In some embodiments, the compound of formula 5 is synthesized as the free base, whereas in other embodiments, the compound of formula 5 is synthesized as a salt. In one embodiment, the compound of formula 5 is the salt of the compound of formula 12. In another embodiment, the compound of formula 12 is synthesized as the HCl salt. In yet other embodiments, the compound of formula 12 is synthesized as free base. In additional embodiments, the compound of formula 5 is the free base of the compound of formula 18. In some other embodiments, the compound of formula 5 is the salt of the compound of formula 18. By way of example, preparation of the salt can be followed by a neutralization step to synthesize the free base.
The choice of synthesizing either a salt or free base form may depend on the materials physical properties. In one embodiment, for stability reasons and manufacturing reasons, such as ease of handling, the compound of formula 12 is synthesized and/or isolated as the salt. In another example, the compound of formula 18 is synthesized and/or isolated as the free base, which is sufficiently stable and easy to handle.
In some embodiments, the compound of formula 5 or a salt thereof is crystallized from one or more solvents independently selected from the group comprising water, methanol, ethanol, isopropanol, n-propanol, concentrated NH4OH, acetonitrile, MTBE (tert-butyl methyl ether), DCM (dichloromethane), EtOAc (ethyl acetate), iPrOAc (isopropylacetate), toluene, 2-Me-THF, DIPE (diisopropylether), heptane and heptanes. In some embodiments, the compound of formula 5 or a salt thereof is crystallized from one or more solvents selected from the group consisting of water, NH4OH, acetonitrile, isopropanol, toluene, and mixtures thereof. In one embodiment, the one or more solvents are i) water, NH4OH, and acetonitrile; or ii) isopropanol and toluene.
In some embodiments, step d) comprises a step of combining a base selected from the group consisting of triethylamine, pyridine, Hunig's base, and a carbonate base. In some embodiments, step d) comprises a step of combining a base selected from the group consisting of triethylamine, pyridine, Hunig's base, a carbonate base, and combinations thereof.
In some embodiments, step d) further comprises combining a solvent selected from the group consisting of water, an alcoholic solvent, and combinations thereof.
In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a base or a solvent. In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a base. In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a solvent. In some embodiments, step d) includes combining the compound of formula 5 or a salt thereof and a compound of formula 6 with a base and a solvent.
In some embodiments, step d) is performed at a temperature between 35 and 110 degrees Celsius; between 40 and 90 degrees Celsius; between 50 and 80 degrees Celsius; or between 60 and 90 degrees Celsius.
In some embodiments, the compound of formula 7 or a salt thereof is crystallized from one or more solvents selected from the group consisting of alcohol and water. In other embodiments, the one or more solvents are i) methanol and water; ii) ethanol and water; iii) propanol and water; or iv) isopropanol and water.
In some embodiments, the compound of formula 6 is an unprotected purinyl compound, wherein R6 is hydrogen. In alternative embodiments, the compound of formula 6 is a protected purinyl compound wherein R6 is an amino protecting group. Use of the protected purinyl compound, such as the compound of formula 13, to synthesize a compound of formula 7 or a salt thereof has been observed to proceed faster, with less dipurine adducts, and at a higher yield compared to use of an unprotected purinyl compound.
In one embodiment, if R6 is an amino protective group, the process further comprises step e) combining the compound of formula 7, or a salt thereof, and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group, wherein a compound of formula I:
or a salt thereof is synthesized. In one embodiment, R6 is an amino protective group.
In one embodiment, if R6 is an amino protective group, the process further comprises step e) combining the compound of formula 7, or a salt thereof, and
one or more reagents, wherein the one or more reagents are used to remove the amino protective group, wherein a compound of formula I:
is synthesized.
As noted above, in certain embodiments, step e) comprises combining one or more reagents for the deprotection of amino protective groups. For instance, if the amino protective group is an alkoxymethyl or a carbamate, such as a t-butyl carbamate or Fmoc, then the one or more reagents is an acid. In further embodiments, the acid is a mineral acid. Non-limiting examples of mineral acids include hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), and perchloric acid (HClO4). In some embodiments, the reagent is hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobromic acid (HBr), perchloric acid (HClO4), or a mixture thereof. In other embodiments, the acid is trifluoroacetic acid (TFA). In another example, if the amino protective group is an alkyl silyl group, the one or more reagents are tetra-n-butylammonium fluoride (TBAF) and/or trifluoroacetic acid (TFA). In yet another example, if the amino protective group is benzyl, then the one or more reagents are Pd/C and H2.
In yet further embodiments R6 is THP (tetrahydropyranyl). In some embodiments, R6 is THP and the one or more reagents used to remove the amino protective group is an acid. It has been discovered that non-aqueous acidic reaction conditions help avoid undesirable reactions such as degradation and formation of ring-opening side products. In some embodiments, the acid is generated in situ. In some embodiments, removal of the THP protective group proceeds to completion or near completion in the absence of water. In one embodiment, removal of the THP protective group proceeds to completion or near completion under anhydrous conditions. In another embodiment, removal of the THP protective group proceeds to completion or near completion with less than 0.5% water present. In a further embodiment, the acid is generated in situ. For example, ethanol and acetyl chloride may be used to generate HCl in situ. In some embodiments, step e) comprises an acid selected from the group consisting of a mineral acid, TFA and a Lewis acid. In some embodiments the acid is HCl. In another embodiment, R6 is methyl 2-trimethylsilylethyl ether (SEM) and the one or more reagents used to remove the protective group is a fluoride ion.
Deprotection is considered near completion when at least 90%, 95%, 97%, 98%, 99%, 99.5% or 99.9% of the protected material is deprotected.
In some embodiments, step e) is performed at a temperature between 30 and 70 degrees Celsius; between 40 and 60 degrees Celsius; or between 25 and 50 degrees Celsius.
In some embodiments, the compound of formula I or a salt thereof is crystallized from one or more solvents selected from the group comprising water, ethanol, methanol, isopropanol, n-propanol and acetone. In other embodiments, the one or more solvents are i) water; ii) ethanol; iii) acetone; iv) water and ethanol; or v) water, ethanol and acetone.
In some of the foregoing embodiments, the compound of formula 1 is
or
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 1 is
or
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 1 is
or
In some of the foregoing embodiments, the compound of formula 2 is
or
In some of the foregoing embodiments, the compound of formula 3 is
In some of the foregoing embodiments, the compound of formula 4 is
or
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 4 is
or
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 4 is
or
In some of the foregoing embodiments, the compound of formula 5 is
or
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 5 is
or
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 5 is
or
In some of the foregoing embodiments, the compound of formula 6 is
In some of the foregoing embodiments, the compound of formula 7 is
or
or a salt thereof.
In some of the foregoing embodiments, the compound of formula 7 is
or
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula 7 is
or
In some of the foregoing embodiments, the compound of formula I is
or
or a salt thereof.
In some of the foregoing embodiments, the compound of formula I is
or
or a pharmaceutically acceptable salt thereof.
In some of the foregoing embodiments, the compound of formula I is
or
The processes described herein provide an efficient synthesis. In addition, the processes reduce or minimize certain process steps and/or side products, such as racemization of chiral centers during deprotection conditions. Furthermore, the processes disclosed herein may be suitable for various purposes, such as one or more of laboratory, industrial, commercial, non-commercial, manufacturing, non-manufacturing, regulatory, non-regulatory, medical, non-medical, pharmaceutical, and experimental uses.
By way of example, the processes of the present application may be suitable for making compounds of the formulas disclosed herein, in the amounts of 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1 g, 5 g, 10 g, 50 g, 100 g, 250 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100 kg, 250 kg, 500 kg, 750 kg, 1000 kg, 2500 kg, and 5000 kg, in a single batch. In addition, the processes of the present application may be suitable for making compounds in the amounts between 1-100 mg, 1-500 mg, 1-1000 mg, 1-100 g, 1-500 g, 1-1000 g, 10-1000 kg, 500-1000 kg, 1000-2000 kg, 1000-5000 kg, and more than 5000 kg in a single batch. Additionally, the processes of the present application may be suitable for making compound in the amounts of at least 1 mg, 100 mg, 1 g, 10 g, 100 g, 1 kg, 10 kg, 100 kg, 1000 kg, 2500 kg, and 5000 kg, in a single batch. Also, the processes described herein may be used for making compounds in single or multiple batches, or in continuous/semi-continuous processes. In some embodiments, the process is a batch process. In some embodiments, the process is a continuous process. In some other embodiments, the process is a semi-continuous process.
By way of example, the processes of the present application may utilize at least about 1 mmol, 10 mmol, 100 mmol, 1 mol, 5 mol, 10 mol, 20 mol, 50 mol, or 100 mol of at least one starting material. The starting material includes any of the starting or intermediate compounds disclosed herein, a salt thereof, or a reagent.
Compounds
In some embodiments, the application discloses the compound of formula 1:
or a salt thereof, wherein R1 is selected from the group consisting of halo and optionally substituted C1-C8 alkyl; R2 is selected from the group consisting of H and optionally substituted C1-C8 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In some embodiments, R1 is selected from the group consisting of halo and C1-C8 alkyl. In some embodiments, R1 is halo. In some embodiments, R2 is selected from the group consisting of H and C1-C8 alkyl. In some embodiments, R2 is C1-C8 alkyl. In some embodiments, R2 is C1-C4 alkyl. In some embodiments, R1 is selected from the group consisting of halo and C1-C8 alkyl; R2 is selected from the group consisting of H and C1-C8 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In some embodiments, R1 is halo; R2 is C1-C8 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In some embodiments, R1 is halo; R2 is C1-C4 alkyl, and R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In further embodiments, R3 is an amino protective group and R4 is an optionally substituted purinyl group. In further embodiments, R3 and R4 are amino protective groups. In further embodiments, R3 is an amino protective group and R4 is a purinyl group.
In some embodiments, the application discloses the compound of formula 1:
or a salt thereof; and wherein the compound of formula 1 or a salt thereof is synthesized by a process comprising
step a) combining a compound of formula 2:
or a salt thereof,
and a compound of formula 3:
wherein the compound of formula 1 or a salt thereof is synthesized,
wherein R1 is halo;
R2 is selected from the group consisting of H, and optionally substituted C1-C8 alkyl; and
R3 and R4 are each independently selected from the group consisting of an amino protective group and an optionally substituted purinyl group. In other embodiments, R1, R2, R3 and R4 are as defined above for the compound of formula 1.
In some embodiments, the application discloses the compound of formula 8:
or a salt thereof, wherein the compound of formula 8 or a salt thereof is synthesized by the process comprising combining a compound of formula 9:
or a salt thereof,
and a compound of formula 10:
wherein the compound of formula 8 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 14:
or a salt thereof, wherein the compound of formula 14 or a salt thereof is synthesized by a process comprising combining a compound of formula 12:
or a salt thereof, and
a compound of formula 13:
wherein the compound of formula 14 is synthesized. In further embodiments, the process further comprises combining a compound of formula 11:
or a salt thereof, and
an acid, wherein the compound of formula 12 or a salt thereof is synthesized. In some embodiments, the process comprises combining a compound of formula 11:
and
an acid, wherein the compound of formula 12 or a salt thereof is synthesized. In yet further embodiments, the process further comprises combining a compound of formula 8:
or a salt thereof, and
aniline, wherein the compound of formula 11 is synthesized. In yet another embodiment, the process further comprises combining compound of formula 9:
or a salt thereof,
and a compound of formula 10:
wherein the compound of formula 8 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 15:
or a salt thereof, wherein the compound of formula 15 or a salt thereof is synthesized by a process comprising combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 15 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 15a:
or a salt thereof, wherein the compound of formula 15a or a salt thereof is synthesized by a process comprising combining a compound of formula 16:
or a salt thereof,
wherein BB is halo, and a compound of formula 10a:
wherein AA is an amino protective group and wherein the compound of formula 15 or a salt thereof is synthesized. In some embodiments, BB is F. In some embodiments, the amino protective group is selected from the group consisting of t-butyl carbamate, tetrahydropyranyl, alkylsilyl, benzyl, an optionally substituted purinyl group, and alkoxymethyl. In other embodiments, the amino protective group is carbamate. In some embodiments, the amino protective group is t-butyl carbamate (BOC) or 9-fluoroenylmethyl carbamate (FMOC). In some embodiments, AA is t-butyl carbamate (BOC).
In some embodiments, the application discloses a compound of formula 19:
or a salt thereof, wherein the compound of formula 19 or a salt thereof is synthesized by a process comprising combining a compound of formula 18:
or a salt thereof, and
a compound of formula 13:
wherein a compound of formula 19 or a salt thereof is synthesized. In further embodiments, the process further comprises combining a compound of formula 17:
or a salt thereof, and
an acid, wherein the compound of formula 18 or a salt thereof is synthesized. In some embodiments, the process further comprises combining a compound of formula 17:
and
an acid, wherein the compound of formula 18 or a salt thereof is synthesized. In yet further embodiments, the process further comprises combining a compound of formula 15:
or a salt thereof, and
aniline, wherein the compound of formula 17 is synthesized. In yet another embodiment, the process further comprises combining compound of formula 16:
or a salt thereof,
and a compound of formula 10:
wherein the compound of formula 15 or a salt thereof is synthesized.
In some embodiments, the application discloses a compound of formula 20:
or a salt thereof, wherein the compound of formula 20 or a salt thereof is synthesized by a process comprising combining a compound of formula 9:
and
a compound of formula 10:
wherein the compound of formula 20 or a salt thereof is synthesized. In some embodiments, the process further comprises synthesizing a compound of formula 8:
or a salt thereof. In some embodiments, the compound of formula 8 or a salt thereof ring-opens to form the compound of formula 20 or a salt thereof. In some embodiments, the compound of formula 20 is an intermediate that is formed during the preparation of the compound of formula 8.
A compound of formula 21:
or a salt thereof, wherein the compound of formula 21 or a salt thereof is synthesized by a process comprising
combining a compound of formula 16:
or a salt thereof,
and a compound of formula 10a:
wherein the compound of formula 21 or a salt thereof is synthesized. In some embodiments, the process further comprises synthesizing a compound of formula 15:
or a salt thereof. In some embodiments, the compound of formula 15 or a salt thereof ring-opens to form the compound of formula 21 or a salt thereof. In some embodiments, the compound of formula 21 is an intermediate that is formed during the preparation of the compound of formula 15.
By way of example, the compositions of the present application may comprise at least 2000 kg, 1000 kg, 750 kg, 500 kg, 250 kg, 100 kg, 10 kg, 1 kg, 0.5 kg, 50 g, 5 g, or 0.5 g of a compound of a formula disclosed herein or a salt thereof. In some embodiments, compositions may comprise a multi-kilogram amount of a compound of a formula disclosed herein or salt thereof. In other embodiments, compositions of the present disclosure may comprise at least about 1 mmol, 10 mmol, 100 mmol, 1 mol, 5 mol, 10 mol, 20 mol, 50 mol, or 100 mol of a compound of a formula disclosed herein or a salt thereof. In addition to a compound of a formula disclosed herein or a salt thereof, composition may further comprise solvents, reagents, or combinations thereof. In another aspect, compositions may consist essentially of a compound of a formula disclosed herein or a salt thereof.
By way of example, the resulting compounds from the processes described herein may be used in a pharmaceutical composition. In another embodiment, provided is a pharmaceutical composition comprising a resulting compound from the processes disclosed herein or a salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
EXAMPLES
Example 1. Synthesis of a Compound of Formula 17
A compound of formula 16 (1.0 kg, 1.0 eq), a compound of formula 10 (1.5 kg, 1.2 eq) and pyridine (3.0 kg) were added to reactor A. The mixture was agitated at 19 to 25° C. and diphenylphosphite (6.1 kg, 4.0 eq) was added to the mixture over at least 2 h while maintaining the internal temperature at less than about 35° C. The reaction mixture was adjusted to 19 to 25° C. and agitated until the reaction was deemed complete by HPLC analysis (1-3 h). Aniline (0.7 kg, 1.2 eq) was added over a minimum of 1 h while maintaining the internal temperature at less than about 40° C. The reaction mixture was then adjusted to 45 to 55° C. and agitated until the reaction is deemed complete. The reaction mixture was cooled to 19 to 25° C. and toluene (13 kg) was added followed by a prepared IM HCl solution (10 kg) while maintaining the internal temperature at less than about 30° C. The biphasic mixture was agitated at about 22° C. for at least 30 minutes and then allowed to settle. The aqueous layer was separated and discarded. A second portion of IM HCl (10 kg) was added to the organic layer in reactor A. The biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The aqueous layer was separated and discarded. A compound of formula 17 was carried forward to the next step as a stock solution in toluene.
Example 2. Synthesis of a Compound of Formula 18
To the stock solution of a compound of formula 17 in toluene was added acetonitrile (8.4 kg) and concentrated HCl (2.2 kg) while maintaining the internal temperature at no more than 30° C. The reaction mixture was adjusted to 19 to 25° C. and agitated until the reaction was deemed complete. Water (5 kg) was added and the biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor B (product was in the aqueous layer). Water (10 kg) was then added to the organic layer in reactor A. The biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor B (combining with the first aqueous phase). Toluene (4 kg) was added to the combined aqueous layers in reactor B and the biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor A. Toluene (4 kg) was added to reactor A and the biphasic mixture was agitated at 19 to 25° C. for at least 30 minutes and then allowed to settle. The bottom aqueous layer was separated and transferred to reactor B. The aqueous phase was then partially concentrated under vacuum to 18 L to remove toluene and reduce acetonitrile levels to no more than 3.5%. The aqueous phase was then transferred, in portions, to reactor B containing water (5 kg), ammonium hydroxide (6.5 kg, 8.0 eq) and acetonitrile (0.8 kg) while maintaining the internal temperature at no more than 19 to 25° C. The resulting slurry was agitated at 19 to 25° C. for ca 1 h before filtering. The filter cake was rinsed with water (3 kg) and then dried under vacuum at no more than 50° C. to afford 18. 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J=8.4, 2.2 Hz, 1H), 7.71 (dd, J=9.2, 5.0 Hz, 1H), 7.55-7.45 (m, 4H), 7.27 (d, J=6.4 Hz, 2H), 3.69 (q, J=6.4 Hz, 1H), 2.01 (s, 2H), 1.27 (d, J=6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 162.3, 161.9, 160.5, 159.8, 144.4, 136.6, 130.3, 130.2, 129.9, 129.0, 128.9, 128.4, 123.4, 123.2, 122.3, 122.2, 112.1, 111.9, 48.7, 23.7 (signal splitting due to fluorine results in additional peaks).
Example 3. Synthesis of a Compound of Formula 19
A compound of formula 18 (1.0 kg, 1 eq), a compound of formula 13 (0.9 kg, 1.1 eq), triethylamine (0.5 kg, 1.5 eq), water (4 kg) and EtOH (2 kg) were added to reactor A. The mixture was adjusted to 75 to 85° C. and agitated until the reaction was deemed complete. The mixture was then adjusted to 19 to 25° C. and agitated for ca 1 h before filtering. The isolated compound of formula 19 solid was rinsed with water (2 kg) and heptanes (2×3 kg) and then dried under vacuum. 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J=2 Hz, 1H), 8.00 (bs, 1H), 7.89 (dd, J=8.8, 3.0 Hz, 1H), 7.73 (m, 1H), 7.59 (m, 3H), 7.48 (m, 2H), 7.35 (m, 1H), 6.68 (m, 1H), 5.69 (dd, J=10.0, 3.0 Hz, 1H), 5.24 (bs, 1H), 4.16 (dd, J=11.6, 2.0 Hz, 1H), 3.77 (tt, J=11.2, 1.4 Hz, 1H), 2.06 (m, 3H), 1.75 (m, 3H), 1.47 (d, J=6.8 Hz, 3H).
Example 4. Synthesis of a Compound of Formula III
To reactor A was added a compound of formula 19 followed by EtOH (4.2 kg). Acetyl chloride (0.33 kg, 1.2 eq) was then added slowly while maintaining the internal temperature at less than about 40° C. The mixture was then adjusted to 19 to 25° C. and agitated until the reaction was deemed complete. After adjusting the temperature to 5 to 15° C., 0.84 kg of a prepared 4.5% sodium carbonate solution was added to the reaction mixture followed by water (1 kg) while maintaining the internal temperature at 5 to 15° C. To reactor B was added 5.44 kg of a prepared 4.5% sodium carbonate solution and the contents were warmed to 65 to 75° C. Approximately 20% of the solution held in reactor A was then transferred to the aqueous solution in reactor B while keeping the internal temperature at 65 to 75° C. The mixture was aged for about 30 minutes until a slurry was formed. The remaining solution from reactor A was transferred to reactor B over a period of about 1 h while maintaining the internal temperature at 65 to 75° C. The slurry was agitated at 65 to 75° C. for 1 to 5 h until a thick slurry was formed. The contents were then adjusted to 19 to 25° C. over about 1 h and agitated about 1 h before filtering. The wet cake was rinsed with water (10 kg) and then dried under vacuum at about 65° C. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.98 (br, 1H), 7.90 (dd, J=8.4, 2.8 Hz, 1H), 7.74 (dd, J=8.8, 5.2 Hz, 1H), 7.65-7.57 (m 3H), 7.51-7.45 (m, 2H), 7.37 (m, 1H), 6.84 (bd, J=8.8 Hz, 1H), 5.27 (br, 1H), 1.75 (br, 1H), 1.50 (d, J=6.8 Hz, 3H). 19F NMR (400 MHz, CDCl3): δ −111.11 (referenced to TFA at −76.5 ppm).
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15817044
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Apr 8th, 2014 12:00AM
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Jul 21st, 2010 12:00AM
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https://www.uspto.gov?id=US08691829-20140408
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Treatment of liver disorders with PI3K inhibitors
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The invention provides methods to treat certain liver disorders by administering a compound that inhibits PD K isoforms, particularly the delta isoform. It further provides specific compounds useful for these methods and ways to identify subjects who are particularly suitable for receiving these treatments.
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8691829
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1. A method to treat a liver disorder, which method comprises administering to a subject in need thereof an effective amount of a selective inhibitor of at least one isoform of PI3K kinase.
2. The method of claim 1, wherein the inhibitor is selective for inhibition of PI3Kδ or PI3Kβ or both, relative to its inhibition of other Class I PI3K isoforms.
3. The method of claim 2, wherein the disorder is nonalcoholic steatohepatitis.
4. The method of claim 2, wherein the liver disorder is nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, cirrhosis, hepatitis, a liver adenoma, insulin hypersensitivity, or a liver cancer.
5. The method of claim 1, wherein the inhibitor is a compound of formula (1a) or formula (1b):
wherein:
W is selected from the group consisting of H, Me, Cl, and F;
X and X′ are independently selected from the group consisting of H, Me, Cl, and F;
Y is selected from the group consisting of H, Me and Et;
Z is NH or a bond; and
A is NH2, or A is absent and indicates the point of attachment of Z to the purine ring;
Q is H when A is absent, or Q is absent and indicates the point of attachment of Z to the purine ring when A is NH2;
provided that not more than two of W, X, and Y represents H;
or a pharmaceutically acceptable salt thereof.
6. The method of claim 5, wherein not more than one of W, X, and Y represents H.
7. The method of claim 5, wherein W is Me, and/or wherein X is H, Me or F.
8. The method of claim 5, wherein Z is NH.
9. The method of claim 5, wherein Z is a bond.
10. The method of claim 8, wherein A is absent and Q is H.
11. The method of claim 9, wherein A is NH2 and Q indicates the point of attachment of Z to the purine ring.
12. The method of claim 10, wherein at least one of W, X and Y is Me.
13. The method of claim 11, wherein at least one of W, X and Y is Me.
14. The method of claim 10, wherein Y is Me or Et.
15. The method of claim 11, wherein Y is H.
16. The method of claim 5, wherein the compound is a compound of formula (1b), and wherein X and X′ are different.
17. The method of claim 15, wherein X′ is H, and X is selected from Cl and Me.
18. The method of claim 1, wherein the inhibitor is a compound of formula (3):
wherein:
one of Q1, Q2 and Q3 is S, and the other of two of Q1, Q2 and Q3 are —CR1—;
wherein each R1 is independently H, halo, OR, NR2, NROR, NRNR2, SR, SOR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRCOOR, NRCOR, CF3, CN, COOR, CONR2, OOCR, COR, or NO2,
or R1 can be an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl groups,
wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two N, O or S as ring members;
and wherein each R group other than H, and each ring formed by linking two R groups together, is optionally substituted;
Z is a bond, or is O, NR2, C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted with up to two C1-C6 alkyl or C2-C6 heteroalkyl groups, where two of said alkyl or heteroalkyl groups can optionally cyclize to form a 3-7 membered ring containing up to two heteroatoms selected from O, N and S as ring members;
R3 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with up to three R1,
or R3 can be H if Z is not a bond;
L is selected from the group consisting of —C(R2)2—, —C(R2)2—C(R2)2—,
—C(R2)2—NR2—, and —C(R2)2—S(O)n—,
wherein each R2 is independently H or an optionally substituted member selected from C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, and n is 0-2;
and two R2, if present on L, can cyclize to form a 3-7 membered ring that may contain up to two heteroatoms selected from N, O and S as ring members;
Het is a monocyclic or bicyclic ring system wherein at least two ring atoms are N and wherein at least one ring is aromatic, and Het is optionally substituted with up to three substituents selected from R4,N(R4)2,S(O)pR4, OR4, halo, CF3, CN, NR4OR4, NR4N(R4)2, SR4, SOR4,SO2R4, SO2N(R4)2, NR4SO2R4, NR4CON(R4)2, NR4COOR4, NR4COR4, CN, COOR4, CON(R4)2, OOCR4, COR4, or NO2,
wherein each R4 is independently H or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl,
and wherein two R4 on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two heteroatoms selected from N, O and S;
wherein the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, CF3, CN, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, OOCR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; and
p is 0-2;
or a pharmaceutically acceptable salt thereof.
19. The method of claim 18, wherein the inhibitor is a compound of formula (3a), (3b), or (3c):
wherein:
each J and each Y is independently selected from the group consisting of F, Cl, Br, CN, Me, CF3, OMe, CONR22, COOR2, NMe2, NH2, NHMe, -Q-(CH2)q—OR2, and -Q-(CH2)q—N(R2)2, where q is 0-4, and Q is absent or is selected from O, S and NR2;
m is 0-2, and k is 0-3;
L is selected from —C(R2)2—, —C(R2)2—NR2—, and —C(R2)2—S—,
each R2 is independently H or an optionally substituted C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, or an optionally substituted C2-C4 heteroalkyl;
and two R2, if present on a single atom or on adjacent atoms, can cyclize to form a 3-7 membered ring that is optionally substituted and may contain up to two heteroatoms selected from N, O and S as ring members;
Het is selected from the group consisting of:
wherein [L] indicates the atom of Het to which L is attached; and
each X is independently H, F, Cl, Br, Me, CF3, OH, OMe, NH2, NHAc, or NHMe;
and the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, OOCR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S;
and p is 0-2;
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1, wherein the compound is selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
21. The method of claim 1, wherein the subject is one having a reduced levels of hepatic Pten activity.
22. The method of claim 21, wherein the subject has a Pten mutation.
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RELATED APPLICATIONS
This application is a National Phase filing under 35 U.S.C. §371 of International Application PCT/US2010/042801, with an International Filing Date of Jul. 12, 2010, entitled “TREATMENT OF LIVER DISORDERS WITH P13K INHIBITORS, which claims priority to U.S. provisional application 61/227,343 filed Jul. 21, 2009. The contents of that provisional application are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to methods for treating certain liver disorders using compounds that inhibit phosphatidylinositol-3,4,5-triphosphate kinase (PI3K) enzymes in vivo. It provides compounds, compositions and combinations useful for treating a variety of disorders that primarily affect the liver.
BACKGROUND ART
Various phosphorylated forms of phosphatidylinositol are critical regulators of many cell functions, including primary metabolism, growth and proliferation of cells, differentiation, cell migration, immune responses, and apoptosis. Because they are involved in many aspects of cell regulation, it is not always predictable what effect a drug candidate may have when it inhibits conversion of phosphatidylinositol between its various phosphorylated forms. For example, FIG. 1 illustrates some of the known roles played by phosphatidylinositol-4,5-diphosphate (PI-4,5-P2, also referred to herein as PIP2) and phosphatidylinositol-3,4,5-triphosphate (PI-3,4,5-P3, also referred to herein as PIP3). PIP3 activates a number of receptors, some of which are involved in cell growth, replication, and death (apoptosis).
It has recently been reported that the tumor suppressor Pten is mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. Pten's major substrate is PIP3, which it dephosphorylates to form PIP2. Its strong association with liver cancers in particular suggests that Pten is especially important for maintaining homeostasis and preventing tumor formation in the liver. It has also been shown that hepatocyte-specific Pten deficiency leads to steatohepatitis and hepatic carcinomas. Y. Horie, et al., J. Clin. Investigation, 113(12), 1774-83 (2004). Horie concludes that controlled blocking of the PI3K pathway may be beneficial for treatment of patients predisposed to NASH, liver cirrhosis or hepatic carcinomas. It has also been reported recently that steatosis (accumulation of fat) induced by exposure of hepatocytes to conditions that generate reactive oxygen species can be inhibited by LY294002, an inhibitor of kinases that phosphorylate PIP2 to form PIPS. R. Kohli, et al., J. Biol. Chem. 282, 21327-36 (July 2007). Kohli demonstrated that LY294002 blocked steatosis development in a model system where diet induced p85 expression and steatosis, demonstrating that an inhibitor of PI3Ks can prevent development of steatosis.
Liver disorders are increasingly common due to high calorie diets and high obesity rates in the developed world. These are risk factors for fatty liver conditions that can progress to cirrhosis. NASH (non-alcoholic steatohepatitis) is one such condition: it was first identified in 1980, but is now a widely recognized condition affecting millions of Americans. Kohli, et al. As many as 30 million Americans are believed to have nonalcoholic fatty liver disease (FALD), and about 30% of those are believed to have NASH. Methods to treat liver disorders associated with excessive fatty deposits are therefore needed. The present invention provides compounds and methods for preventing and/or treating such conditions.
DISCLOSURE OF THE INVENTION
The invention provides compounds useful for the treatment of liver disorders, especially ones wherein Ptenis underexpressed or mutated. Conditions that can be prevented and/or treated according to the invention include, for example, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, cirrhosis, hepatitis, liver adenomas, insulin hypersensitivity, and liver cancers such as hepatoma, liver cell adenoma and hepatocellular carcinoma. The invention further provides methods for identifying patients who are most likely to respond to these treatments.
In one aspect, the invention provides a method to treat a subject having a liver disorder, which comprises administering to the subject an effective amount of a compound that inhibits PI3K. Suitable compounds for use in these methods are described herein.
PI3K exists as a heterodimer, combining a p110 unit with a p85 unit, and there are several isoforms of PI3K that contain different p110 and/or p85 subunits. In particular, there are four p110 subunits known, referred to as p110α, p110β, p110γ, and p110δ. Tissue distribution of these varies, with p110α occurring widely; p110β dominating in certain tissues like brain and liver; and p110δ dominating in the spleen and hematopoietic tissues.
In tissues where more than one isoform occurs, it may be desirable to selectively inhibit one particular isoform to achieve a desired therapeutic effect, or it may be desirable to inhibit two of these isoforms, or all of them. Compounds that inhibit all of the isoforms are known, and are referred to as pan-PI3K inhibitors; compounds that selectively inhibit one or two of the isoforms are particularly useful in certain disorders, and offer a reduced likelihood of undesired side effects in tissues other than the one targeted. The methods described herein thus preferably use a selective PI3K inhibitor, such as an inhibitor that is more active against PI3Kβ or PI3Kδ, or both of these isoforms over the others.
In one aspect, the inhibitor of PI3K is a selective that inhibits one isoform of PI3K more effectively than another isoform of PI3K. For treatment of liver disorders, some embodiments of the invention utilize a PI3K inhibitor that is effective against at least PI3Kβ; in some embodiments the inhibitor is selective for inhibition of PI3Kβ relative to PI3Kγ and/or PI3Kα. In certain embodiments, the inhibitor has an IC-50 against PI3Kβ that is less than about 100 nM, and preferably less than about 60 nM.
The methods and compounds described herein can be used to combat the effects of insufficient Pten activity, by restoring a normal ‘balance’ of PIP3 and PIP2. In one embodiment, the methods of the invention can be monitored by assessing levels of PIP2 in the subject, or by assessing the ratio of PIP2 to PIP3 and adjusting dosage of a compound of the invention to produce a ratio within the normal range for similar subjects.
In one aspect, the PI3K inhibitor is a substituted pyrimidine: suitable compounds are described in WO 2007/12175; WO 2007/042810; WO 2007/132171; WO 2007/129161; WO 2006/046031; and WO 2009/070524. Preferably, the pyrimidine compound exhibits an IC-50 against PI3Kβ that is less than about 100 nM, and preferably less than about 60 nM.
In another aspect, the PI3K inhibitor is a quinazolinone compound such as those disclosed in U.S. Pat. Nos. 6,518,277 or 6,667,300, which are incorporated herein by reference for their disclosures of specific quinazolinone compounds and methods of making such compounds. Preferably, the quinazolinone compound exhibits an IC-50 against PI3Kβ that is less than about 100 nM, and preferably less than about 60 nM.
In one aspect, the PI3K inhibitor is a compound of formula (1):
wherein:
W is selected from the group consisting of H, Me, Cl, and F;
X is selected from the group consisting of H, Me, Cl, and F;
Y is selected from the group consisting of H, Me and Et;
Z is NH or a bond; and
A is NH2, or A is absent and indicates the point of attachment of Z to the purine ring;
Q is H when A is absent, or Q is absent and indicates the point of attachment of Z to the purine ring when A is NH2;
provided that not more than two of W, X, and Y represents H; or a pharmaceutically acceptable salt thereof.
Selected embodiments of the compounds of Formula (1) that are particularly useful in the present methods include compounds of formula (2a) and (2b):
wherein W, X and Y are as defined for formula (1), and wherein not more than two of W, X and Y represent H. In certain embodiments, Y is Me or Et.
In another aspect, the methods of the invention can utilize as the PI3K inhibitor a compound of formula (3):
wherein:
one of Q1, Q2 and Q3 is S, and the other of two of Q1, Q2 and Q3 are —CR1—;
wherein each R1 is independently H, halo, OR, NR2, NROR, NRNR2, SR, SOR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRCOOR, NRCOR, CF3, CN, COOR, CONR2, OOCR, COR, or NO2,
or R1 can be an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl groups,
wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two N, O or S as ring members;
and wherein each R group other than H, and each ring formed by linking two R groups together, is optionally substituted;
Z is a bond, or is O, NR2, C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted with up to two C1-C6 alkyl or C2-C6 heteroalkyl groups, where two of said alkyl or heteroalkyl groups can optionally cyclize to form a 3-7 membered ring containing up to two heteroatoms selected from O, N and S as ring members;
R3 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with up to three R1,
or R3 can be H if Z is not a bond;
L is selected from the group consisting of —C(R2)2—, —C(R2)2—C(R2)2—, —C(R2)2—NR2—, and —C(R2)2—S(O)n—,
wherein each R2 is independently H or an optionally substituted member selected from C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, and n is 0-2;
and two R2, if present on L, can cyclize to form a 3-7 membered ring that may contain up to two heteroatoms selected from N, O and S as ring members;
Het is a monocyclic or bicyclic ring system wherein at least two ring atoms are N and wherein at least one ring is aromatic, and Het is optionally substituted with up to three substituents selected from R4, N(R4)2, S(O)pR4, OR4, halo, CF3, CN, NR4OR4, NR4N(R4)2, SR4, SOR4, SO2R4, SO2N(R4)2, NR4SO2R4, NR4CON(R4)2, NR4COOR4, NR4COR4, CN, COOR4, CON(R4)2, OOCR4, COR4, or NO2,
wherein each R4 is independently H or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl,
and wherein two R4 on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two heteroatoms selected from N, O and S;
wherein the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, CF3, CN, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, OOCR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; and
p is 0-2;
or a pharmaceutically acceptable salt thereof. Specific embodiments of such compounds are further described below.
In some embodiments, the selective inhibitor is a compound that selectively inhibits PI3Kδ, relative to its inhibition of PI3Kγ. In some embodiments, the selective inhibitor is a compound that selectively inhibits PI3Kδ, relative to its inhibition of PI3Kβ. In some embodiments, the selective inhibitor is a compound that selectively inhibits PI3Kδ, relative to its inhibition of PI3Kα. In some embodiments, the selective inhibitor is a compound that selectively inhibits PI3Kβ, relative to its inhibition of PI3Kγ. In some embodiments, the selective inhibitor is a compound that selectively inhibits PI3Kβ, relative to its inhibition of PI3Kα. In some embodiments, the selective inhibitor is a compound that selectively inhibits PI3Kβ and PI3Kδ relative to its inhibition of either PI3Kα or PI3Kγ.
In some embodiments, the compound is selective for PI3Kδ relative to both PI3Kγ and PI3Kα. In other embodiments, the compound is selective for PI3Kβ relative to both PI3Kα and PI3Kγ. In some embodiments, the compound is selective for PI3Kδ and PI3Kβ relative to both PI3Kα and PI3Kγ.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts some of the cellular pathways in which phosphatidylinositol phosphate species are known to participate.
MODES OF CARRYING OUT THE INVENTION
Unless otherwise defined herein, terms used herein take their ordinary meaning in the art.
As used herein, the term “alkyl” is defined as straight chained and/or branched hydrocarbon groups containing the indicated number of carbon atoms and an open valence by which the alkyl group is attached to a base molecule; typical examples include methyl, ethyl, and straight chain and branched propyl and butyl groups. The hydrocarbon group can contain up to 16 carbon atoms, unless otherwise specified, and often contain one to eight carbon atoms. The term “alkyl” includes cycloalkyl and “bridged alkyl,” i.e., a C6-C16 bicyclic or polycyclic hydrocarbon group, for example, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or decahydronaphthyl. The term “cycloalkyl” is defined as a cyclic C3-C8 hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl.
The term “alkenyl” is defined identically as “alkyl,” except the alkenyl group contains at least one carbon-carbon double bond, and as a result, the minimum size for an alkenyl group is C2. “Alkynyl” is defined similarly, except that an alkynyl group contains at least one carbon-carbon triple bond.
“Cycloalkenyl” is defined similarly to cycloalkyl, except at least one carbon-carbon double bond is present in the ring.
The term “alkylene” is defined as an alkyl group having a second open valence to which another group is attached, i.e., an alkylene must connect two other substructures. For example, the term “aryl-C1-C3-alkylene” refers to an alkylene group containing one to three carbon atoms, and substituted at one valence with an aryl group, which leaves one remaining valence of the alkylene portion of the group as the point at which it is connected to a base molecule.
The terms “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and “heteroalkylene” as used herein are defined similarly to the terms alkyl, alkenyl, alkynyl and alkylene, except that the tetero' forms include at least one heteroatom selected from N, O and S as a replacement for one of the carbons of the corresponding alkyl, alkenyl, alkynyl or alkylene moiety. In these heteroforms, S can be further oxidized to S═O or —SO2—, i.e., it can have one or more ═O substituents. These groups include at least one carbon atom, and are typically linked to a base molecule through carbon rather than by the heteroatom. Examples of heteroalkyl include methoxymethyl and dimethylaminoethyl, for example, and —CH2—SO2—CH2— is an example of a heteroalkylene.
The term “halo” or “halogen” is defined herein to include fluorine, bromine, chlorine, and iodine. Frequently, fluoro or chloro is preferred in the compounds of formula (1) and (2).
The term “aryl,” alone or in combination, is defined herein as a monocyclic or polycyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an “aryl” group can be unsubstituted or substituted, for example, with one or more, and in particular one to three substituents. Preferred substituents for the aryl groups of the invention include halo, alkyl, phenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, and amino. Exemplary aryl groups include phenyl, naphthyl, biphenyl, tetrahydronaphthyl, chlorophenyl, fluorophenyl, aminophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, carboxyphenyl, and the like. Fluoro, chloro, CF3, CN, methyl, methoxy, dimethylamino, amino, and amine-substituted alkyl and heteroalkyl groups are typical examples suitable as substituents for an aryl ring, whether it is a single ring or is fused to another aryl, nonaryl, or heteroaryl ring.
The term “heteroaryl” is defined herein as a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom as a ring member of an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, and amino. F, Cl, NH2, MeNH (methylamine), OMe, Me, and CF3 as well as amine-substituted alkyl or heteroalkyl groups are often preferred substituents for the heteroaryl groups of the invention. Examples of heteroaryl groups include thienyl, furyl, pyridyl, oxazolyl, quinolyl, isoquinolyl, indolyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
As used herein, the term “amount effective” or “effective amount” means a dosage sufficient to produce a desired or stated effect.
“Treating” as used herein refers to preventing a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it; inhibiting the disorder, i.e., arresting its development; relieving the disorder, i.e., causing its regression; or ameliorating the disorder, i.e., reducing the severity of symptoms associated with the disorder.
“Disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
In one aspect, the PI3K inhibitor is a compound of formula (1a) or (1b):
wherein:
W is selected from the group consisting of H, Me, Cl, and F;
X and X′ are independently selected from the group consisting of H, Me, Cl, and F;
Y is selected from the group consisting of H, Me and Et;
Z is NH or a bond; and
A is NH2, or A is absent and indicates the point of attachment of Z to the purine ring;
Q is H when A is absent, or Q is absent and indicates the point of attachment of Z to the purine ring when A is NH2;
provided that not more than two of W, X, and Y represents H;
or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds of formula (la), not more than one of W, X, and Y represents H.
In some embodiments of formula (1a) and (1b), A is absent and the atom it appears to be connected to in the purine ring of formula (1a) or (1b) is actually connected to Z. In these embodiments, Q represents H, and Z is often NH.
In some embodiments, Q is absent and the atom it appears to be connected to in the purine ring of formula (1) is actually connected to Z. In these embodiments, A represents H, and Z is often a bond, i.e., the nitrogen atom on which Q is depicted in formula (1) is directly bonded to the carbon atom to which Y is attached.
In some embodiments of the compounds described above, at least one of W, X, and Y is methyl (Me). In some embodiments, W is Me. In some embodiments, X is Me. In some embodiments, Y is Me.
In some embodiments of the compounds described above, X is H, Me or F.
In some embodiments of the compounds described above, Z is NH.
In some embodiments of the compounds described above, Z is a bond.
In some embodiments of the compounds described above, Y is H.
In some embodiments of the compounds described above, Y is Me.
In some embodiments of the compounds described above, Y is Et.
In some of the embodiments of formula (1b), X and X′ are the same. In some such embodiments, they each represent a group other than H. In specific examples of such compounds, X and X′ each represent F.
Selected embodiments of the compounds of Formula (1) that are particularly useful in the present methods include compounds of formula (2a) and (2b):
wherein W, X and Y are as defined for formula (1), and wherein not more than two of W, X and Y represent H.
In some embodiments of the compounds of formula (2a) and (2b), Y is H, Me or Et. Preferably, Y is Me or Et.
In some of these embodiments of compounds of formula (2a) and (2b), W is H, Me, Cl or F: in formula (2a), W is sometimes F or Me, and in formula (2b), W is sometimes Me or F.
In some of these embodiments of compounds of formula (2a) and (2b), X is H, Me, Cl or F: in formula (2a), X is sometimes F or H, and in formula (2b), X is sometimes Me or H.
Certain compounds of Formula (1a) and (lb) are selective for PI3Kδ or PI3Kβ or both.
Some specific compounds of this type that are particularly useful in the methods described herein include:
including its separable atropisomers, (2c′) and (2c″):
including the R and S isomers of the chiral center between the two bicyclic groups, and particularly the S isomer;
including the R and S isomers of the chiral center between the two bicyclic groups, and particularly the S isomer.
In another aspect, the methods of the invention can utilize as the PI3K inhibitor a compound of formula (3):
wherein:
one of Q1, Q2 and Q3 is S, and the other of two of Q1, Q2 and Q3 are —CR1—;
wherein each R1 is independently H, halo, OR, NR2, NROR, NRNR2, SR, SOR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRCOOR, NRCOR, CF3, CN, COOK, CONR2, OOCR, COR, or NO2,
or R1 can be an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl groups,
wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two N, O or S as ring members;
and wherein each R group other than H, and each ring formed by linking two R groups together, is optionally substituted;
Z is a bond, or is O, NR2, C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted with up to two C1-C6 alkyl or C2-C6 heteroalkyl groups, where two of said alkyl or heteroalkyl groups can optionally cyclize to form a 3-7 membered ring containing up to two heteroatoms selected from O, N and S as ring members;
R3 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with up to three R1,
or R3 can be H if Z is not a bond;
L is selected from the group consisting of —C(R2)2—, —C(R2)2—C(R2)2—, —C(R2)2—NR2—, and —C(R2)2—S(O)n—,
wherein each R2 is independently H or an optionally substituted member selected from C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, and n is 0-2;
and two R2, if present on L, can cyclize to form a 3-7 membered ring that may contain up to two heteroatoms selected from N, O and S as ring members;
Het is a monocyclic or bicyclic ring system wherein at least two ring atoms are N and wherein at least one ring is aromatic, and Het is optionally substituted with up to three substituents selected from R4, N(R4)2, S(O)pR4, OR4, halo, CF3, CN, NR4OR4, NR4N(R4)2, SR4, SOR4, SO2R4, SO2N(R4)2, NR4SO2R4, NR4CON(R4)2, NR4COOR4, NR4COR4, CN, COOR4, CON(R4)2, OOCR4, COR4, or NO2,
wherein each R4 is independently H or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl,
and wherein two R4 on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two heteroatoms selected from N, O and S;
wherein the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, CF3, CN, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, 00CR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; and
p is 0-2;
or a pharmaceutically acceptable salt thereof.
In certain embodiments of the compounds of formula (3), Q1 is S and Q2 and Q3 each represent CR1. In other embodiments of the compounds of formula (3), Q2 is S and Q1 and Q3 each represent CR1. In still other embodiments, Q3 is S and Q1 and Q2 each represent CR1. At least one of Q′, Q2 and Q3 is often CH, and in some of these embodiments, two of them are CH. Where R1 in Q1, Q2 or Q3 is other than H, it is frequently C1-C4 alkyl, CF3, CN, or halo, or it may be an amine-substituted alkyl or heteroalkyl group as described below.
In some embodiments of the compounds of formula (3), R1 on the thiophene ring represents an amine-substituted alkyl or heteroalkyl group such as —(CH2)p—NR′2 or —O—(CH2)p—NR′2 or —NR′—(CH2)p—N(R′)2, wherein p is 1-4 and each R′ is H or C1-C4 alkyl, and wherein two R′ present on one N may cyclize to form a 3-8 membered ring, which can optionally include an additional heteroatom selected from N, O and S, specific examples of these amine-substituted alkyl and heteroalkyl groups include, without limitation:
In some embodiments of the compounds of formula (3), Z represents a bond; in other embodiments, it represents (CH2)1-4. Where Z is a bond, R3 often represents an aryl or heteroaryl ring; in some of these embodiments, R3 is an optionally substituted phenyl or pyridyl ring. In these embodiments, R3 is often substituted with at least one substituent, which is frequently ortho or meta to the point of attachment of the aryl ring to Z. In some of these embodiments, R3 is substituted with 1-3 substituents such as halo, CN, methyl, CF3, or an amine-substituted alkyl or heteroalkyl as described above for R1. When Z is a bond, R3 is frequently phenyl, halo-substituted phenyl, dihalo phenyl, or cyanophenyl. In other embodiments, Z is a bond or (CH2)1-2, and R3 represents a cycloalkyl group, which can be substituted.
In some preferred embodiments of the compounds of formula (3), L is C(R2)2 or C(R2)2NH or C(R2)2S, where each R2 is independently H or C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl. In certain embodiments, L is CH(R2) or CH(R2)NH or CH(R2)S, where R2 represents methyl or ethyl or any optionally substituted C1-C6 alkyl group, or R2 can be an amine-substituted alkyl group as described above for R1. Where one terminus of L is a heteroatom, L is often linked to Het via this heteroatom; and the heteroatom of L is typically attached to a carbon atom of Het.
In many embodiments of the compounds of formula (3), the center CH(R2) of the linker “L” is chiral, and frequently the S enantiomer of this stereocenter is preferred. In other embodiments, this stereocenter is an R enantiomer. Typically, where L is CH(R2)NH or CH(R2)S, the N or S is linked to Het, and CH(R2) is directly bonded to the pyrimidinone ring. In still other embodiments, L is —CH(R2)—NR2—, wherein the two R2 groups are linked to form a ring, which is often a 5-6 atom ring. In these cyclic linkers, a chiral center is also present at CH(R2), and that center may be in either the R or S configuration; the S enantiomer is often preferred. An exemplary ring for such cyclic linkers is pyrrolidine.
Het is an optionally substituted monocyclic or bicyclic ring, and at least one ring of Het is typically a heteroaryl ring containing at least two nitrogen atoms as ring members; in many embodiments, Het is a bicyclic aromatic heterocycle. In certain embodiments of the compounds of formula (3), Het represents a purine ring, which may be substituted with a C1-C4 alkyl group, C6-C10 aryl group, C5-C10 heteroaryl group, halo, amine, alkylamine, dialkylamine, or an amine-substituted alkyl or heteroalkyl group as described above for R1. In other embodiments, Het represents a pyrazolopyrimidine or a pyrrolopyrimidine ring, each of which can be similarly substituted. In still other embodiments, Het represents a pyrimidine or triazine ring, which can also be similarly substituted.
Where Het represents a bicyclic group, it can be attached to L at any available ring position of Het. In many embodiments, L is attached to a carbon or nitrogen atom that is adjacent to an atom shared by both rings of the bicyclic group. In many embodiments, Het represents a 6,5-bicyclic heteroaromatic group, and L may be attached to either the 5-membered ring or the 6-membered ring. In some embodiments, Het is a purine ring, for which the following atom numbering convention is used:
Some specific examples of Het, without limiting its scope, include the following, where [L] indicates the point at which Het is attached to linker “L”, and —X represents a preferred point of attachment for a substituent when one is present. In some embodiments, no substituents other than H are present (each X represents H); in others where more than one X is shown, at least one X is H. In many embodiments, each X that is not H represents an amine or substituted amine, an alkyl or aryl group, or a halogen. Some preferred groups for X include NH2, F, Cl, Me, CF3, and phenyl.
Where L in the compounds of formula (3) is attached at N-9 of a purine or purine analog (using the purine numbering scheme for simplicity, even when the ring is a purine analog), such as the heterocycles depicted below, L represents CH2 or CH(R2). Where L is attached to C-6 of a purine or purine analog such as the heterocycles depicted here, L is frequently CH(R2)—NH, CH(R2)—S or CH(R2)—N(R2), and the heterocycle represented by Het is typically linked to the heteroatom of L in these embodiments. In many of these embodiments, R2 on a carbon atom of the linker L is methyl or ethyl, and when R2 is on nitrogen of the linker, it is often H.
In some preferred embodiments of the compound of formula (3), R3 represents optionally substituted phenyl and Z is a bond. Particularly preferred phenyl groups include unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, and 2,6-difluorophenyl.
In some preferred embodiments of the compounds of formula (3), -L-Het represents —CH2-Het, —CH2-NH-Het, —CH2-S-Het, —CHMe-Het, —CHMe-S-Het, —CHMe-NH-Het, —CHEt-Het, —CHEt-S-Het, or —CHEt-NH-Het.
In some preferred embodiments of the compounds of formula (3), Het represents a purine that is linked to L at position 6. In other preferred embodiments, when -L-Het is —CH2-Het, —CHMe-Het, or —CHEt-Het, Het is purine that is linked to L at position 9 of the purine. When Het is a purine ring, it is sometimes substituted by amino, fluoro, methyl or CF3; and sometimes it is unsubstituted. In other preferred embodiments, Het is a pyrazolopyrimidine and is linked to L at a position that corresponds to position 6 or position 9 of the purine ring, when the pyrimidine rings of the pyrazolopyrimidine and purine are overlaid for purposes of labeling the ring positions.
Compounds of formula (3) having any combination of the preferred features described above are sometimes particularly preferred.
In specific embodiments, the PI3K inhibitor may be a compound having formula (3a) or (3b) or (3c) or a pharmaceutically acceptable salt or solvate thereof:
wherein:
each J and each Y is independently selected from the group consisting of F, Cl, Br, CN, Me, CF3, OMe, CONR22, COOR2, NMe2, NH2, NHMe, -Q-(CH2)q—OR2, and -Q-(CH2)q—N(R2)2, where q is 0-4, and Q is absent or is selected from O, S and NR2;
m is 0-2, and k is 0-3;
L is selected from —C(R2)2—C(R2)2—NR2—, and —C(R2)2—S—,
each R2 is independently H or an optionally substituted C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, or an optionally substituted C2-C4 heteroalkyl;
and two R2, if present on a single atom or on adjacent atoms, can cyclize to form a 3-7 membered ring that is optionally substituted and may contain up to two heteroatoms selected from N, O and S as ring members;
Het is selected from the group consisting of:
wherein [L] indicates the atom of Het to which L is attached; and
each X is independently H, F, Cl, Br, Me, CF3, OH, OMe, NH2, NHAc, or NHMe;
and the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, OOCR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S;
and p is 0-2;
or a pharmaceutically acceptable salt thereof.
The compounds of formula (3), which includes formula (3a) and formula (3b) and formula (3c), are preferred compounds within the scope of the invention. Particularly preferred are compounds of any one of these formulas that are selective inhibitors of PI3Kβ and/or PI3Kδ. In these compounds, m is frequently 0 or 1, and J, if present, is frequently F, Cl or CF3. Each Y is independently selected, and at least one Y often represents Me, OMe, CN, CF3, or halo. In certain embodiments, Y is F, Me or CN. Each X for the Het group in formula (3) is independently selected, and frequently each X is H, F, Cl, Me, CF3, phenyl, or NH2.
In some preferred embodiments of the compound of formula (3), the phenyl ring shown is an selected from unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, and 2,6-difluorophenyl.
In some preferred embodiments of the compounds of formula (3), -L-Het represents —CH2-Het, —CH2—NH-Het, —CH2—S-Het, —CHMe-Het, —CHMe-S-Het, —CHMe-NH-Het, —CHEt-Het, —CHEt-S-Het, or —CHEt-NH-Het.
In some preferred embodiments of the compounds of formula (3), Het represents a purine that is linked to L at position 6. In other preferred embodiments, when -L-Het is —CH2-Het, —CHMe-Het, or —CHEt-Het, Het is purine that is linked to L at position 9 of the purine. When Het is a purine ring, it is sometimes unsubstituted, and it is sometimes substituted by amino, fluoro, aryl, methyl or CF3; and sometimes it is unsubstituted. In other preferred embodiments, Het is a pyrazolopyrimidine and is linked to L at a position that corresponds to position 6 or position 9 of the purine ring, when the pyrimidine rings of the pyrazolopyrimidine and purine are overlaid for purposes of labeling the ring positions.
In certain embodiments, the compounds and methods include PI3Kβ or PI3Kδ selective inhibitors of formula (3) containing an amine-substituted alkyl or heteroalkyl group that improves solubility properties, such as by providing for formation of salts. This amine-substituted alkyl or heteroalkyl group may be attached to any of part of these compounds, including Het or the linker “L” in formula (3), or it may be on Z or R3 in formula (3). The amine-substituted groups provide improved solubility characteristics for these compounds, and thus improve their pharmacokinetic properties without adversely affecting their selectivity for the delta isoform of PI3K. Suitable amine-substituted groups that may be present as substituents on the compounds of the invention include —(CH2)p—NR′2 and —O—(CH2)p—NR′2, wherein p is 1-4 and each R′ is H or C1-C4 alkyl (frequently Me), and wherein two R′ present on one N may cyclize to form a 3-8 membered ring, which can optionally include an additional heteroatom such as N, O or S.
The compounds of formula (3) are readily prepared from available starting material using methods that are known in the art. Examples of methods for constructing the thienopyrimidinone portion of the compounds of formula (1) and (2) are provided, for example, in published PCT application WO 03/050064. Scheme A in that application provides a route by which the thienopyrimidinone portions of compounds of formula (2a) can be prepared, and Schemes B-G provide routes by which the thienopyrimidinone portions of compounds of formula (2b) can be prepared. Compounds of formula (2c) can similarly be prepared from the available starting material corresponding to the appropriate thiophene isomer of compound B1. Methods to convert the protected amines attached to position 2 of the pyrimidinone ring of these thienopyrimidinone intermediates are known in the art, and can be found, for example, in U.S. Pat. Nos. 6,518,277; 6,667,300; 6,949,535; and 6,800,620, and in published U.S. Patent Application US 2006/0106038 and PCT application WO 2005/113554. Additional methods for synthesis of the compounds of formula (3) are disclosed in unpublished U.S. Patent Application Ser. No. 60/858,850, filed Nov. 13, 2006. These references also provide methods for determining the activity of these compounds as inhibitors of PI3Kδ; thus those methods are known in the art.
Certain of these compounds are highly active, and also highly selective for inhibition of PI3Kδ relative to their activity on other PI3K isoforms, as illustrated in the following table, where two compounds of formula (3) are compared to other PI3K inhibitors (reference compounds 4a and 4b) having similar purine and linking components:
TABLE 1
Activity and Selectivity of Selected PI3K Inhibitors
Ref.
Ki (nM)
Selectivity
Selectivity
Selectivity
No.
COMPOUND
(PI3Kδ)
(α/δ)
(β/δ)
(γ/δ)
3d
40
1447
126
187
4a
7
2963
119
61
3e
6
528
123
28
4b
5
132
29
12
Compounds of the invention can be depicted in different tautomeric forms, and can include multiple isomers in some cases. The invention includes each tautomeric form that is generally considered stable by those skilled in the art. In particular, the purine rings of compounds of the invention can exist in different tautomeric forms, and each is included even though at times only one is depicted for convenience. It includes each individual isomer of each compound, except where a particular isomer is depicted in a way that excludes other isomers. For example, where compound (2d) is shown as a single isomer, it is intended to describe a material consisting primarily of that isomer and containing only minor amounts of the opposite enantiomer, such as less than 20% or less than 10%; preferably, a specifically depicted isomer contains less than 5% of the enantiomeric isomer.
Some of the compounds of the invention can exist as separable rotational isomers, or atropisomers, and the invention includes use of each of these isomers. However, in some instances one of the atropisomers is preferred, or a single atropisomer is preferred over a mixture of such isomers. For example, where compound (2c′) is shown as a single isomer, it is intended to describe a material consisting primarily of that isomer and containing only minor amounts of the opposite atropisomer, such as less than 20% or less than 10%; preferably, a specifically depicted atropisomer contains less than 5% of the enantiomeric atropisomer. Atropisomers in this type of compound have been found to exhibit surprising differences in pharmacokinetic behavior, resulting in substantially different biological activities such as differential absorption rates, and different metabolic rates. Thus even when two atropisomers provide similar direct effects on the pathway in cellular assays, they can provide quite different PK profiles as demonstrated by different AUC and t1/2 values.
The invention further includes mixtures of isomers, including racemic mixtures and mixtures enriched in any particular isomer. In some embodiments, one isomer is preferred as indicated herein; however, as is well known, the other isomer may be present in addition to the preferred isomer without departing from the scope of the invention. Where the linking group between the quinazolinone ring and a purine heterocycle contains a chiral carbon, the S isomer of that chiral center is sometimes preferred.
The compounds of the invention can often be obtained and used as salts. In some embodiments, salts of the compounds of the invention are used in methods of treating liver disorders; in such embodiments, the salts are often pharmaceutically acceptable salts. ‘Pharmaceutically acceptable’ salts are well known in the art, and include acid addition salts and base addition salts that comprise a counterion that is not significantly detrimental when administered along with a compound of the invention to a subject in need of treatment.
“Pharmaceutically acceptable salts” refer to any salt that is physiologically acceptable insofar as it is compatible with other ingredients of the formulation and not deleterious to the recipient thereof. Some specific preferred examples are: acetate, trifluoroacetate, hydrochloride, methanesulfonate, succinate, malonate, maleate, hydrobromide, sulfate, citrate, tartrate, glycolate, and oxalate salts, which may be formed when the compound includes a basic (protonatable) feature. Similarly, the pharmaceutically acceptable salts include base addition products when the compound of the invention includes an acidic (de-protonatable) feature. Non-limiting examples of counterions for the deprotonated compounds of the invention include sodium, magnesium, calcium, ammonium, potassium, lithium, zinc, and similar cations.
As previously described, the term “PI3Kδ selective inhibitor” or “PI3Kβ selective inhibitor” generally refers to a compound that inhibits the activity of the PI3Kδ or β isozyme more effectively than other isozymes of the PI3K family. The relative efficacies of compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or “IC50”. IC50 determinations can be accomplished using conventional techniques known in the art. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC50 value. Analogously, other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it can be desirable to establish a 90% inhibitory concentration, i.e., IC90, etc.
Accordingly, a PI3Kδ selective inhibitor alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to PI3Kδ that is at least 10-fold, in another aspect at least 20-fold, and in another aspect at least 30-fold, lower than the IC50 value with respect to any or all of the other Class I PI3K family members. In an alternative embodiment of the invention, the term PI3Kδ selective inhibitor can be understood to refer to a compound that exhibits an IC50 with respect to PI3Kδ that is at least 50-fold, in another aspect at least 100-fold, in an additional aspect at least 200-fold, and in yet another aspect at least 500-fold, lower than the IC50 with respect to any or all of the other PI3K Class I family members. A PI3Kδ selective inhibitor is typically administered in an amount such that it selectively inhibits PI3Kδ activity in vivo, as described above.
PI3Kβ selective inhibitors are similarly defined, where the above descriptions relate to PI3Kβ instead of PI3Kδ.
PI3Kγ selective inhibitors are similarly defined, where the above descriptions relate to PI3Kγ instead of PI3Kδ.
In some embodiments, the methods of the invention employ more than one compound of the invention to achieve a target level of selectivity among the isoforms of PI3K. Thus the invention includes methods using two compounds selected from the compounds disclosed herein to treat a liver disorder. The two compounds are typically selective for different isoforms of PI3K, and may be administered together, as individual compositions or combined in a single composition; or they may be administered separately, including administration on different schedules and/or by different routes of administration.
In some embodiments, the compound is selected from the compounds in Table 1 above.
In some embodiments, the methods utilize a compound selected from the following group:
The subject for the treatments disclosed herein is a mammal, such as a human, afflicted with a liver disorder such as nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis, liver adenoma, insulin hypersensitivity, or a liver cancer such as hepatocellular carcinoma. In some embodiments, the subject is one diagnosed with NAFLD or NASH, or a subject diagnosed with cirrhosis not associated with alcohol consumption. Alternatively, the subject may be at risk of NAFLD or NASH, and the methods of the invention may be used to prevent or delay development of NAFLD or NASH.
In some embodiments, the subject's Pten level is determined, and the subject is identified as a suitable subject for treatment by the present methods if the subject's Pten level is lower than normal for the subject's population, considering age and gender. In one embodiment, the subject is suitable for treatment by the present methods if the subject's Pten level is about half, or less than half, of the level that would be normal for the subject based on the subject's gender and age.
In some embodiments, a subject's lipid levels are determined in order to determine whether the subject is an especially good candidate for treatment with the compounds of the invention. In one embodiment, the subject's liver triglyceride level (in mg/g) is compared to the subject's serum triglyceride level (in mg/dl), and the subject is considered particularly suitable for treatment with a PI3K inhibitor if the subject's liver triglyceride level is higher than the subject's serum triglyceride level.
The compounds of the invention are readily prepared from available starting material using methods that are known in the art. Examples of methods for synthesizing the compounds useful in the methods of the invention are provided in U.S. Pat. Nos. 6,518,277; 6,667,300; 6,949,535; and 6,800,620, and in published U.S. Patent Application US 2006/0106038 and PCT application WO 2005/113554. These references also provide methods for determining the activity of these compounds as selective inhibitors of PI3Kδ or PI3Kβ, etc. Thus methods for making and selecting a selective inhibitor for use in the methods described herein are known.
The inhibitors of the invention may be covalently or noncovalently associated with a carrier molecule including but not limited to a linear polymer (e.g., polyethylene glycol, polylysine, dextran, etc.), a branched-chain polymer (see U.S. Pat. Nos. 4,289,872 and 5,229,490; PCT Publication No. WO 93/21259), a lipid, a cholesterol group (such as a steroid), or a carbohydrate or oligosaccharide. Specific examples of carriers for use in the pharmaceutical compositions of the invention include carbohydrate-based polymers such as trehalose, mannitol, xylitol, sucrose, lactose, sorbitol, dextrans such as cyclodextran, cellulose, and cellulose derivatives. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
Other carriers include one or more water soluble polymer attachments such as polyoxyethylene glycol, or polypropylene glycol as described U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. Still other useful carrier polymers known in the art include monomethoxy-polyethylene glycol, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of these polymers.
Methods include administration of an inhibitor to an individual in need, by itself, or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, excipients, buffers, stabilizers, solubilizers, other materials well known in the art and combinations thereof.
Any pharmaceutically acceptable (i.e., sterile and non-toxic) liquid, semisolid, or solid diluents that serve as pharmaceutical vehicles, excipients, or media may be used. Exemplary diluents include, but are not limited to, polyoxyethylene sorbitan monolaurate, magnesium stearate, calcium phosphate, mineral oil, cocoa butter, and oil of theobroma, methyl- and propylhydroxybenzoate, talc, alginates, carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, dextrose, sorbitol, modified dextrans, gum acacia, and starch. Some commercially available diluents are Fast-Flo®, Emdex®, STA-Rx 1500®, Emcompress® and Avicel®. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the PI3Kδ inhibitor compounds (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. pp. 1435-1712 (1990), which is incorporated herein by reference).
Pharmaceutically acceptable fillers can include, for example, lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, calcium sulfate, dextrose, mannitol, and/or sucrose.
Inorganic salts including calcium triphosphate, magnesium carbonate, and sodium chloride may also be used as fillers in the pharmaceutical compositions Amino acids may be used such as use in a buffer formulation of the pharmaceutical compositions.
Disintegrants may be included in solid dosage formulations of the inhibitors. Materials used as disintegrants include but are not limited to starch including the commercial disintegrant based on starch, Explotab®. Sodium starch glycolate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, natural sponge and bentonite may all be used as disintegrants in the pharmaceutical compositions. Other disintegrants include insoluble cationic exchange resins. Powdered gums including powdered gums such as agar, karaya or tragacanth may be used as disintegrants and as binders. Alginic acid and its sodium salt are also useful as disintegrants.
Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) can both be used in alcoholic solutions to facilitate granulation of the therapeutic ingredient.
An antifrictional agent may be included in the formulation of the therapeutic ingredient to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic ingredient and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax® 4000 and 6000.
Glidants that might improve the flow properties of the therapeutic ingredient during formulation and to aid rearrangement during compression might be added. Suitable glidants include starch, talc, pyrogenic silica and hydrated silicoaluminate.
To aid dissolution of the therapeutic into the aqueous environment, a surfactant might be added as a wetting agent. Natural or synthetic surfactants may be used. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents such as benzalkonium chloride and benzethonium chloride may be used. Nonionic detergents that can be used in the pharmaceutical formulations include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants can be present in the pharmaceutical compositions of the invention either alone or as a mixture in different ratios.
Controlled release formulation may be desirable. The inhibitors of the invention can be incorporated into an inert matrix which permits release by either diffusion or leaching mechanisms, e.g., gums. Slowly degenerating matrices may also be incorporated into the pharmaceutical formulations, e.g., alginates, polysaccharides. Another form of controlled release is a method based on the Oros® therapeutic system (Alza Corp.), i.e., the drug is enclosed in a semipermeable membrane which allows water to enter and push the inhibitor compound out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect.
Colorants and flavoring agents may also be included in the pharmaceutical compositions. For example, the inhibitors of the invention may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a beverage containing colorants and flavoring agents.
The therapeutic agent can also be given in a film coated tablet. Non-enteric materials for use in coating the pharmaceutical compositions include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy-ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, sodium carboxy-methyl cellulose, povidone and polyethylene glycols. Enteric materials for use in coating the pharmaceutical compositions include esters of phthalic acid. A mix of materials might be used to provide the optimum film coating. Film coating manufacturing may be carried out in a pan coater, in a fluidized bed, or by compression coating.
The compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder, such as lyophilized form. The pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, lozenges or other forms known in the art. The type of packaging will generally depend on the desired route of administration. Implantable sustained release formulations are also contemplated, as are transdermal formulations.
In the methods according to the invention, the inhibitor compounds may be administered by various routes. For example, pharmaceutical compositions may be for injection, or for oral, nasal, transdermal or other forms of administration, including, e.g., by intravenous, intradermal, intramuscular, intramammary, intraperitoneal, intrathecal, intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) or subcutaneous injection (including depot administration for long term release, e.g., embedded under the splenic capsule, brain, or in the cornea); by sublingual, anal, vaginal, or by surgical implantation, e.g., embedded under the splenic capsule, brain, or in the cornea. The treatment may consist of a single dose or a plurality of doses over a period of time. In general, the methods of the invention involve administering effective amounts of an inhibitor of the invention together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers, as described above.
In one aspect, the invention provides methods for oral administration of a pharmaceutical composition of the invention. Oral solid dosage forms are described generally in Remington's Pharmaceutical Sciences, supra at chapter 89. Solid dosage forms include tablets, capsules, pills, troches or lozenges, and cachets or pellets. Also, liposomal or proteinoid encapsulation may be used to formulate the compositions (as, for example, proteinoid microspheres reported in U.S. Pat. No. 4,925,673). Liposomal encapsulation may include liposomes that are derivatized with various polymers (e.g., U.S. Pat. No. 5,013,556). In general, the formulation will include a compound of the invention and inert ingredients which protect against degradation in the stomach and which permit release of the biologically active material in the intestine.
The inhibitors can be included in the formulation as fine multiparticulates in the form of granules or pellets of particle size about 1 mm The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The capsules could be prepared by compression.
Also contemplated herein is pulmonary delivery of the PI3K inhibitors in accordance with the invention. According to this aspect of the invention, the inhibitor is delivered to the lungs of a mammal by inhalation of a suitable composition, and the PI3K inhibitor traverses across the lung epithelial lining to the blood stream.
Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices suitable for the practice of this invention are the UltraVent™ nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II® nebulizer, manufactured by Marquest Medical Products, Englewood, Colorado; the Ventolin® metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler® powder inhaler, manufactured by Fisons Corp., Bedford, Mass.
All such devices require the use of formulations suitable for the dispensing of the inventive compound. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to diluents, adjuvants and/or carriers useful in therapy.
In practice of the methods of the invention, the pharmaceutical compositions are generally provided in doses ranging from 1 pg compound/kg body weight to 1000 mg/kg, 0.01 mg/kg to 100 mg/kg, 0.1 mg/kg to 20 mg/kg, given in daily doses or in equivalent doses at longer or shorter intervals, e.g., every other day, twice weekly, weekly, or twice or three times daily. The inhibitor compositions may be administered by an initial bolus followed by a continuous infusion to maintain therapeutic circulating levels of drug product. Those of ordinary skill in the art will readily optimize effective dosages and administration regimens as determined by good medical practice and the clinical condition of the individual to be treated. The frequency of dosing will depend on the pharmacokinetic parameters of the agents and the route of administration.
The optimal pharmaceutical formulation will be determined by one skilled in the art depending upon the route of administration and desired dosage (see, for example, Remington's Pharmaceutical Sciences, latest ed., the disclosure of which is hereby incorporated by reference). Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface area or organ size. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages may be ascertained by using established assays for determining blood level dosages in conjunction with an appropriate physician considering various factors which modify the action of drugs, e.g., the drug's specific activity, the severity of the indication, and the responsiveness of the individual, the age, condition, body weight, sex and diet of the individual, the time of administration and other clinical factors. As studies are conducted, further information will emerge regarding the appropriate dosage levels and duration of treatment for various indications involving aberrant proliferation of hematopoietic cells.
The following enumerated items are additional embodiments of the invention:
1. In one embodiment, the invention provides a method to treat a liver disorder, which method comprises administering to a subject in need thereof an effective amount of a selective inhibitor of at least one isoform of PI3K kinase.
2. The method of embodiment 1, wherein the inhibitor is selective for inhibition of PI3Kδ or PI3Kβ or both, relative to its inhibition of other Class I PI3K isoforms.
3. The method of embodiment 1 or 2, wherein the disorder is nonalcoholic steatohepatatis.
4. The method of embodiment 1 or 2, wherein the liver disorder is nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, cirrhosis, hepatitis, a liver adenoma, insulin hypersensitivity, or a liver cancer.
5. The method of any of embodiments 1-4, wherein the inhibitor is a compound of formula (1a) or formula (1b):
wherein:
W is selected from the group consisting of H, Me, Cl, and F;
X and X′ are independently selected from the group consisting of H, Me, Cl, and F;
Y is selected from the group consisting of H, Me and Et;
Z is NH or a bond; and A is NH2, or A is absent and indicates the point of attachment of Z to the purine ring;
Q is H when A is absent, or Q is absent and indicates the point of attachment of Z to the purine ring when A is NH2;
provided that not more than two of W, X, and Y represents H;
or a pharmaceutically acceptable salt thereof.
6. The method of embodiment 5, wherein not more than one of W, X, and Y represents H.
7. The method of any of embodiments 5-6, wherein W is Me.
8. The method of any of embodiments 5-7, wherein X is H, Me or F.
9. The method of any of embodiments 5-8, wherein Z is NH.
10. The method of any of embodiments 5-8, wherein Z is a bond.
11. The method of embodiment 9 or 10, wherein A is absent and Q is H.
12. The method of embodiment 9 or 10, wherein A is NH2 and Q indicates the point of attachment of Z to the purine ring.
13. The method of any of embodiments 5-12, wherein at least one of W, X and Y is Me.
14. The method of any of embodiments 5-13, wherein Y is H.
15. The method of any of embodiments 5-13, wherein Y is Me.
16. The method of any of embodiments 5-13, wherein Y is Et.
17. The method of any one of embodiments 5-16, wherein the compound is a compound of formula (1b), and wherein X and X′ are different.
18. The method of embodiment 17, wherein X′ is H, and X is selected from Cl and Me.
19. The method of any one of embodiments 1-4, wherein the inhibitor is a compound of formula (3):
wherein:
one of Q1, Q2 and Q3 is S, and the other of two of Q1, Q2 and Q3 are —CR1—;
wherein each R1 is independently H, halo, OR, NR2, NROR, NRNR2, SR, SOR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRCOOR, NRCOR, CF3, CN, COOR, CONR2, OOCR, COR, or NO2,
or R1 can be an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl groups,
wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl,
and wherein two R on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two N, O or S as ring members;
and wherein each R group other than H, and each ring formed by linking two R groups together, is optionally substituted;
Z is a bond, or is O, NR2, C1-C6 alkylene or C1-C6 heteroalkylene, each of which is optionally substituted with up to two C1-C6 alkyl or C2-C6 heteroalkyl groups, where two of said alkyl or heteroalkyl groups can optionally cyclize to form a 3-7 membered ring containing up to two heteroatoms selected from O, N and S as ring members;
R3 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with up to three R1,
or R3 can be H if Z is not a bond;
L is selected from the group consisting of —C(R2)2—, —C(R2)2—C(R2)2—, —C(R2)2—NR2—, and —C(R2)2—S(O)n—,
wherein each R2 is independently H or an optionally substituted member selected from C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, and n is 0-2;
and two R2, if present on L, can cyclize to form a 3-7 membered ring that may contain up to two heteroatoms selected from N, O and S as ring members;
Het is a monocyclic or bicyclic ring system wherein at least two ring atoms are N and wherein at least one ring is aromatic, and Het is optionally substituted with up to three substituents selected from R4, N(R4)2, S(O)pR4, OR4, halo, CF3, CN, NR4OR4, NR4N(R4)2, SR4, SOR4, SO2R4, SO2N(R4)2, NR4SO2R4, NR4CON(R4)2, NR4COOR4, NR4COR4, CN, COOR4, CON(R4)2, OOCR4, COR4, or NO2,
wherein each R4 is independently H or an optionally substituted member selected from the group consisting of C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-C12 arylalkyl, and C6-C12 heteroarylalkyl,
and wherein two R4 on the same atom or on adjacent atoms can be linked to form a 3-8 membered ring, optionally containing one or two heteroatoms selected from N, O and S;
wherein the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, CF3, CN, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, OOCR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; and
p is 0-2;
or a pharmaceutically acceptable salt thereof.
20. The method of embodiment 19, wherein the inhibitor is a compound of formula (3a), (3b), or (3c):
wherein:
each J and each Y is independently selected from the group consisting of F, Cl, Br, CN, Me, CF3, OMe, CONR22, COOR2, NMe2, NH2, NHMe, -Q-(CH2)q—OR2, and -Q-(CH2)q-N(R2)2, where q is 0-4, and Q is absent or is selected from O, S and NR2;
m is 0-2, and k is 0-3;
L is selected from —C(R2)2—, —C(R2)2—NR2—, and —C(R2)2—S—,
each R2 is independently H or an optionally substituted C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, or an optionally substituted C2-C4 heteroalkyl;
and two R2, if present on a single atom or on adjacent atoms, can cyclize to form a 3-7 membered ring that is optionally substituted and may contain up to two heteroatoms selected from N, O and S as ring members;
Het is selected from the group consisting of:
wherein [L] indicates the atom of Het to which L is attached; and
each X is independently H, F, Cl, Br, Me, CF3, OH, OMe, NH2, NHAc, or NHMe;
and the optional substituents on each optionally substituted alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, heteroacyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are selected from C1-C4 alkyl, halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′2, SR′, SO2R′, SO2NR′2, NR′SO2R′, NR′CONR′2, NR′COOR′, NR′COR′, CN, COOR′, CONR′2, OOCR′, COR′, and NO2,
wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12 arylalkyl, or C6-12 heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O;
and wherein two R′ on the same or adjacent atoms can be linked to form a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S;
and p is 0-2;
or a pharmaceutically acceptable salt thereof.
21. The method of embodiment 4, wherein the compound is selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
22. The method of any of the preceding embodiments, wherein the subject is one having a reduced levels of hepatic Pten activity.
23. The method of embodiment 22, wherein the subject has a Pten mutation.
The following examples are offered to illustrate but not to limit the invention.
EXAMPLE 1
Preparation of 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one
2-amino-6-methylbenzoic acid is reacted with 2-chloroacetyl chloride to produce the 2-(-2-chloroacetamido)-6-methylbenzoic acid. Reaction with o-toluidine and phosphoryl trichloride yields the cyclized intermediate. Further reaction with diBOC-protected adenine give the BOC protected product, which is deprotected resulting in 2-((6-amino-9H-purin-9-yl) methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one (2c).
The atropisomers of compound (2c) may be resolved by high-pressure liquid chromatography (HPLC).
EXAMPLE 2
Preparatory HPLC Separation of Atropisomers
This example demonstrates the separation of the two atropisomers of compound (2c) using HPLC.
A small sample of the enantiomeric mixture was dissolved in isopropanol at a concentration of 1.45 mg/mL and 5 μL injected into a normal phase column using the following conditions: CHIRALPAK® IA, 4.6 mm ID×250 mm L, 40/60/0.1 hexanes/IPA/DEA, 0.8 mL/min, 30° C. Two peaks are resolved at 8.7 min. and 13.0 min These analytical conditions and HPLC trace were used to identify the compositions of the separated products.
2.80 g of compound (2c) was separated on a CHIRALPAK® IA preparative column using 40/60/0.1 hexanes/IPA/DEA mobile phase at room temperature and using a detection wavelength of 275 nm. Two enantiomers were isolated, (2c′) and (2c″), and were cleanly separated from each other. It was not immediately determined which peak corresponded to which atropisomer.
1.24 g of the first eluted enantiomer, atropisomer was isolated, and was analyzed under the analytical method described above (0.96 mg in 0.8 mL IPA). The HPLC trace has a major peak at 8.7 min and indicates 99.0% e.e.
1.38 g of the second eluted enantiomer, atropisomer was isolated, and was analyzed under the same analytical method (1.72 mg in 1 mL IPA) described above. The HPLC trace has a major peak at 13.0 min and indicates 98.8% e.e.
For purposes of discussion, resolved atropisomers of compound (2c) that were isolated by normal phase chromatographic separation and eluted at time 8.7 min and 13.0 min as described in this example, will be referred to as atropisomers (2c′) and (2c″).
EXAMPLE 3
Treatment of NASH in Pten Knock-out Mice
Sato, et al. describe production of Pten KO mice that are a suitable model for certain NASH patient populations, and exhibit all stages of NASH (inflammation; fibrosis' and carcinogenesis), beginning by about 10 weeks of age. Compounds of the invention can therefore be shown to be effective for treating NASH by their efficacy in delaying progression of symptomology in such Pten KO mice.
Pten KO mice as described by Sato, et al. (Hepatology Res., vol 34, 256-65 (2006)) are produced as described, and are treated with a compound described herein beginning at 6 weeks of age. The compound can be administered orally or by injection, at an initial dosage of 100 mg/kg/day. Progression of NASH is measured as described in Sato, and is compared to progression in untreated (control) Pten KO mice. Dosage can be adjusted up or down in the treated mice at 10 weeks of age, depending upon the effectiveness of the initial dosage. The mice are assessed weekly until 35 weeks of age; dosage is adjusted as needed based on biopsy analyses of the livers of treated mice in comparison to controls. Statistically significant reduction of the progression of NASH in these mice demonstrates usefulness for treating NASH.
EXAMPLE 4
Cell Culture Testing of Compounds
Sato et al. (Id.) also describes isolation of hepatocytes from Pten KO mice. The compounds of the invention can be tested in cultured hepatocytes to demonstrate their effectiveness for slowing progression of cellular abnormalities associated with NASH.
EXAMPLE 5
In Vivo Model for NASH Treatment
Horie, et al. (J. Clinical Investigation, vol. 112(12), 1774-1783 (2004)) describes generation of AlbCrePtetflox/flox mice, which were shown to be highly prone to hepatomegaly and steatohepatitis. These mice can be used to demonstrate the effectiveness of compounds of the invention for treating these NASH-like conditions.
The AlbCrePtenflox/flox mice as described by Horie, et al., are treated with a compound described herein beginning at 6 weeks of age. The compound can be administered orally or by injection, at an initial dosage of 100 mg/kg/day. Progression of NASH-like symptoms is measured, and is compared to progression in untreated (control) mice. Dosage can be adjusted up or down in the treated mice at 10 weeks of age, depending upon the effectiveness of the initial dosage. The mice are assessed weekly until 35 weeks of age; dosage is adjusted as needed based on biopsy analyses of the livers of treated mice in comparison to controls. Statistically significant reduction of the progression of hepatomegaly and/or steatohepatitis in these mice demonstrates usefulness for treating NASH.
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13386387
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/260.1
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Oct 21st, 2014 12:00AM
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Mar 5th, 2013 12:00AM
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https://www.uspto.gov?id=US08865730-20141021
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Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
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Polymorphs of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are disclosed.
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8865730
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1. A polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern comprising characteristic peaks plus or minus 0.2 degrees 2θ, at 17.7 degrees 2θ and 24.9 degrees 2θ.
2. The polymorph of claim 1, wherein the X-ray powder diffraction pattern further comprises characteristic peaks plus or minus 0.2 degrees 2θ, at 14.3 degrees 2θ, 17.2 degrees 2θ, 20.9 degrees 2θ, and 23.9 degrees 2θ.
3. The polymorph of claim 1, wherein the polymorph has an X-ray powder diffraction pattern substantially as shown in FIG. 1A.
4. A polymorph of claim 1 obtained by:
a) combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form a mixture;
b) heating the mixture to form a solution; and
c) cooling the heated solution to form the polymorph of claim 1.
5. The polymorph of claim 4, wherein:
the mixture is heated to a temperature of at least 50° C.; and
the heated solution is cooled to a temperature of at least about 30° C.
6. A pharmaceutical composition comprising the polymorph of claim 1, and one or more pharmaceutically acceptable carriers or excipients.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a tablet.
8. A method of preparing the polymorph of claim 1, comprising:
a) combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form a mixture;
b) heating the mixture to form a solution; and
c) cooling the heated solution to form the polymorph of claim 1.
9. The method of claim 8, wherein:
the mixture is heated to a temperature of at least about 50° C.; and
the solution is cooled to a temperature of at least about 30° C.
10. A method of treating a human in need of a cancer treatment, comprising administering to the human a composition comprising the polymorph of claim 1, and one or more pharmaceutically acceptable carriers or excipients wherein the cancer is a hematologic malignancy.
11. A method of treating a human in need of a cancer treatment, comprising administering to the human a composition comprising the polymorph of claim 1, and one or more pharmaceutically acceptable carriers or excipients, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).
12. The method of claim 11, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL.
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12
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional patent application Ser. No. 61/606,870, filed Mar. 5, 2012, the disclosure of which is hereby incorporated herein by reference in its entirety.
FIELD
Provided are polymorphs of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use.
BACKGROUND
Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. See Rameh et al., J. Biol. Chem., 274:8347-8350 (1999) for a review. The enzyme responsible for generating these phosphorylated signaling products is phosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally was identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring. See Panayotou et al., Trends Cell Biol. 2:358-60 (1992).
PI 3-kinase activation is believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis. See Parker et al., Curr. Biol., 5:577-99 (1995); Yao et al., Science, 267:2003-05 (1995). PI 3-kinase also appears to be involved in a number of aspects of leukocyte activation. See e.g., Pages et al., Nature, 369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996); Fraser et al., Science, 251:313-16 (1991).
Several compounds have been identified as PI 3-kinase inhibitors. For example, compounds capable of inhibiting the biological activity of human PI3K, including (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and their uses are disclosed in U.S. Pat. No. 6,518,277, U.S. Pat. No. 6,667,300, and U.S. Pat. No. 7,932,260. Each of these references is hereby incorporated herein by reference in its entirety.
BRIEF SUMMARY
(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, has been chosen for further development. Consequently, it is desired to produce this compound in a form that is bioavailable and stable. In one aspect, provided herein are polymorphs of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, a compound having the molecular structure:
Specifically, polymorphic Forms I, II, III, IV, V, VI and VII of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and methods of making and using these polymorphic forms are provided. Also provided are polymorphic products obtained by the processes (e.g. methods of making). Pharmaceutical compositions comprising one or more polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (any one or more of polymorphic Forms I, II, III, IV, V, VI and VII) and a pharmaceutically acceptable carrier are provided. Articles of manufacture and unit dosage forms comprising any one of more of the polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., any one of more of polymorphic Forms I, II, III, IV, V, VI and VII) are provided. Kits comprising any one of more of the polymorphic forms (e.g., polymorphic Forms I, II, III, IV, V, VI and VII of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one), and instructions for use (e.g., instructions for use in PI3K-mediated disorder, such as cancer) are also provided.
These polymorphs are characterized by a variety of solid state analytical data, including for example X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern substantially as shown in FIG. 1A.
Provided is also a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern that includes characteristic peaks at about 17.7 degrees 2θ and about 24.9 degrees 2θ. In some embodiments, the X-ray powder diffraction pattern further includes any one or more of characteristic peaks at about 14.3 degrees 2θ, about 17.2 degrees 2θ, about 20.9 degrees 2θ, and about 23.9 degrees 2θ. In some embodiments, the polymorphic Form I has a melting temperature of about 254° C. to about 256° C. In one variation, polymorphic Form I has an X-ray powder diffraction pattern that includes any one or more characteristic peaks at about 14.3 degrees 2θ, about 17.2 degrees 2θ, about 17.7 degrees 2θ, about 20.9 degrees 2θ, about 23.9 degrees 2θ, and about 24.9 degrees 2θ; and a melting temperature of about 254° C. to about 256° C.
It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein (including for polymorphic Form I) are intended to encompass variations of plus or minus 0.2 degrees 2θ.
In some embodiments, the polymorphic Form I described herein is obtained by: a) combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form a mixture; b) heating the mixture to form a solution; and c) cooling the heated solution to form the polymorphic Form I. In certain embodiments, the heated solution is cooled to a temperature of at least about 30° C. In other embodiments, the heated solution is cooled to a temperature of at least about 35° C., or between about 30° C. and about 40° C., or between about 30° C. and about 35° C., or between about 35° C. and about 40° C. In some embodiments, polymorphic Form I is further obtained by isolating the solids, such as polymorphic Form I solids, from the cooled solution. In yet other embodiments, polymorphic Form I is further obtained by washing the isolated solids; and drying the washed isolated solids. In some embodiments, the solvent used to obtain polymorphic Form I includes water, an organic solvent, or a mixture thereof. In certain embodiments, the solvent includes water, an alcohol (e.g., methanol, ethanol), or a mixture thereof. In some embodiments, the solvent includes a mixture of alcohol and water in a ratio between 2 to 1 and 10 to 1, or between 4 to 1 and 5 to 1. In certain embodiment, the solvent includes a mixture of alcohol and water in a ratio of 2 to 1, or 2.5 to 1, or 3 to 1, or 3.5 to 1, or 4 to 1, or 4.5 to 1, or 5 to 1. In certain embodiments, the solvent includes a mixture of methanol and water in a ratio between 2 to 1 and 10 to 1, or between 4 to 1 and 5 to 1. In one embodiment, the solvent includes a mixture of methanol and water in a ratio of 2 to 1, or 2.5 to 1, or 3 to 1, or 3.5 to 1, or 4 to 1, or 4.5 to 1, or 5 to 1.
It should be understood, however, one or more of the steps described above to obtain polymorphic Form I may be omitted or the order of the steps may be varied. For example, in other embodiments, polymorphic Form I may be obtained by heating (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prior to combining with a solvent to form a mixture. In yet other embodiments, polymorphic Form I may be obtained by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form a mixture, and cooling the mixture to obtain polymorphic Form I.
In other embodiments, the polymorphic Form I described herein is obtained by: a) combining a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and a solvent to form an acidic mixture or solution; b) neutralizing the acidic mixture or solution, wherein the neutralized mixture or solution includes free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; c) heating the neutralized mixture or solution; and d) adding water to the heated mixture or solution to convert at least a portion of the free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one into polymorphic Form I. Optionally, one or more seed crystals of polymorphic Form I may be added to the neutralized mixture or solution before heating. In certain embodiments, the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In some embodiments, the solvent includes water, an alcohol, or a mixture thereof. In certain embodiments, the solvent includes water, ethanol, or a mixture thereof. In some embodiments, the acidic mixture or solution is neutralized using an aqueous sodium carbonate solution. In other embodiments, the neutralized mixture or solution is heated to a temperature between 40° C. and 60° C., or to a temperature of about 50° C.
It should be understood, however, one or more of the steps described above to obtain polymorphic Form I from the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be omitted or the order of the steps may be varied. For example, in other embodiments, the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be combined with a solvent to form an acidic mixture or solution, and the acidic mixture or solution may be heated before neutralization. In yet other embodiments, the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be combined with a solvent to form an acidic mixture or solution, the acidic mixture or solution may then be neutralized, and water may be added to the neutralized mixture or solution to convert at least a portion of the free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one into polymorphic Form I.
Provided is also a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one which is bioequivalent to the polymorphic Form I described herein.
In some embodiments, the polymorphic Form I described herein is isolated, e.g., from a mixture or solution comprising (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and one or more impurities. In some embodiments, the polymorphic Form I described herein is a substantially pure polymorph.
Provided is also a composition including the polymorphic Form I described herein, wherein the composition is substantially free of polymorphs other than polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of the composition, at least about 95% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form I. In yet other embodiments, at least 96%, at least 97%, at least 98%, or at least 99% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is the polymorphic Form I described herein.
In other embodiments of the composition, less than about 5% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphs other than polymorphic Form I. In yet other embodiments, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphs other than polymorphic Form I.
Provided is also a pharmaceutical composition including polymorphic Form I described herein and one or more pharmaceutically acceptable carriers or excipients.
Provided is also a kit including the polymorphic Form I described herein and packaging. Provided is also a kit including the composition of polymorphic Form I described herein and packaging.
Provided is a method of preparing the polymorphic Form I described herein, by: a) combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form a mixture; b) heating the mixture to form a solution; and c) cooling the heated solution to form the polymorphic Form I described herein. In some embodiments, the solution is cooled to a temperature of at least about 30° C. In other embodiments, the heated solution is cooled to a temperature of at least about 35° C., or between about 30° C. and about 40° C., or between about 30° C. and about 35° C., or between about 35° C. and about 40° C. In some embodiments, the method further includes isolating the solids, such as polymorphic Form I solids. In yet other embodiments, the method further includes: washing the isolated solids; and drying the washed isolated solids. In some embodiments, the solvent includes water, an organic solvent, or a mixture thereof. In certain embodiments, the organic solvent is selected from solvent groups such as the alcohols (e.g., methanol, ethanol, propanol, etc.), acetates (e.g., isopropyl acetate, ethyl acetate, etc.), ethers (e.g., methyl t-butyl ether, 2-methyl tetrahydrofuran, etc.), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone, etc.), other polar aprotics (e.g., dimethylsulfoxide, etc.) and nonpolars (e.g., hexane, heptane, etc.) or a mixture thereof.
It should be understood, however, one or more of the steps of the method to prepare polymorphic Form I may be omitted or the order of the steps may be varied. For example, in other embodiments, the method includes heating (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prior to combining with a solvent to form a mixture. In yet other embodiments, the method includes combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form a mixture, and cooling the mixture to obtain polymorphic Form I.
Provided is also a method of preparing the polymorphic Form I described herein, by: a) combining a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and a solvent to form an acidic mixture or solution; b) neutralizing the acidic mixture or solution, wherein the neutralized mixture or solution includes free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; c) heating the neutralized mixture or solution; and d) adding water to the heated mixture to convert at least a portion of the free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one into polymorphic Form I. Optionally, one or more seed crystals of polymorphic Form I may be added to the neutralized mixture or solution before heating. In some embodiments, the method further includes isolating the polymorphic Form I. In certain embodiments, the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In some embodiments, the solvent includes water, an alcohol, or a mixture thereof. In certain embodiments, the solvent includes water, ethanol, or a mixture thereof. In some embodiments, the acidic mixture or solution is neutralized using an aqueous sodium carbonate solution. In other embodiments, the neutralized mixture or solution is heated to a temperature between 40° C. and 60° C., or about 50° C.
It should be understood, however, one or more of the steps of the method to prepare polymorphic Form I from the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be omitted or the order of the steps may be varied. For example, in other embodiments, the method includes combining the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form an acidic mixture or solution, heating the acidic mixture or solution, neutralizing the heated acidic mixture or solution, and adding water to the heated mixture or solution to convert at least a portion of the free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one into polymorphic Form I. In yet other embodiments, the method includes combining the salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to form an acidic mixture or solution, neutralizing the acidic mixture or solution, and adding water to the neutralized mixture or solution to convert at least a portion of the free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one into polymorphic Form I.
Provided is also a method of treating a patient with a cancer, by administering to the patient a composition comprising the polymorphic Form I described herein and a pharmaceutically acceptable excipient. In some embodiments, the cancer is a hematologic malignancy. In other embodiments, the hematologic malignancy is leukemia, wherein leukemia is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In particular embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The non-Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin's lymphoma (iNHL).
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form II having an X-ray powder diffraction pattern substantially as shown in FIG. 2A.
Provided is also a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form II having an X-ray powder diffraction pattern that includes a characteristic peak at about 18.6 degrees 2θ. In some embodiments, the X-ray powder diffraction pattern further includes characteristic peaks at about 24.3 degrees 2θ and about 14.0 degrees 2θ.
It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein (including for polymorphic Form II described herein) are intended to encompass variations of plus or minus 0.2 degrees 2θ.
In certain embodiments, polymorphic Form II described herein is obtained by: a) providing a polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; b) grinding the polymorphic Form I; and c) stirring the ground polymorphic Form I in a solvent to form the polymorphic Form II described herein. In one variation, polymorphic Form II described herein is obtained by grinding the polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and stirring the ground polymorphic Form I in a solvent to form the polymorphic Form II described herein. In some embodiments, polymorphic Form II is obtained by further heating the ground polymorphic Form I stirred in the solvent to form the polymorphic Form II described herein. In some embodiments, polymorphic Form I is ground to a particle size of between about 1 microns to about 10 microns. In some embodiments, polymorphic Form II is obtained by further isolating the polymorphic Form II. In certain embodiments, the stirred mixture is heated at a temperature of less than about 30° C. In one embodiment, the stirred mixture is heated at a temperature of between about 25° C. and about 30° C. In another embodiment, the ground polymorphic Form I is stirred in the solvent at a temperature of between about 10° C. and about 25° C. In some embodiments, the grinding may be performed using any suitable methods or techniques known to one of skill in the art, including for example using a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mill, a ball mill, or a combination of methods or techniques. In one embodiment, the grinding is performed using a ball mill. In some embodiments, the solvent includes an organic solvent. In one embodiment, the solvent includes acetone.
It should be understood, however, one or more of the steps described above to obtain polymorphic Form II from polymorphic Form I may be omitted or the order of the steps may be varied. For example, in other embodiments, polymorphic Form I may be combined with a solvent before grinding to obtain the polymorphic Form II.
In some embodiments, the polymorphic Form II described herein is obtained by: a) providing a polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and b) compressing the polymorphic Form I at a pressure of between about 500 psi and about 5000 psi to convert at least a portion of the polymorphic Form I to the polymorphic Form II described herein. In one embodiment, the polymorphic Form II described herein is obtained by compressing polymorphic Form I at a pressure of between about 500 psi and about 5000 psi to convert at least a portion of the polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to the polymorphic Form II described herein.
In some embodiments, the compressing is performed using a tablet press or a rotary press. In some embodiments, the polymorphic Form I is compressed at a pressure of between 500 psi and 2000 psi, between 1000 psi and 4500 psi, or between 3000 psi and 4500 psi.
Provided is also a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one which is bioequivalent to the polymorphic Form II described herein.
In some embodiments, the polymorphic Form II described herein is isolated. In some embodiments, the polymorphic Form II described herein is a substantially pure polymorph.
Provided is also composition comprising the polymorphic Form II described herein, wherein the composition is substantially free of polymorphs other than polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments, at least about 95% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form II. In yet other embodiments, at least 96%, at least 97%, at least 98%, or at least 99% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is the polymorphic Form II described herein.
In other embodiments, less than about 5% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphs other than polymorphic Form II. In yet other embodiments, less than about 4%, less than about 3%, less than about 2%, less than about 1% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphs other than polymorphic Form II.
Provided is also a pharmaceutical composition including the polymorphic Form II described herein and one or more pharmaceutically acceptable carriers or excipients.
Provided is also a kit including the polymorphic Form II and packaging. Provided is also a kit including the composition of polymorphic Form II and packaging.
Provided is a method of preparing the polymorphic Form II described herein, by: a) providing a polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; b) grinding the polymorphic Form I; and c) stirring the ground polymorphic Form I in a solvent to form the polymorphic Form II described herein. In one embodiment, provided is a method for preparing the polymorphic Form II described herein, by grinding the polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and stirring the ground polymorphic Form I in a solvent to form the polymorphic Form II described herein. In certain embodiments, the polymorphic Form I is ground to a particle size of between about 1 microns to about 10 microns. In some embodiments, the method further includes heating the ground polymorphic Form I stirred in the solvent to form the polymorphic Form II described herein. In some embodiments, the method further includes isolating the polymorphic Form II. In certain embodiments, the stirred mixture is heated at a temperature of less than about 30° C. In one embodiment, the stirred mixture is heated at a temperature of between about 25° C. and about 30° C. In other embodiments, the ground polymorphic Form I is stirred in the solvent at a temperature of between about 10° C. and about 25° C. In some embodiments, the grinding may be performed using any suitable methods or techniques known to one of skill in the art, including for example using a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mill, a ball mill, or a combination of methods or techniques. In one embodiment, the grinding is performed using a ball mill. In some embodiments, the solvent includes an organic solvent. In one embodiment, the solvent includes acetone.
It should be understood, however, one or more of the steps of the method to prepare polymorphic Form II from polymorphic Form I may be omitted or the order of the steps may be varied. For example, in other embodiments, polymorphic Form I may be combined with a solvent before grinding to obtain the polymorphic Form II.
Provided is also a method of preparing the polymorphic Form II described herein, by: a) providing a polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and b) compressing the polymorphic Form I at a pressure of between about 500 psi and 5000 psi to form the polymorphic Form II described herein. In one embodiment, provided is a method of preparing the polymorphic Form II described herein, by compressing the polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one at a pressure of between about 500 psi and 5000 psi to form the polymorphic Form II described herein. In some embodiments, the compressing is performed using a tablet press or a rotary press. In some embodiments, the polymorphic Form I is compressed at a pressure of between 500 psi and 2000 psi, between 1000 psi and 4500 psi, or between 3000 psi and 4500 psi.
Provided is also a method of treating a patient with a cancer, by administering to the patient a composition including the polymorphic Form II described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the cancer is a hematologic malignancy. In other embodiments, the hematologic malignancy is leukemia, wherein leukemia is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In particular embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The non-Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin's lymphoma (iNHL).
Provided is also a composition comprising a mixture of polymorphic Form I and Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In some embodiments, the polymorphic Form I has an X-ray powder diffraction pattern comprising characteristic peaks at about 17.7 degrees 2θ and about 24.9 degrees 2θ; and the polymorphic Form II has an X-ray powder diffraction pattern comprising a characteristic peak at about 18.6 degrees 2θ.
In certain embodiments of the composition, the X-ray powder diffraction pattern for the polymorphic Form I further comprises one or more characteristic peaks at about 14.3 degrees 2θ, about 17.2 degrees 2θ, about 20.9 degrees 2θ, and about 23.9 degrees 2θ. In one embodiment of the composition, the X-ray powder diffraction pattern for the polymorphic Form I has one or more characteristic peaks at about 14.3 degrees 2θ, about 17.2 degrees 2θ, about 17.7 degrees 2θ, about 20.9 degrees 2θ, about 23.9 degrees 2θ, and about 24.9 degrees 2θ.
In some embodiments of the composition, the X-ray powder diffraction pattern for the polymorphic Form II further comprises characteristic peaks at about 24.3 degrees 2θ and about 14.0 degrees 2θ. In one embodiment of the composition, the X-ray powder diffraction pattern for the polymorphic Form I has one or more characteristic peaks at about 14.0 degrees 2θ, about 18.6 degrees 2θ, and about 24.3 degrees 2θ. In certain embodiments of the composition, the polymorphic Form I is present in excess of the polymorphic Form II. In one embodiment of the composition, the polymorphic Form I and polymorphic Form II are present in a ratio of between 99 to 1 and 55 to 45, or a ratio of 99 to 1, 90 to 10, 85 to 15, 80 to 20, 75 to 25, 70 to 30, 65 to 35, 60 to 40, or 55 to 45. In one embodiment, the weight ratio of polymorphic Form I to polymorphic Form II is between 90:1 and 99:1.
Provided is also a composition including a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorphic Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1A, and wherein the polymorphic Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 2A. In certain embodiments, the composition is substantially free of polymorphs other than polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Provided is also a pharmaceutical composition including the composition of a mixture of polymorphic Form I and polymorphic Form II and one or more pharmaceutical acceptable carriers or excipients. In one embodiment, the pharmaceutical composition is for oral administration. For example, the pharmaceutical composition may be in the form a tablet.
In some of the foregoing embodiments, the polymorph (e.g. polymorphic Form I, polymorphic Form II, or both) is not hygroscopic. In some of the foregoing embodiments, the polymorph (e.g. polymorphic Form I, polymorphic Form II, or both) is anhydrous or non-crystalline.
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form III having an X-ray powder diffraction pattern substantially as shown in FIG. 10A.
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form IV having an X-ray powder diffraction pattern substantially as shown in FIG. 11.
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form V having an X-ray powder diffraction pattern substantially as shown in FIG. 12.
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form VI having an X-ray powder diffraction pattern substantially as shown in FIG. 13.
Provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form VII having an X-ray powder diffraction pattern substantially as shown in FIG. 14A.
Provided is a polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=12.6971(7)Å; b=11.3577(8)Å; c=15.2065(10)Å; α=90.00°; β=104.112°; and γ=90.00°.
Provided is a polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=9.1183(3)Å; b=11.3299(3)Å; c=20.7936(5)Å; α=90.00°; β=98.498°; and γ=90.00°.
Provided is a polymorphic Form III of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=8.6133(4)Å; b=11.0763(5)Å; c=14.3996(7)Å; α=99.457°; β=93.897°; and γ=107.275°.
Provided is a polymorphic Form IV of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=7.9394(5)Å; b=16.9606(11)Å; c=17.4405(13)Å; α=90.00°; β=90.00°; and γ=90.00°.
Provided is a polymorphic Form V of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=9.2354(3)Å; b=9.7692(4)Å; c=35.4252(12)Å; α=90.00°; β=90.00°; and γ=90.00°.
DESCRIPTION OF THE FIGURES
FIG. 1A shows an X-ray powder diffraction pattern (XRPD) pattern of polymorph Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. FIG. 1B shows a differential scanning calorimetry (DSC) and thermographic analysis (TGA) graph of polymorph Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 2A shows an XRPD pattern of polymorph Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. FIG. 2B shows a DSC and TGA graph of polymorph Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 3 shows XRPD patterns of Form I and Form II after 18 hours and 40 hours, where the Form I solids were ball milled and stirred in acetone at 28° C.
FIG. 4 shows XRPD patterns of polymorphic forms after wet grinding of Form I in acetone over a period of 1-8 days.
FIG. 5A shows an XRPD pattern of Form I solids before compression (top) and after compression (bottom). FIG. 5B shows XRPD patterns of compressed Form I solids at various pressures and duration, where from top to bottom the patterns are for the pressures and duration as indicated. FIG. 5C shows an XRPD of Form I compressed at 3000 psi for 60 minutes.
FIG. 6 shows XRPD patterns of Form I versus Form II at different temperatures, where from top to bottom the patterns are for the temperature as indicated.
FIG. 7 is a graph showing the trend of chord length (related to particle size) distribution during the conversion of ball milled Form I to Form II.
FIG. 8 is a graph showing Form II and Form I peak ratio (the peaks at 17.8 and 18.6 degrees) during the conversion of ball milled Form I to Form II at 1 g and 10 g scales.
FIGS. 9A and 9B show the moisture content in Form I and II, respectively, over a range of relative humidities.
FIGS. 10A and 10B show an XRPD pattern and a TGA graph, respectively, of polymorph Form III of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 11 shows an XRPD pattern of polymorph Form IV of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 12 shows an XRPD pattern of polymorph Form V of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 13 shows an XRPD pattern of polymorph Form VI of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 14A and 14B show an XRPD pattern and a TGA graph, respectively, of polymorph Form VII of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
DETAILED DESCRIPTION
The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.
Terms used in the singular will also include the plural and vice versa.
The use of the term “about” includes and describes the value or parameter per se. For example, “about x” includes and describes “x” per se. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−5%.
Polymorphs of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and Compositions Thereof
In some embodiments, the therapeutic use and commercialization of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one involves the development of a crystalline form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one that is bioavailable and stable. Development dosage forms, including suitable oral unit dosage forms (such as tablets and capsules), is vital for commercialization of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one dosage forms. As one of skill in the art would appreciate, variations in the crystal structure of a pharmaceutical drug substance may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product, particularly when formulated in a solid oral dosage form.
During the formulation process and the development of a commercial scale manufacturing process for (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, two distinct crystalline forms, termed polymorph Form I and polymorph Form II, were observed. In particular, it was unpredictably observed that Form I partially converts to Form II upon compression, such as in the tableting process.
Specific processes were developed to consistently produce polymorphic Form I and Form II, and allowed the characterization of these polymorphic forms. The processes for the preparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.
Accordingly, in one aspect, the application discloses particular polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, a compound having the molecular structure shown below:
The compound name provided above is named using ChemBioDraw Ultra 12.0 and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols. By way of example, the compound may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Accordingly, the compound structure provided above may also be named or identified as 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one under IUPAC and 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone under CAS.
In one aspect is provided polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1A. In other embodiments, polymorphic Form I exhibits a differential scanning calorimetry pattern substantially as shown in FIG. 1B.
In some embodiments, the term “substantially as shown in” when referring to an X-ray powder diffraction pattern or a differential scanning calorimetry pattern means that a pattern that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations, when considered by one of ordinary skill in the art.
In other embodiments, polymorphic Form I is characterized as having a melting temperature onset as determined by differential scanning calorimetry at about 254° C. In yet other embodiments, polymorphic Form I is characterized as an anhydrous, crystalline solid. In yet other embodiments, polymorph Form I is substantially free of water, substantially free of solvent, or a combination thereof.
In some embodiments of polymorphic Form I, at least one, at least two, at least three, at least four, or all of the following (a)-(f) apply: (a) polymorphic Form I is anhydrous; (b) polymorphic Form I is crystalline; (c) polymorphic Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1A; (d) polymorphic Form I has a differential scanning calorimetry thermogram substantially as shown in FIG. 1B; (e) a melting temperature onset as determined by differential scanning calorimetry at about 254° C.; and (f) polymorph Form I absorbs less than 1 wt % moisture at 90% relative humidity at 25° C.
In some embodiments, polymorphic Form I comprises at least one, at least two, or all of the following properties:
(a) having an X-ray powder diffraction pattern substantially as shown in FIG. 1A;
(b) having a differential scanning calorimetry thermogram substantially as shown in FIG. 1B; and
(c) a melting temperature onset as determined by differential scanning calorimetry at about 254° C.
In some embodiments, the polymorphic Form I has an X-ray powder diffraction pattern displaying at least two of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1A. In some embodiments, the polymorphic Form I has an X-ray powder diffraction pattern displaying at least three of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1A. In some embodiments, the polymorphic Form I has an X-ray powder diffraction pattern displaying at least four of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1A. In some embodiments, the polymorphic Form I has an X-ray powder diffraction pattern displaying at least five of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1A. In some embodiments, the polymorphic Form I has an X-ray powder diffraction pattern displaying at least six of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1A.
In certain embodiments, the polymorphic Form I has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles expressed in degrees 2θ of about 14.3, about 17.2, about 17.7, about 20.9, about 23.9 and about 24.9. In one embodiment, the polymorphic Form I has an X-ray powder diffraction pattern having a characteristic peak at a diffraction angle expressed in degrees 2θ of about 17.7 degrees 2θ. In another embodiment, the polymorphic Form I has an X-ray powder diffraction pattern having a characteristic peak at a diffraction angle expressed in degrees 2θ of about 17.7 and about 24.9. In yet another embodiment, the polymorphic Form I has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles expressed in degrees 2θ of 14.3, 17.2, 17.7, 20.9, 23.9 and 24.9. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein are intended to encompass variations of plus or minus 0.2 degrees 2θ.
In another aspect is provided polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 2A. In other embodiments, polymorphic Form II exhibits a differential scanning calorimetry pattern substantially as shown in FIG. 2B. In yet other embodiments, polymorphic Form II is characterized as an anhydrous, crystalline solid. In yet other embodiments, polymorph Form II is substantially free of water, substantially free of solvent, or a combination thereof.
In some embodiments of polymorphic Form II, at least one, at least two, at least three, or all of the following (a)-(e) apply: (a) polymorphic Form II is anhydrous; (b) polymorphic Form II is crystalline; (c) polymorphic Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 2A; (d) polymorphic Form II has a differential scanning calorimetry thermogram substantially as shown in FIG. 2B; and (e) polymorphic Form II absorbs less than 1 wt % moisture at 90% relative humidity at 25° C.
In some embodiments, polymorphic Form II comprises at least one or both of the following properties:
(a) having an X-ray powder diffraction pattern substantially as shown in FIG. 2A; and
(b) having a differential scanning calorimetry thermogram substantially as shown in FIG. 2B.
In some embodiments, polymorphic Form II has a melting temperature that may be different from the melting temperature of polymorphic Form I.
In some embodiments, the polymorphic Form II has an X-ray powder diffraction pattern displaying at least two of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 2A. In some embodiments, the polymorphic Form II has an X-ray powder diffraction pattern displaying at least three of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 2A. In some embodiments, the polymorphic Form II has an X-ray powder diffraction pattern displaying at least four of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 2A.
In certain embodiments, the polymorphic Form II has an X-ray powder diffraction pattern having one or more characteristic peaks at diffraction angles expressed in degrees 2θ of about 14.0, about 18.6 and about 24.3. In one embodiment of polymorphic Form II, the X-ray powder diffraction pattern has a characteristic peak at about 18.6 degrees 2θ. In another embodiment of polymorphic Form II, the pattern has characteristic peaks at about 18.6 degrees 2θ and 14.0 degrees 2θ. In yet another embodiment of polymorphic Form II, the pattern has characteristic peaks at about 18.6 degrees 2θ and 24.3 degrees 2θ. In yet another embodiment of polymorphic Form II, the pattern has characteristic peaks at about 14.0 degrees 2θ and 24.3 degrees 2θ. In one embodiment, the polymorphic Form II has an X-ray powder diffraction pattern having one or more characteristic peaks at diffraction angles expressed in degrees 2θ of 14.0, 18.6 and 24.3.
In another aspect, provided are compositions comprising the polymorphs (e.g., polymorphic Form I, polymorphic Form II, or both) as described herein. In some embodiments, the composition comprises polymorphic Form I, polymorphic Form II, or a combination thereof. In some embodiments, the composition incorporates polymorphic Form I. In other embodiments, the composition incorporates polymorphic Form II.
In some embodiments are provided compositions incorporating the polymorphic Form I as described herein, wherein the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form I. In particular embodiments of compositions incorporating the polymorphic Form I, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form I.
In other embodiments of compositions incorporating the polymorphic Form I, the composition is substantially free of polymorphic Form II. In certain embodiments of compositions incorporating the polymorphic Form I, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form II.
In some embodiments of the compositions comprising polymorphic Form I, the composition is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. For example, in certain embodiments, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of the compositions comprising polymorphic Form I, the composition is substantially free of salts of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment of the compositions comprising polymorphic Form I, the composition is substantially free of an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. For example, in certain embodiments, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments, the term “substantially pure” or “substantially free” with respect to a particular polymorphic form of a compound means that the polymorphic form contains about less than 30%, about less than 20%, about less than 15%, about less than 10%, about less than 5%, or about less than 1% by weight of impurities. In other embodiments, “substantially pure” or “substantially free of” refers to a substance free of impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
In some embodiments of compositions incorporating the polymorphic Form I, the composition is substantially free of polymorphs other than polymorphic Form I. In other embodiments, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphs other than polymorphic Form I. In yet other embodiments of compositions incorporating the polymorphic Form I, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form I present. Impurities may, for example, include by-products from synthesizing (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents.
In some embodiments are provided compositions incorporating the polymorphic Form II as described herein, wherein (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form II. In certain embodiments of compositions incorporating the polymorphic Form II, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form II.
In other embodiments of compositions incorporating the polymorphic Form II, the composition is substantially free of polymorphic Form I. In certain embodiments of compositions incorporating the polymorphic Form II, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form I.
In some embodiments of compositions incorporating the polymorphic Form II, the composition is substantially free of polymorphs other than polymorphic Form II. In other embodiments, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphs other than polymorphic Form II.
In some embodiments of the compositions comprising polymorphic Form II, the composition is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. For example, in certain embodiments, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of the compositions comprising polymorphic Form II, the composition is substantially free of salts of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment of the compositions comprising polymorphic Form II, the composition is substantially free of an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. For example, in certain embodiments, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments of compositions incorporating the polymorphic Form II, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form II present. Impurities may, for example, include by-products from synthesizing (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents.
In another aspect, provided are compositions comprising a mixture of two or more of the polymorphic forms described herein. In certain embodiments, provided is a composition comprising a mixture of polymorphic Form I and Form II as described herein. In some embodiments, the composition consists essentially of polymorphic Form I and 5%, 4%, 3%, 2%, 1%, or less than 1% of Form II. In other embodiments, the composition consists essentially of polymorphic Form II and 5%, 4%, 3%, 2%, 1%, or less than 1% of Form I.
In some embodiments of the compositions comprising a mixture of polymorphic Form I and polymorphic Form II, the composition is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. For example, in certain embodiments, the composition comprising a mixture of polymorphic Form I and polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of the compositions comprising a mixture of polymorphic Form I and polymorphic Form II, the composition is substantially free of salts of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment of the compositions comprising a mixture of polymorphic Form I and polymorphic Form II, the composition is substantially free of an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. For example, in certain embodiments, the composition comprising a mixture of polymorphic Form I and polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, the composition comprising a mixture of polymorphic Form I and polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In another embodiment of the composition comprising a mixture of polymorphic Form I and polymorphic Form II, the polymorphic Form I in the composition is present in excess of polymorphic Form II. For example, in one embodiment of the composition comprising a mixture of polymorphic Form I and polymorphic Form II, the weight ratio of polymorphic Form I to polymorphic Form II in the composition is between 99 to 1 and 55 to 45, or about 60 to 40, about 70 to 30, about 75 to 25, about 80 to 20, about 85 to 15, about 90 to 10, about 95 to 5, or about 99 to 1. In one embodiment, the weight ratio of polymorphic Form I to polymorphic Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphic Form II in the composition is present in excess of polymorphic Form I. For example, the weight ratio of polymorphic Form II to polymorphic Form I in the composition is between 99 to 1 and 55 to 45, or about 60 to 40, about 70 to 30, about 75 to 25, about 80 to 20, about 85 to 15, about 90 to 10, about 95 to 5, or about 99 to 1. In yet another embodiment, polymorphic Form I and polymorphic Form II are present in approximately the same amounts in the composition.
In another embodiment, provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form III having an X-ray powder diffraction pattern substantially as shown in FIG. 10. In yet another embodiment, provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form IV having an X-ray powder diffraction pattern substantially as shown in FIG. 11. In yet another embodiment, provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form V having an X-ray powder diffraction pattern substantially as shown in FIG. 12. In yet another embodiment, provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form VI having an X-ray powder diffraction pattern substantially as shown in FIG. 13. In yet another embodiment, provided is a polymorph of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph is Form VII having an X-ray powder diffraction pattern substantially as shown in FIG. 14. Provided are also compositions that include any of polymorphic Form III, IV, V, VI or VII as described herein.
Preparation of the Polymorphs
One method of synthesizing (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one has been previously described in U.S. Pat. No. 7,932,260. This reference is hereby incorporated herein by reference in its entirety, and specifically with respect to the synthesis of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. The methods for preparing the polymorphs (including polymorphic Form I and Form II) may yield quantity and quality differences compared to the methods for preparing (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced on laboratory scale.
Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one have been discovered. The choice of a particular temperature may affect the formation favoring one polymorphic form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one over another. In one aspect, polymorphic Form I described herein may be prepared by dissolving crude (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one in a solvent or solvent combination (e.g., by heating under reflux), followed by cooling the solution to a temperature of at least about 30° C. In certain embodiments, cooling the solution to a temperature between about 30° C. and about 40° C., or more specifically between about 30° C. and about 35° C. or between about 35° C. and about 40° C., may favor producing the polymorphic Form I over the polymorphic Form II. Suitable solvents may include, for example, water or an organic solvent (e.g., methanol, ethanol, propanol, isopropyl acetate, methyl t-butyl ether, dimethylsulfoxide, ethyl acetate, 2-methyl tetrahydrofuran, methyl ethyl ketone, and methyl isobutyl ketone, hexane, heptane), or a mixture thereof. In yet other embodiments, the method further includes isolating the solids, such as polymorphic Form I solids; washing the isolated solids; and drying the washed isolated solids to obtain substantially pure polymorphic Form I.
In other embodiments, polymorphic Form I may be obtained from a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, such as, for example, a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be combined with a solvent or solvent combination to form an acidic mixture or solution. The solvent or solvent combination may be, for example, water and/or an organic solvent. In one embodiment, the solvent includes water, ethanol, or a mixture thereof. The acidic mixture or solution is then neutralized to form free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and heated to convert at least a portion of the free (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to polymorphic Form I. In certain embodiments, polymorphic Form I crystals may be added to the neutralized mixture or solution before heating. The neutralized mixture or solution may be heated at a temperature of at least about 30° C., and more specifically between 40° C. and 60° C., or about 50° C.
In another aspect, polymorphic Form II described herein can be prepared by converting a polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to polymorphic Form II. Polymorphic Form I can be converted into polymorphic Form II by grinding or compression.
In some embodiments, the method to prepare polymorphic Form II includes grinding the polymorphic Form I to a micron particle size (e.g., between about 1 micron to about 10 microns); and stirring the ground polymorphic Form I in a solvent at a temperature of less than about 30° C. to form the polymorphic Form II. In certain embodiments, the ground polymorphic Form I is stirred at a temperature of between about 25° C. and about 30° C. to form the polymorphic Form II.
Certain solvents or solvent combinations used in the grinding method described above to prepare polymorphic Form II may favor the rate of formation of polymorphic Form II over the rate of formation of polymorphic Form I. For example, in certain embodiments, the use of acetone may increase rate of formation of polymorphic Form II over polymorphic Form I. In one variation of the methods to prepare polymorphic Form II, polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is suspended in an acetone at a temperature less than about 30° C., or between about 25° C. and about 30° C.
The grinding in the method described above to prepare polymorphic Form II may be performed using any suitable methods or techniques known to one of skill in the art, including for example, a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mill, a ball mill, or a combination thereof. In certain embodiments, the grinding is performed using a ball mill. Furthermore, as discussed above, stirring the suspension of polymorphic Form I in the solvent or solvent combinations described above at a temperature of between about 25° C. and about 30° C. may unexpectedly favor the production of the polymorphic Form II over polymorphic Form I.
In other embodiments, polymorphic Form II described herein can be prepared by compressing polymorphic Form I at a pressure of between about 500 psi and about 5000 psi to convert at least a portion of polymorphic Form I to polymorphic Form II. In certain embodiments, the polymorphic Form I is compressed at a pressure of between 1000 psi and about 4500 psi. Any suitable methods known in the art may be used to compress polymorphic Form I, including for example a tablet press or a rotary press. It should be understood that the compression duration may vary depending on the type of press used. For example, in some embodiments where a tablet press is used, the polymorphic Form I may be compressed for about 30 seconds, about 1 minute, or up to about 5 minutes to produce polymorphic Form II. In other embodiments where a rotary press is used, the polymorphic Form I may be compressed in less than about 1 second, or between about 1 second to about 30 seconds to produce polymorphic Form II.
Compressing polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one unexpectedly converts at least a portion of polymorphic Form I into polymorphic Form II.
The other polymorphic forms described herein that are solvates (e.g., Forms III, IV, V, VI and VII) can be prepared by converting polymorphic Form I into the other forms in the presence of one or more solvents. In some embodiments, polymorphic Form III can be prepared by mixing polymorphic Form I with water and isopropyl alcohol (IPA). In other embodiments, polymorphic Form IV can be prepared by mixing polymorphic Form I with dimethylformamide (DMF). In yet other embodiments, polymorphic Form V can be prepared by mixing polymorphic Form I with dimethylformamide (DMF). In yet other embodiments, polymorphic Form VI can be prepared by mixing polymorphic Form I with dichloromethane (DCM). In yet other embodiments, polymorphic Form V can be prepared by mixing polymorphic Form I with dimethylsulfoxide (DMSO). In yet other embodiments, polymorphic Form VII can be prepared by mixing polymorphic Form I with water and ethanol. In some of the foregoing embodiments to convert polymorphic Form I into one of polymorphic Forms III, IV, V, VI and VII, polymorphic Form I can be mixed with the one or more solvents at room temperature.
Pharmaceutical Compositions
The polymorphic forms described herein can be administered as the neat chemical, but it is typical, and preferable, to administer the compound in the form of a pharmaceutical composition or formulation. Accordingly, provided are pharmaceutical compositions that include the polymorphic forms described herein (e.g., Form I and/or Form II) and a biocompatible pharmaceutical carrier, excipient, adjuvant, or vehicle. The composition can include the polymorphic forms described herein either as the sole active agent or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones mixed with one or more pharmaceutically acceptable carriers or excipients. Carriers, excipients, and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.
For example, in some embodiments, provided herein is a pharmaceutical composition comprising polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In other embodiments, provided herein is a pharmaceutical composition comprising polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet other embodiments, provided herein is a pharmaceutical composition comprising a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient.
In one embodiment of the pharmaceutical composition, the polymorphic Form I in the composition is present in excess of polymorphic Form II. For example, the weight ratio of polymorphic Form I to polymorphic Form II in the pharmaceutical composition may be between 99 to 1 and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1. In one embodiment, the weight ratio of polymorphic Form I to polymorphic Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphic Form II in the pharmaceutical composition is present in excess of polymorphic Form I. For example, the weight ratio of polymorphic Form II to polymorphic Form I in the pharmaceutical composition may be between 99 to 1 and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1. In yet another embodiment, polymorphic Form I and polymorphic Form II are present in approximately the same amounts in the pharmaceutical composition.
Techniques for formulation and administration of pharmaceutical compositions can be found in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co, Easton, Pa., 1990. The pharmaceutical compositions described herein can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Depending on the condition being treated, these pharmaceutical compositions can be formulated and administered systemically or locally.
The pharmaceutical compositions can be formulated to contain suitable pharmaceutically acceptable carriers, and optionally can comprise excipients and auxiliaries that facilitate processing of the polymorphic forms described herein into preparations that can be used pharmaceutically. The mode of administration generally determines the nature of the carrier. For example, formulations for parenteral administration can include aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration are physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For preparations including proteins, the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
Alternatively, formulations for parenteral use can include dispersions or suspensions of polymorphic forms described herein prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, dextran, and mixtures thereof. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT™ series available from Rohm America Inc. (Piscataway, N.J.). Emulsions, e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants). Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
Liposomes containing the polymorphic forms described herein also can be employed for parenteral administration. Liposomes generally are derived from phospholipids or other lipid substances. The compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, Academic Press, New York (1976).
In some embodiments, the polymorph or composition thereof disclosed herein is formulated for oral administration using pharmaceutically acceptable carriers well known in the art. Preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders. To illustrate, pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or more excipients, which include, without limitation:
a) diluents, such as microcrystalline cellulose and sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
b) binders, such as sodium starch glycolate, croscarmellose sodium, magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.;
c) cellulose materials, such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof, such as sodium alginate, or effervescent compositions;
e) lubricants, such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol;
f) flavorants and sweeteners;
g) colorants or pigments, e.g., to identify the product or to characterize the quantity (dosage) of active compound; and
h) other ingredients, such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
For example, provided is a tablet comprising one or more of the polymorphic forms described herein (e.g., Form I and/or Form II), and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the tablet comprises substantially pure polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In other embodiments, the tablet comprises substantially pure polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In yet other embodiments, the tablet comprises a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients.
In one embodiment of the tablet, the polymorphic Form I in the composition is present in excess of polymorphic Form II. For example, the weight ratio of polymorphic Form I to polymorphic Form II in the tablet is between 99 to 1 and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1. In one embodiment, the weight ratio of polymorphic Form I to polymorphic Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphic Form II in the tablet is present in excess of polymorphic Form I. For example, the weight ratio of polymorphic Form II to polymorphic Form I in the tablet is between 99 to 1 and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1. In yet another embodiment, polymorphic Form I and polymorphic Form II are present in approximately the same amounts in the tablet.
In any of the foregoing tablets, in one variation, the tablet is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In any of the foregoing tablets, in one variation, the unit dosage form is substantially free of a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one).
Provided herein are also methods of preparing a tablet comprising polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises compressing polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one under conditions suitable to produce polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. Suitable conditions may include, for example, applying a force of between about 500 psi and about 5000 psi, or between 1000 psi and about 4500 psi, during the tableting process.
Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The polymorphs described herein are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the polymorph actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
The tablets or pills described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage element, the latter being in the form of an envelope over the former. The two elements can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner element to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymorphic acids and mixtures of polymorphic acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
For example, provided is a unit dosage comprising one or more of the polymorphic forms described herein (e.g., Form I and/or Form II). In one embodiment, the unit dosage comprises substantially pure polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other embodiments, the unit dosage comprises substantially pure polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet other embodiments, the unit dosage comprises a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In one embodiment of the unit dosage, the polymorphic Form I in the composition is present in excess of polymorphic Form II. For example, the weight ratio of polymorphic Form I to polymorphic Form II in the unit dosage is between 99 to 1 and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1. In one embodiment, the weight ratio of polymorphic Form I to polymorphic Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphic Form II in the unit dosage is present in excess of polymorphic Form I. For example, the weight ratio of polymorphic Form II to polymorphic Form I in the unit dosage is between 99 to 1 and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1. In yet another embodiment, polymorphic Form I and polymorphic Form II are present in approximately the same amounts in the unit dosage.
In any of the foregoing unit dosage forms, in one variation, the unit dosage form is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In any of the foregoing unit dosage forms, in one variation, the unit dosage form is substantially free of a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., an HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one). In one embodiment, unit dosage form is a tablet comprising polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorphic Form II is produced upon applying a force to polymorphic Form I during the tableting process.
Provided herein are also methods of preparing a unit dosage comprising polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises compressing polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one under conditions suitable to produce polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. Suitable conditions may include, for example, applying a force of between about 500 psi and about 5000 psi, or between 1000 psi and about 4500 psi, during the tableting process.
Modes of Administration and Dosages
Pharmaceutical compositions including the polymorphic forms described herein can be administered to the subject by any conventional method, including parenteral and enteral techniques. Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enteral administration modalities include, for example, oral, buccal, sublingual, and rectal administration. Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and buccal and sublingual administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Parenteral administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT™.
Moreover, the therapeutic index of the compound having the polymorphic forms described herein can be enhanced by modifying or derivatizing the compound for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compound can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described. See e.g., Pietersz et al., Immunol. Rev., 129:57 (1992); Trail et al., Science, 261:212 (1993); and Rowlinson-Busza et al., Curr. Opin. Oncol., 4:1142 (1992). Tumor-directed delivery of the compound can enhance the therapeutic benefit by, inter alia, minimizing potential nonspecific toxicities that can result from radiation treatment or chemotherapy. In some embodiments, the compound having a polymorphic form described herein, and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibody.
Pharmacokinetic and pharmacodynamic information about the polymorphic forms described herein and the formulation of the compound having a polymorphic form described herein can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for the compound having a polymorphic form described herein used in the methods described herein, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range that modulates PI3δ expression or activity. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the “therapeutic index”, which typically is expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantially higher than the effective dose, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity.
It should be understood that any effective administration regimen regulating the timing and sequence of doses can be used. A compound having a polymorphic form described herein and pharmaceutical compositions thereof may include those wherein the active ingredient is administered in an effective amount to achieve its intended purpose.
In some embodiments, a “therapeutically effective amount” means an amount sufficient to modulate PI3Kδ expression or activity, and thereby treat an individual suffering an indication, or to alleviate the existing symptoms of the indication. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
Exemplary dosage levels for a human subject are of the order of from about 0.001 milligram of active agent per kilogram body weight (mg/kg) to about 1000 mg/kg. Typically, dosage units of the active agent comprise from about 0.01 mg to about 1000 mg, preferably from about 0.1 mg to about 100 mg, depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosage regimen is determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
The frequency of dosing depends on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent. Short-acting pharmaceutical compositions (i.e., short half-life) can be administered once a day or more than once a day (e.g., two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks.
Bioequivalents of the Polymorphs
Also provided herein are polymorphs that are bioequivalent to the polymorphic Form I and the polymorphic Form II described herein.
In certain embodiments, bioequivalence between two polymorphs refers to polymorphs having substantially similar bioavailability, substantially similar efficacy, substantially similar safety profiles, or a combination thereof.
In yet other embodiments, bioequivalence refers to polymorphs that exhibit substantially similar pharmacokinetic profiles or therapeutic effects. Bioequivalence may be demonstrated through several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies. In some embodiments, bioequivalence can be demonstrated using any suitable pharmacokinetic measures or combination of pharmacokinetic measures known in the art, including loading dose, steady-state dose, initial or steady-state concentration of drug, biological half-life, elimination rate, area under the curve (AUC), clearance, the peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency. In some embodiments, bioequivalence is achieved with similar dosing amounts. In alternative embodiments, bioequivalence is achieved with different dosing amounts.
Therapeutic Use of the Polymorphs and Compositions Thereof
Provided are also a use of the polymorphs or compositions thereof described herein to selectively or specifically inhibiting PI3δ activity therapeutically or prophylactically. The method comprises administering the polymorphs or compositions thereof to an individual in need thereof in an amount sufficient to inhibit PI3δ activity. The method can be employed to treat humans or animals suffering from, or subject to, a condition whose symptoms or pathology is mediated by PI3δ expression or activity.
In some embodiments, “treating” refers to preventing a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it; inhibiting the disorder, i.e., arresting its development; relieving the disorder, i.e., causing its regression; or ameliorating the disorder, i.e., reducing the severity of symptoms associated with the disorder. In some embodiments, “disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
The methods disclosed in the application embrace various modes of treating an animal subject, preferably a mammal, more preferably a primate, and still more preferably a human. Among the mammalian animals that can be treated are, for example, humans; companion animals (pets), including dogs and cats; farm animals, including cattle, horses, sheep, pigs, and goats; laboratory animals, including rats, mice, rabbits, guinea pigs, and nonhuman primates; and zoo specimens. Among the non-mammalian animals that can be treated include, for example, birds, fish, reptiles, and amphibians.
In one aspect, the polymorphs and compositions thereof described herein can be employed in methods of inhibiting the growth or proliferation of cancer cells of hematopoietic origin, such as cancer cells. In some embodiments, the cancer cells are of lymphoid origin, and in specific embodiments, the cancer cells are related to or derived from B lymphocytes or B lymphocyte progenitors. Cancers amenable to treatment using the method disclosed in the application include, without limitation, lymphomas (e.g., malignant neoplasms of lymphoid and reticuloendothelial tissues, such as Burkitt's lymphoma, Hodgkins' lymphoma, non-Hodgkins' lymphomas, lymphocytic lymphomas); multiple myelomas; leukemias (e.g., lymphocytic leukemias, chronic myeloid (myelogenous) leukemias). Other cancer cells, of hematopoietic origin or otherwise, that express p110δ also can be treated by administration of the polymorphs and compositions thereof described herein.
In particular embodiments, the cancer is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The non-Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin's lymphoma (iNHL).
In another aspect, the polymorphs and compositions thereof described herein can be employed in methods of treating a patient with a cancer. In some embodiments, the cancer is a hematologic malignancy. In specific embodiments, the hematologic malignancy is leukemia (e.g., chronic lymphocytic leukemia) or lymphoma (e.g., non-Hodgkin's lymphoma).
In yet another aspect, provided are methods of treating an individual having a PI3K-mediated disorder by administering polymorphic Form I, polymorphic Form II, or a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to the individual. Provided are also methods of modulating PI3K an individual by administering polymorphic Form I, polymorphic Form II, or a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to the individual. In one variation, the polymorphic Form I, polymorphic Form II, or a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is substantially free of other polymorphic forms. In another variation, the polymorphic Form I, polymorphic Form II, or a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another variation, the polymorphic Form I, polymorphic Form II, or a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is substantially free of amorphous or non-crystalline (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one substantially free of a salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., a HCl salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one).
In any of the foregoing methods, the polymorphic form may be administered to the individual as unit dosage, for example in the form of a tablet. Variations in which polymorphic Form II are administered in the form a tablet, the polymorphic Form II is produced upon compression of polymorphic Form I in the tableting process. For example, a force of between about 500 psi and about 5000 psi, between about 500 psi and about 5000 psi, or between 1000 psi and about 4500 psi, may be applied during the tableting process.
Articles of Manufacture and Kits
Compositions comprising the polymorphs disclosed herein and formulated in a pharmaceutically acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a label containing instructions for use of the compound.
In some embodiments, the article of manufacture is a container comprising a dosage form of polymorphic Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In other embodiments, the article of manufacture is a container comprising a dosage form of polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In yet other embodiments, the article of manufacture is a container comprising a dosage form of a mixture of polymorphic Form I and polymorphic Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In one embodiment of the articles of manufacture described herein, the dosage form is a tablet.
Kits also are contemplated. For example, a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. The instructions for use in the kit may be for treating a PI3K-mediated disorder, including, for example, a hematologic malignancy. In certain embodiments, the instructions for use in the kit may be for treating leukemia. In one embodiment, the instructions for use in the kit may be for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In certain embodiments, conditions indicated on the label can include, for example, treatment of cancer.
EXAMPLES
The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular materials and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof.
The polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one were characterized by various analytical techniques, including X-ray powder diffraction pattern (XPPD), differential scanning calorimetry (DSC), and thermographic analysis (TGA) using the procedures described below.
X-Ray Powder Diffraction:
XRPD patterns were collected using a PANalytical X'Pert MPD Pro Powder X-Ray Diffractometer configured with reflectance stage with spinning, data acquisition range: 2-40 degrees 2θ, Copper (Cu) anode; Kα1/Kα2 radiation; tube current 40 mA; tube tension 45 kV; automatic divergence and anti-scatter slits. Samples were prepared for analysis by distributing solid material as a thin layer on a silicon holder. Each holder was mounted on a reflectance/transmittance stage and rotated during data acquisition.
Differential Scanning Calorimetry:
DSC was performed using a TA Instruments Q2000 DSC instrument. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid, and then either crimped or hermetically sealed. The same cell was equilibrated at 25° C. and heated under a nitrogen purge at a rate of 10° C./min, up to a final temperature of 300° C. Indium was used as the calibration standard.
Thermogravimetric Analysis:
TGA was performed using a TA Instruments Q5000 TGA instrument. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was first equilibrated at 25° C., and then heated under nitrogen at a rate of 10° C./min, up to a final temperature of 300° C. The TGA furnace was calibrated using the magnetic Curie point method.
Example 1
Preparation of Form I
20.6 g of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was suspended in a mixture of 164 mL methanol and 36 mL water. Under stirring, the mixture was heated to reflux (about 66° C.) for about 1.5 hours. Upon complete dissolution water was slowly added. The solution temperature was allowed to reach about 75° C. When about 100 mL water was added solids were formed and the solution was then slowly cooled to about 30-35° C. Form I was isolated by vacuum filtration at about 35° C., and dried under vacuum at about 40° C. The dried solids were analyzed by XRPD and DSC. FIGS. 1A and 1B and depict the XRPD and DSC patterns of polymorphic Form I.
Example 2
Preparation of Form II from Form I by Grinding
Form I was prepared as described in Example 1. Form I solids were ball milled in batches for 10 minutes at 30 Hz. Samples were analyzed by XRPD. Table 1 below summarizes the amount of polymorphic Form II observed from conversion of polymorphic Form I.
TABLE 1
Ball Milling Experiments
Scale
Temp
Time
Form II
(g)
Solvents
(° C.)
Stirring mode
(days)
Product (g)
10
20 vol acetone
28
magnetic
6
6.9
10
20 vol acetone
28
magnetic
5
5
10
20 vol acetone +
28
magnetic
7
6.5
20 vol MTBE
10
acetone
10/28
magnetic
5
6
37
14 vol acetone +
10/28
Half moon
7
31.3
14 vol MTBE
blade +
magnetic
Results in Table 1 showed that Form I was successfully converted into Form II using the ball milling technique.
Additionally, 10 g of Form I was ball milled at 30 Hz for 10 minutes and stirred in 300 mL of acetone at 28° C. As seen in FIG. 3, about 50% conversion of Form I into Form II was observed after 18 hours, and about 90% conversion was observed after 40 hours.
Example 3
Comparison of Dry and Wet Grinding in Conversion of Form I into Form II
Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was pre-processed using various grinding methods before forming a slurry in either acetone or THF and stirring at either room temperature, 22° C. or 30° C. Table 2 below summarizes the conditions and the result of the experiment. As used in this Example, “enriched” describes a sample that contains substantially more Form II than Form I.
TABLE 2
Dry and Wet Grinding Experiments
Slurry
Temp
Stirring
Scale (g)
Pre-processing
Solvent
(° C.)
condition
Form II content
0.2
Dry/wet grinding
acetone
r.t.
magnetic
Enriched after 1 day
Highly enriched after 2 days
1
Dry/wet grinding
acetone
r.t.
magnetic
Trace amount after 1 week
20
Dry grinding
acetone
30
overhead
Undetectable after 3 days
5
High shear wet mill
acetone
30
overhead
Undetectable after 3 days
1
High shear mixer
acetone
r.t.
magnetic
Trace amount after 1 day
(dry)
1
High shear mixer
THF
r.t.
magnetic
Trace amount after 1 day
(dry)
1
Jet milled
acetone
22
magnetic
Small amount after 1 day
Enriched after 4 days
r.t. = room temperature
The results in Table 2 above show that some Form I was converted into Form II at small scale using dry grinding with mortar and pestle. In addition, Form I was converted into Form II using jet milling after several days. Additionally, FIG. 4 shows an XRPD comparison of polymorphic forms over a period of 8 days, where Form I solids were suspended in acetone after wet grinding.
Example 4
Preparation of Form II from Form I by Compression
Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was subjected to high pressure in a hydraulic tablet press (ENERPAC Model P142 hydraulic press; #9166 0.275 inch punch) as shown in Table 3 below. The relaxation time is the time between compressions. A sample of the compressed solids was analyzed by XRPD and DSC. FIGS. 2A and 2B depict the XRPD and DSC patterns of polymorphic Form II.
TABLE 3
Compression conditions and observations
(S)-2-(1-(9H-purin-6-
ylamino)propyl)-5-
fluoro-3-
Relaxation
phenylquinazolin-
Pressure
Duration
Time
4(3H)-one (mg)
(psi)
(min)
(hours)
XRPD
NA
atm
—
—
Form I &
minor II
~150
atm
—
—
Form I and II
(excess of I)
~160
4500
<0.5
—
Form I and II
(excess of I)
~150
1000
<0.5
24
Form I and II
(excess of I)
163
2000
5
72
I & II (~1:1)
167
2000
10
72
I & II (~1:1)
164
3000
5
2
I & II (~1:1)
168
3000
10
2
I & II (~1:1)
171
3000
60
72
I & II (excess
of II)
Results of Table 3 indicated that Form I was partially converted to Form II during compression at the 100-200 mg scale. FIGS. 5A and 5B show XRPD patterns for two lots of Form I solids before and after compression at various pressures, respectively. FIG. 5C shows an XRPD pattern of compressed Form I solids using 3000 psi for 60 minutes. With reference to this figure, conversion of over 50% of Form I to Form II was observed under this condition.
Example 5
Effect of Temperature on Form Conversion in Acetone Suspension
Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was suspended in acetone at a concentration of 50 mg/mL, and stirred magnetically over a period of 5-6 days. Four experiments at different temperature were conducted.
Table 4 summarizes the reaction conditions and the amount of polymorphic forms observed for each of the four experiments. As used in this Example, “Enriched II” described a sample that contains substantially more Form II than Form I.
TABLE 4
Form I Suspensions in Acetone at temperature
between 27° C. and 37° C.
(S)-2-(1-(9H-purin-6-
ylamino)propyl)-5-fluoro-3-
phenylquinazolin-4(3H)-one
Temp
Suspension Time (Days)
(mg/mL)
(° C.)
5
6
52
37
—
Form I
52
33
—
Form I
50
30
Enriched II
—
51
27
Enriched II
—
From the results in Table 4 above, it was unexpectedly observed that the rate of conversion from Form I to Form II at 27° C. and 30° C. was higher than the rate of conversion at 33° C. and 37° C.
Example 6
Effect of Temperature on Form Conversion of Solids
DSC indicated close melting points for each polymorph and a solid-solid transition in Form II at about 115° C. to produce Form I. To confirm this finding, 200-500 g of Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was heated at 50° C., 60° C., 70° C., 80° C., 90° C., 100° C., 110° C. and 120° C. jacket temperature using Destiny for 22 hours. Samples were analyzed by X-ray powder diffraction pattern, which are shown in FIG. 6. With reference to this figure, conversion from Form I to Form II was observed at around 90° C.
Example 7
Hydrate Screen
About 50 mg of Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was slurried in either (A) a 1-mL mixture of a isopropyl alcohol (IPA) and water, or (B) a 1-mL mixture of ethanol and water, for several days at room temperature. The results of the IPA/water and ethanol/water hydrate screens are summarized in Tables 5 and 6, respectively. As used herein, water activity (aw) in liquid phase corresponds to relative humidity in the atmosphere. For example, 0.5 aw is equivalent to 50% relative humidity.
TABLE 5
Hydrate screen results in IPA/water system
(S)-2-(1-
(9H-purin-
6-
ylamino)propyl)-
5-
fluoro-3-
phenylquinazolin-
4(3H)-one
IPA/water
IPA
Water
48 Hour
48 Hour
15-16 Day
15-16 Day
(mg)
aw (1 mL)
(mL)
(mL)
Solubility
XRPD
Solubility
XRPD
86
0.2
0.16
9.84
24
Form I & II
20
Form I & II
93
0.3
0.27
9.73
19
Form I & II
19
Form I & II
85
0.4
0.4
9.60
18
Form I & II
20
Form I & II
113
0.5
0.56
9.44
23
Form I & II
20
Form I & II
88
0.6
0.76
9.24
23
Form I & II
24
Form I & II
125
0.7
1.05
8.95
9.8
Form III
8.7
Form III
138
0.8
1.59
8.41
11
Form III
9.5
Form III
121
0.9
6.62
3.38
1
Form III
1
Form III
TABLE 6
Hydrate screen results in ethanol/water system
(S)-2-(1-(9H-
purin-6-
ylamino)propyl)-
5-fluoro-3-
TGA
%
%
%
%
phenylquinazolin-
Ethanol/
mass loss
water
ethanol
ethanol
ethanol
4(3H)-one (mg)
Water (aw)
Form
by 125° C.
(KF)
(GC)
(NMR)
(SCXC)
246
0.7
VII
16.41
14.2
TBD
4.9
TBD
281
0.8
VII
16.45
17.8
TBD
4.0
NA
295
0.9
I & VII
NA
NA
NA
NA
NA
Results in Table 5 show that, when water activity in an IPA/water system was below 0.7, Form I was observed to slowly convert to Form II. Also, when water activity in IPA/water system was 0.7 to 0.9, a new crystalline Form III was observed. Form III of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a mixed solvate/hydrate.
In an ethanol/water system, when water activity was from 0.2 to 0.4, Form I was slowly converted to Form II (data not shown in Table 6 above). Additionally, when water activity was 0.5 and 0.6, no conversion was observed (data not shown in Table 6 above). Table 6 shows that, when water activity was 0.7 and 0.8, a new crystalline Form VII was observed. Form VII of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was a mixed water/ethanol solvate.
Example 8
Crystal Structure Analysis
Polymorphic Forms I, III, IV and V of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one were analyzed by single crystal X-ray crystallography. Polymorphic Form II was analyzed by capillary XRPD. Table 7 summarizes crystal structure data for these five polymorphs of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
TABLE 7
Crystal unit cell parameters
Unit Cell Dimensions
Density
axis length (Å)
axis angle (°)
Form
g/cm3
a
b
c
α
β
γ
I
anhydrous
1.297
12.6971 (7)
11.3577 (8)
15.2065 (10)
90.00
104.112
90.00
II
anhydrous
1.299
9.1183 (3)
11.3299 (3)
20.7936 (5)
90.00
98.498
90.00
III
IPA/water
1.323
8.6133 (4)
11.0763 (5)
14.3996 (7)
99.457
93.897
107.275
IV
DMF
1.382
7.9394 (5)
16.9606 (5)
17.4405 (13)
90.00
90.00
90.00
V
DMSO
1.350
9.2354 (3)
9.7692 (4)
35.4252 (12)
90.00
90.00
90.00
Example 9
Monitoring of Form Conversion
Conversion of Form I into Form II of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was monitored using three techniques: (1) a Lasentec Focused Beam Reflectance Measurement (FBRM) probe, (2) microscopy, and (3) XRPD. Form I solids (1 g and 10 g) were first ball milled for 10 minutes, and then slurried in 20 volumes of acetone at 28° C.
FBRM Probe:
The conversion of Form I into Form II was monitored using a Lasentec FBRM probe. FBRM monitors the particle counts and size during the run. FIG. 7 shows three distinct regions as represented by the three arrows.
Region 1: the solids after ball milling broken up and partially dissolved
Region 2: Nucleation of form I (potentially also form II)
Region 3: Conversion of form I to form II
FIG. 7 shows the trend of chord length (related to particle size) distribution during the conversion of ball milled form I to form II.
Microscopy:
After ball milling, the solids were observed to contain a significant amount of amorphous material, in addition to Form I and possibly Form II seed. When slurried in acetone, the amorphous material dissolved and precipitated as Form I (majority) and Form II. At the last stage, Form I converts to Form II although some Form I crystals remain.
XRPD:
The conversion of Form I into Form II was also monitored by XRPD. The XRPD analysis of the slurry in acetone showed that conversion was fast at first and then subsequently slowed down. FIG. 8 shows qualitative changes of solid form versus time, which is in contrast with typical systems where conversion starts slowly and accelerate all the way to the end.
Example 10
Anhydrous Forms and Solid-Solid Transitions of Polymorphs
The TGA traces shown in FIGS. 1B and 2B for polymorphic Form I and polymorphic Form II, respectively, support the characterization of anhydrous solids. These figures show minor mass loss below about 125° C.
Example 11
Hygroscopicity of Form I and Form II
FIGS. 9A and 9B show adsorption and desorption traces for polymorphic Form I and polymorphic II, respectively, at constant temperature over a range of humidities. Both graphs show that the polymorphs absorb less than 1 wt % moisture at 90% relative humidity at 25° C. This Example supports the non-hygroscopic nature of polymorphic Form I and polymorphic Form II.
Example 12
Isolation of Form I from Reaction Mixture
A reaction vessel was charged with 5-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)propyl)quinazolin-4(3H)-one (35.1 grams), absolute ethanol (48 mL), water (24 mL), and 12N hydrochloric acid (HCl) (5 mL). The mixture was agitated at about 21° C. and additional 12N HCl was added in small portions to produce a solution. As the reaction progressed, a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one crystallized from solution, forming a suspension. After approximately two hours, the acidic reaction suspension was combined with 50 mL ethanol. The suspension was neutralized with aqueous sodium carbonate solution (5.5 grams in 50 mL water) via slow addition until the pH reached about 7.5. The volume of base used was about 35-40 mL. Form I seeds of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (187 mg) were added to the reaction mixture. The mixture was agitated, and heated to about 50° C. Water (300 mL) was then added slowly until the ethanol fraction reached about 21% (v/v). Form I solids of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one were isolated by filtration without cooling, washed with water, and dried under reduced pressure at about 40° C. The yield of dried Form I solids was 16.4 grams.
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13786222
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gilead calistoga llc
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USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
514/263.21
|
|
Mar 31st, 2022 02:23PM
|
Mar 31st, 2022 02:23PM
|
Gilead
|
Health Care
|
Pharmaceuticals & Biotechnology
|
|
nasdaq:gild
|
Gilead
|
Oct 15th, 2019 12:00AM
|
Jun 16th, 2017 12:00AM
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https://www.uspto.gov?id=US10442805-20191015
|
Polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
|
Polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are disclosed. Solvent forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are also disclosed.
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10442805
|
1. A solvate of a hydrochloride salt of a compound of Formula (I):
wherein the solvate is selected from the group consisting of Propylacetate solvate, Isopropyl acetate solvate, 1,2-Dimethoxy ethane solvate, Isopropyl alcohol solvate, 2-Methyl-1-propanol solvate, 1,4-Dioxane solvate, and Toluene solvate; and wherein:
Propylacetate solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8;
Isopropyl acetate solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7;
1,2-Dimethoxy ethane solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7;
Isopropyl alcohol solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2;
2-Methyl-1-propanol solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5;
1,4-Dioxane solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1; and
Toluene solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0.
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1
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CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. patent application Ser. No. 14/575,857, filed Dec. 18, 2014, which claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/919,558, filed Dec. 20, 2013, each disclosure of which is hereby incorporated by reference in its entirety.
FIELD
Provided are polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use. Also provided are solvate forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use.
BACKGROUND
Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. See Rameh et al., J. Biol. Chem., 274:8347-8350 (1999) for a review. The enzyme responsible for generating these phosphorylated signaling products is phosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally was identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring. See Panayotou et al., Trends Cell Biol. 2:358-60 (1992).
Studies suggest that PI3K is involved in a range of cellular responses including cell growth, differentiation, and apoptosis. See Parker et al., Curr. Biol., 5:577-99 (1995); Yao et al., Science, 267:2003-05 (1995). PI3K also appears to be involved in a number of aspects of leukocyte activation. See e.g., Pages et al., Nature, 369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996); Fraser et al., Science, 251:313-16 (1991).
Several compounds have been identified as PI3K inhibitors. For example, compounds capable of inhibiting the biological activity of human PI3K, including (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and their uses are disclosed in U.S. Pat. Nos. 6,518,277, 6,667,300, and 7,932,260. Each of these references is hereby incorporated herein by reference in its entirety. In July 2014, ZYDELIG® (idelalisib), a first-in-class inhibitor of PI3K delta, was approved by the U.S. Food and Drug Administration for the treatment of three B-cell blood cancers. ZYDELIG® has also been approved by the European Commission for two blood cancers, chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).
BRIEF SUMMARY
The present application provides a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is substantially crystalline. In certain embodiments, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is crystalline. In certain embodiments, solvates of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are provided.
In one aspect, provided herein are polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and this compound has the following structure:
One or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are provided. In certain embodiments of the polymorphs provided herein, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt.
These polymorphs can be characterized by a variety of solid state analytical data, including for example X-ray powder diffraction pattern (XRPD), differential scanning calorimetry (DSC), thermographic analysis (TGA), and Single Crystal X-Ray Crystallography. One of skill in the art would recognize various techniques or methods that may be used to generate such characterization data. Unless otherwise stated, the XRPD patterns provided herein are generated by a powder X-ray diffractometer at room temperature. In certain instances, an XRPD pattern may also be calculated from the single crystal data acquired at 100K for that polymorphic form.
In another aspect, provided are compositions or pharmaceutical compositions comprising one or more polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) and one or more pharmaceutically acceptable carriers or excipients. Provided are also articles of manufacture and unit dosage forms comprising any one or more of the polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII). Provided are also kits comprising any one or more of the polymorphic forms (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one), and instructions for use (e.g., instructions for use in PI3K-mediated disorder, such as cancer). In one embodiment of the pharmaceutical compositions, articles of manufacture, unit dosage forms, and kits, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt.
Methods of using these polymorphic forms are provided. In another aspect, provided is a method of treating a human in need thereof, comprising administering to the human a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs. The human may be in need of a treatment for cancer or an autoimmune disease.
In one variation, provided is a method of treating a PI3K-mediated disorder in a human in need thereof, comprising administering to the human a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs. The PI3K-mediated disorder, in some embodiments, is cancer (e.g., leukemia or lymphoma) or an autoimmune disease.
Also provided is a method for increasing sensitivity of cancer cells to chemotherapy, comprising administering to a human undergoing chemotherapy with a chemotherapeutic agent an amount of a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs, sufficient to increase the sensitivity of cancer cells to the chemotherapeutic agent.
Also provided is a use of a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs, in the manufacture of a medicament for the treatment of a disease responsive to inhibition of PI3K activity, such as cancer (e.g., leukemia or lymphoma) or an autoimmune disease.
In one embodiment of the methods of using, and the use of, the polymorphic forms described herein, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt.
Methods of making these polymorphic forms are provided. In yet other aspects, provided are methods of producing a composition comprising one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII). The methods comprise combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) with a suitable solvent or a suitable mixture of solvents. In one embodiment, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt. The solvent(S) may be selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, and any mixtures thereof. Also provided are polymorphic products obtained by the processes (e.g. methods of making) detailed herein.
In some embodiments, a solvate of a hydrochloride salt of a compound of Formula (I) is provided:
In some embodiments, the solvate is selected from the group consisting of ethyl acetate, propyl acetate, 1-methyl-1-propanol, isopropyl acetate, 1,2-dimethyoxyethane, 1,4-dioxane, acetone, acetone:water, acetonitrile, chloroform, dicholoromethane, diethyl ether, ethyl acetate, MEK, MIBK, nitromethane, propyl acetate, tetrahydrofuran, toluene, 1-propanol, 2-propanol, IPA:water (5%), and 2-methyl-1-propanol. In some embodiments, the solvate is selected from the group consisting of propyl acetate, isopropyl acetate, 1,2-dimethyoxyethane, isopropyl alcohol, 2-methyl-1-propanol, 1,4-dioxane, and toluene.
In some embodiments, the polymorph is selected from the group consisting of Pattern 1, Pattern 2, Pattern 3, Pattern 4, 2-Methyl-1-propanol solvate, 1,4-Dioxane solvate, and Toluene solvate; and wherein:
Pattern 1 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8;
Pattern 2 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7;
Pattern 3 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7;
Pattern 4 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2;
2-Methyl-1-propanol solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5;
1,4-Dioxane solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1; and
Toluene solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0.
DESCRIPTION OF THE FIGURES
The present disclosure can be best understood by references to the following description taken in conjunction with the accompanying figures.
FIGS. 1A-1E show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, a thermographic analysis (TGA) graph, and two dynamic vapour sorption (DVS) graphs, respectively, of polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 2 shows XRPD patterns of polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 3 shows XRPD patterns of polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 4 shows XRPD patterns of polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 5 shows XRPD patterns of polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 6 shows XRPD patterns of polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 7 shows XRPD patterns of polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 8 shows XRPD patterns of polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 9 shows XRPD patterns of polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 10 shows XRPD patterns of polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 11 shows XRPD patterns of polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 12 shows XRPD patterns of polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 13 shows XRPD patterns of polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 14A shows XRPD Pattern 1 of a solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (damp).
FIG. 14B shows XRPD Pattern 9 of a solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 14C shows XRPD Pattern 9′ of a solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 14D shows a differential scanning calorimetry (DSC) graph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one represented as Pattern 9.
FIG. 14E shows a thermographic analysis (TGA) graph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one represented as Pattern 9.
FIGS. 15A-15C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of Pattern 2, a solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 16A-16C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of Pattern 3, a solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 17A-17C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of Pattern 4, a solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 18A-18D show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, a thermographic analysis (TGA) graph, and an X-ray powder diffraction pattern (XRPD) pattern of a 2-methyl-1-propanol solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 19A-19C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of a 1,4-dioxane solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 20 shows an X-ray powder diffraction pattern (XRPD) pattern of a toluene solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
DETAILED DESCRIPTION
The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific compounds, methods, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.
Terms used in the singular will also include the plural and vice versa. The use of the term “about” includes and describes the value or parameter per se. For example, “about x” includes and describes “x” per se. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−5%.
Polymorphs of a Hydrochloride Salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
A form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be present as an intermediate to the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, where a different polymorphic form or polymorphs may be beneficial for certain purposes, such as medical or pharmaceutical uses.
It is desirable to develop a crystalline form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof, that is useful in the synthesis of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. A form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be an intermediate to the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. A polymorphic form or polymorph has properties such as bioavailability and stability at certain conditions that are suitable for medical or pharmaceutical uses. By way of example, a crystalline form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is an intermediate to an active agent or ingredient in a pharmaceutical composition.
A crystalline form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof, may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage form including tablets and capsules. Compared to other forms such as non-crystalline or amorphous forms, crystalline forms may provide desired or suitable hygroscopicity, particle size controls, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and/or process control. Thus, crystalline forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof, provides advantage of improving the manufacturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingredient, or having suitable bioavailability and/or stability as an active agent.
The use of certain solvents has been found to produce different polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, including any one or more of polymorphic Forms I to XIII, which may exhibit one or more favorable characteristics described above. The processes for the preparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.
One aspect of the application provides polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, a compound having the molecular structure shown below:
In certain embodiments, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, one or more of the polymorphic forms provided may be a channel solvate. The crystal lattice of such polymorphic forms may contain tunnels that penetrate the lattice, and the tunnels can be occupied by one or more molecules (e.g., solvent molecules) and ions (e.g., chloride ions).
The compound name provided above is named using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols. By way of example, the compound may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Accordingly, the compound structure provided above may also be named or identified as 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one under IUPAC and 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino) propyl]-4(3H)-quinazolinone under CAS.
Form I
In one aspect, provided is polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1A. Polymorphic Form I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 1B. Polymorphic Form I may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 1C. Polymorphic Form I may exhibit dynamic vapour sorption (DVS) graphs substantially as shown in FIGS. 1D and 1E.
The term “substantially as shown in” when referring, for example, to an XRPD pattern, a DSC thermogram, or a TGA graph includes a pattern, thermogram or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art.
Polymorphic Form I may have a unit cell as determined by crystal X-ray crystallography of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948(17)°; and γ=90°.
In some embodiments of polymorphic Form I, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or all of the following (a)-(k) apply: (a) polymorphic Form I has an XRPD pattern substantially as shown in FIG. 1A; (b) polymorphic Form I has a DSC thermogram substantially as shown in FIG. 1B; (c) polymorphic Form I has a TGA graph substantially as shown in FIG. 1C; (d) polymorphic Form I has DVS graphs substantially as shown in FIGS. 1D and 1E; (e) polymorphic Form I has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948(17)°; and γ=90°; (f) polymorphic Form I has a melting temperature onset as determined by DSC at about 202° C.; (g) polymorphic Form I has a monoclinic crystal system; (h) polymorphic Form I has a C2 space group; (i) polymorphic Form I has a volume of 4555(4) Å3; (j) polymorphic Form I has a Z value of 8; and (k) polymorphic Form I has a density of 1.356 g/cm3.
In some embodiments, polymorphic Form I has at least one, at least two, at least three, or all of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 1A;
(b) a DSC thermogram substantially as shown in FIG. 1B;
(c) DVS graphs substantially as shown in FIGS. 1D and/or 1E; and
(d) a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948(17)°; and γ=90°.
In some embodiments, polymorphic Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 1A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form I, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 11.6, 13.8, 16.6, 18.2, 19.4, 22.5, 23.2 and 25.1.
In certain embodiments, the hydrochloride salt of polymorphic Form I is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form I may be a channel solvate. As commonly referred to by a person skilled in the art, the term “channel solvate”, or a variant thereof, refers to a crystal lattice containing tunnels that can be occupied by solvent molecules (e.g., channel solvents), and other molecules and ions. Examples of other molecules and ions that may be present in the channels of polymorphic Form I include water, ethanol and/or chloride ions.
Form II
In another aspect, provided is polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°.
Polymorphic Form II may have a calculated XRPD pattern substantially as shown in FIG. 2. It should be understood that the XPRD provided in FIG. 2 is a calculated XRPD from the single crystal data acquired at 100K for polymorphic Form II.
In some embodiments of polymorphic Form II, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply: (a) polymorphic Form II has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form II, substantially as shown in FIG. 2; (b) polymorphic Form II has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°; (c) polymorphic Form II has an orthorhombic crystal system; (d) polymorphic Form II has a C222(1) space group; (e) polymorphic Form II has a volume of 5702(2) Å3; (f) polymorphic Form II has a Z value of 8; and (g) polymorphic Form I has a density of 1.254 g/cm3.
In some embodiments, polymorphic Form II has at least one, or both of the following properties:
(a) an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form II, substantially as shown in FIG. 2; and
(b) a unit cell, as determined by Single Crystal X-ray Crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°.
In some embodiments, polymorphic Form II has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form II, displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 2. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments disclosed herein, including for polymorphic Form II, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the hydrochloride salt of polymorphic Form II is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form III
In another aspect, provided is polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967(3)°; and γ=90°.
Polymorphic Form III may have a calculated XRPD pattern substantially as shown in FIG. 3. It should be understood that the XPRD provided in FIG. 3 is a calculated XRPD from the single crystal data acquired at 100K for polymorphic Form III.
In some embodiments of polymorphic Form III, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply: (a) polymorphic Form III has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form III, substantially as shown in FIG. 3; (b) polymorphic Form III has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967(3)°; and γ=90°; (c) polymorphic Form III has an monoclinic crystal system; (d) polymorphic Form III has a C2 space group; and (e) polymorphic Form III has a volume of 3052.2(5) Å3.
In some embodiments, polymorphic Form III has at least one, or both of the following properties:
(a) an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form III, substantially as shown in FIG. 3; and
(b) a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967(3)°; and γ=90°.
In some embodiments, polymorphic Form III has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 3. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments disclosed herein, including for polymorphic Form III, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the hydrochloride salt of polymorphic Form III is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form III may have one or more channels. Such channels may be occupied by certain molecules and/or ions, such as water and/or chloride ions.
Form IV
In another aspect, provided is polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°.
Polymorphic Form IV may have a calculated XRPD pattern substantially as shown in FIG. 4. It should be understood that the XPRD provided in FIG. 4 is a calculated XRPD from the single crystal data acquired at 100K for polymorphic Form IV.
In some embodiments of polymorphic Form IV, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(h) apply: (a) polymorphic Form IV has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form IV, substantially as shown in FIG. 4; (b) polymorphic Form IV has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°; (c) polymorphic Form IV has an orthorhombic crystal system; (d) polymorphic Form IV has a C222(1) space group; (e) polymorphic Form IV has a volume of 5919.8(5) Å3; (f) polymorphic Form IV has a Z value of 8; (g) polymorphic Form IV has a density of 1.405 g/cm3; and (h) polymorphic Form IV has an absorption coefficient of 0.184 mm−1.
In some embodiments, polymorphic Form IV has at least one, or both of the following properties:
(a) an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form IV, substantially as shown in FIG. 4; and
(b) a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°.
In some embodiments, polymorphic Form IV has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 4. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments disclosed herein, including for polymorphic Form IV, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the hydrochloride salt of polymorphic Form IV is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form IV may have one or more channels. Such channels may be occupied by certain ions, such as chloride ions.
Form V
In another aspect, provided is polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 5.
In some embodiments, polymorphic Form V has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 5. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form V, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6 and 28.1. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 15.9, 18.9, 20.3, 24.0, 25.6, 28.1 and 36.3.
Form VI
In another aspect, provided is polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 6.
In some embodiments, polymorphic Form VI has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 6. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form VI, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 17.0, 23.2 and 25.1. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1.
Form VII
In another aspect, provided is polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 7.
In some embodiments, polymorphic Form VII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 7. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form VII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0. In certain embodiments, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 11.9, 15.3, 19.7, 20.1, 21.7 and 24.0. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7, and 24.0 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 9.8, 11.9, 15.3, 19.7, 20.1, 21.7, 24.0, 28.4 and 28.9.
Form VIII
In another aspect, provided is polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 8.
In some embodiments, polymorphic Form VIII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 8. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form VIII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1. In certain embodiments, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 12.4, 15.3, 20.3, 21.7 and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and one or more 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and one 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and two 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and three 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and four 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 12.4, 15.3, 19.0, 19.9, 20.3, 21.7, 24.1 and 28.9.
Form IX
In another aspect, provided is polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 9.
In some embodiments, polymorphic Form IX has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 9. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form IX, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0. In certain embodiments, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8, 24.0 and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and one or more 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and one 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and two 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and three 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 9.8, 12.5, 19.6, 20.8, 21.8, 24.0 and 29.0.
Form X
In another aspect, provided is polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 10.
In some embodiments, polymorphic Form X has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 10. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form X, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2. In certain embodiments, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 11.9, 15.5, 21.8, 24.2, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 11.9, 15.5, 19.4, 19.8, 20.3, 21.8, 24.2, 28.6 and 29.0.
Form XI
In another aspect, provided is polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 11.
In some embodiments, polymorphic Form XI has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 11. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form XI, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.5, 15.0, 17.0, 19.3, 20.3, 22.0, 25.5 and 31.7.
Form XII
In another aspect, provided is polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 12.
Polymorphic Form XII may have a unit cell as determined by crystal X-ray crystallography of the following dimensions: a=10.717 Å (3); b=10.161 Å (3); c=12.409 Å (4); α=90°; β=104.021° (4); and γ=90°.
In some embodiments, polymorphic Form XII has at least one, or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 12; and
(b) a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=10.717 Å (3); b=10.161 Å (3); c=12.409 Å (4); α=90°; β=104.021° (4); and γ=90°.
In some embodiments, polymorphic Form XII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 12. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form XII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9, 19.1, 19.6, 23.3, 24.9, 25.4 and 29.4.
In certain embodiments, the hydrochloride salt of polymorphic Form XII is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form XII may have one or more channels.
Form XIII
In another aspect, provided is polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 13.
In some embodiments, polymorphic Form XIII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 13. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form XIII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 8.0, 8.1, 9.7, 11.7, 13.6, 16.8, 18.5, 23.5, 23.9 and 25.7.
In further embodiments, additional patterns of solvate forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are provided.
Pattern 1
In one aspect, provided is Pattern 1 of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein Pattern 1 an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 14A.
In some embodiments, Pattern 1 has an XRPD pattern substantially as shown in FIG. 14A.
In some embodiments, Pattern 1 is a prepared in the presence of propylacetate. In some embodiments, Pattern 1 corresponds to a propylacetate solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments, Pattern 1 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 14A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 1, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, 25.8, 22.9, 11.7, 8.3, and 17.0. Table 1 shows the full XRPD peak list for Pattern 1.
TABLE 1
XRPD Peak List for Pattern 1
Angle (2-Theta °)
Intensity (%)
7.0
21.5
7.5
18.6
8.3
33.6
9.2
100.0
11.7
37.6
12.0
26.7
12.8
22.1
14.1
21.2
16.8
52.1
17.0
31.4
18.5
43.9
19.3
15.5
20.1
24.0
20.8
16.1
21.5
18.6
22.5
19.7
22.9
40.1
23.1
23.5
23.4
63.3
24.0
21.6
24.7
20.8
25.1
25.9
25.8
41.5
28.0
23.4
28.6
18.0
Pattern 9
In one aspect, provided is Pattern 9 of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein Pattern 9 an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 14B.
In some embodiments, Pattern 9 has an XRPD pattern substantially as shown in FIG. 14B.
In some embodiments, Pattern 9 is a prepared in the presence of propylacetate. In some embodiments, Pattern 9 corresponds to a propylacetate solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments, Pattern 9 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 14B. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 1, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, 23.4, 27.9, 22.9, 14.0, and 17.0. Table 2 shows the full XRPD peak list for Pattern 9.
TABLE 2
XRPD Peak List for Pattern 9
Angle (2-Theta °)
Intensity (%)
6.9
6.3
7.5
11.4
8.3
8.9
9.2
100.0
11.7
13.8
12.0
9.4
12.8
4.7
14.0
15.8
16.7
29.0
17.0
14.7
17.7
4.5
18.5
31.5
19.3
6.0
20.1
7.3
20.8
10.4
21.4
7.6
22.6
12.9
22.9
18.9
23.4
27.9
23.9
7.1
24.8
9.5
25.1
8.5
25.8
30.1
27.9
19.7
28.5
9.6
Pattern 2
In one aspect, provided is Pattern 2 of the polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 15A. Pattern 2 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 15B. Pattern 2 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 15C.
In some embodiments, Pattern 2 is a prepared in the presence of isopropyl acetate. In some embodiments, Pattern 2 corresponds to an isopropyl acetate solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments of Pattern 2, at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply: (a) Pattern 2 has an XRPD pattern substantially as shown in FIG. 15A; (b) Pattern 2 has a DSC thermogram substantially as shown in FIG. 15B; (c) Pattern 2 has a TGA graph substantially as shown in FIG. 15C; (d) Form 2 has a melting temperature onset as determined by DSC at about 68° C.; (e) Pattern 2 has a second melting temperature onset as determined by DSC at about 153° C.; and (f) Pattern 2 has a third melting temperature onset as determined by DSC at about 179° C.
In some embodiments, Pattern 2 has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 15A;
(b) a DSC thermogram substantially as shown in FIG. 15B;
In some embodiments, Pattern 2 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 15A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 2, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, 16.7, 22.8, 25.0, 18.6, 13.3, and 28.1. Table 3 shows the full XRPD peak list for Pattern 2.
TABLE 3
XRPD Peak List for Pattern 2
Angle (2-Theta °)
Intensity (%)
6.8
5.2
7.8
100.0
9.2
31.0
11.6
8.2
13.3
10.5
14.1
5.4
15.6
4.7
16.7
18.4
18.1
9.9
18.6
12.4
20.1
8.3
21.1
7.5
22.8
18.3
23.4
52.1
25.0
17.8
25.8
20.6
28.1
10.2
Pattern 3
In one aspect, provided is Pattern 3 of the polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 16A. Pattern 3 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 16B. Pattern 3 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 16C.
In some embodiments, Pattern 3 is a prepared in the presence of 1,2-dimethoxyethane. In some embodiments, Pattern 3 corresponds to an 1,2-dimethoxyethane solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments of Pattern 3, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) Pattern 3 has an XRPD pattern substantially as shown in FIG. 16A; (b) Pattern 3 has a DSC thermogram substantially as shown in FIG. 16B; (c) Pattern 3 has a TGA graph substantially as shown in FIG. 16C; and (d) Pattern 3 has a melting temperature onset as determined by DSC at about 172° C.
In some embodiments, Pattern 3 has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 16A;
(b) a DSC thermogram substantially as shown in FIG. 16B;
In some embodiments, Pattern 3 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 16A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 3, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, 19.7, 20.0, 28.7, 15.1, 12.2, and 26.7. Table 4 shows the full XRPD peak list for Pattern 3.
TABLE 4
XRPD Peak List for Pattern 3
Angle (2-Theta °)
Intensity (%)
9.4
5.3
9.8
100.0
11.1
17.6
11.7
62.8
12.2
28.9
12.9
12.6
14.3
10.8
14.6
4.1
15.1
33.6
15.4
10.7
17.0
9.1
17.4
14.1
17.7
15.7
18.5
5.9
18.9
18.7
19.1
28.6
19.7
61.5
20.0
50.1
20.6
14.4
20.9
19.5
21.5
94.2
22.3
11.6
22.6
8.1
23.0
12.6
23.6
10.8
24.0
82.7
24.7
12.2
25.4
6.1
26.0
9.6
26.3
5.0
26.7
28.7
27.4
5.0
27.7
6.1
28.3
19.9
28.7
34.5
29.1
8.5
29.7
9.6
Pattern 4
In one aspect, provided is Pattern 4 of the polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 17A.
Pattern 4 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 17B. Pattern 4 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 17C.
In some embodiments, Pattern 4 is a prepared in the presence of isopropyl alcohol. In some embodiments, Pattern 4 corresponds to an isopropyl alcohol solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments of Pattern 4, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) Pattern 4 has an XRPD pattern substantially as shown in FIG. 17A; (b) Pattern 4 has a DSC thermogram substantially as shown in FIG. 17B; (c) Pattern 4 has a TGA graph substantially as shown in FIG. 17C; and (d) Pattern 4 has a melting temperature onset as determined by DSC at about 170° C.
In some embodiments, Pattern 4 has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 17A;
(b) a DSC thermogram substantially as shown in FIG. 17B;
In some embodiments, Pattern 4 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 17A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 4, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, 20.2, 19.1, 21.8, 7.2, 14.8, and 19.6. Table 5 shows the full XRPD peak list for Pattern 4.
TABLE 5
XRPD Peak List for Pattern 4
Angle (2-Theta °)
Intensity (%)
7.2
13.8
8.4
3.1
11.4
7.0
12.3
100.0
13.0
5.1
14.5
3.4
14.8
11.3
15.2
2.6
16.8
58.7
17.3
1.8
17.7
7.9
18.5
3.2
18.8
4.4
19.1
18.9
19.6
11.3
19.9
9.1
20.2
24.2
20.5
9.7
21.3
7.7
21.8
18.5
23.0
11.3
23.5
6.0
24.0
6.3
24.5
2.8
24.9
70.9
25.3
42.0
25.7
4.2
26.4
3.6
26.8
6.1
27.4
1.8
27.8
4.7
28.0
10.3
28.3
2.2
29.1
4.2
29.5
6.6
2-Methyl-1-Propanol Solvate
In one aspect, provided is the 2-methyl-1-propanol solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 18A. The 2-methyl-1-propanol solvate may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 18B. The 2-methyl-1-propanol solvate may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 18C.
In some embodiments of the 2-methyl-1-propanol solvate, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) 2-methyl-1-propanol solvate has an XRPD pattern substantially as shown in FIG. 18A; (b) 2-methyl-1-propanol solvate has a DSC thermogram substantially as shown in FIG. 18B; (c) 2-methyl-1-propanol solvate has a TGA graph substantially as shown in FIG. 18C; and (d) 2-methyl-1-propanol solvate has a melting temperature onset as determined by DSC at about 113° C.
In some embodiments, the 2-methyl-1-propanol solvate has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 18A;
(b) a DSC thermogram substantially as shown in FIG. 18B;
In some embodiments, the 2-methyl-1-propanol solvate has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 18A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for the 2-methyl-1-propanol solvate, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, 24.5, 24.3, 12.4, 22.5, 12.9, and 28.5. Table 6 shows the full XRPD peak list for the 2-methyl-1-propanol solvate.
TABLE 6
XRPD Peak List for 2-Methyl-1-propanol Solvate Form
Angle (2-Theta °)
Intensity (%)
4.3
2.9
5.9
1.0
8.6
100.0
9.9
0.7
10.3
3.2
11.2
1.2
12.1
2.6
12.4
3.8
12.7
1.1
12.9
3.3
13.8
2.8
14.1
0.6
14.6
0.5
15.4
0.9
16.0
1.6
16.9
3.0
17.3
18.5
17.7
3.0
17.9
0.9
18.5
0.7
18.9
2.7
19.4
0.6
19.9
1.8
20.2
2.7
20.5
2.8
20.7
4.8
20.9
2.9
21.9
1.4
22.5
3.4
22.8
3.2
23.7
1.4
23.9
1.9
24.3
4.1
24.5
4.7
24.8
2.9
25.4
1.7
26.0
60.2
26.9
1.2
27.6
1.7
28.0
1.4
28.3
2.6
28.5
3.3
28.8
3.3
29.6
1.0
29.8
1.1
1,4-Dioxane Solvate
In one aspect, provided is the 1,4-dioxane solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 19A. The 1,4-dioxane solvate may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 19B. The 1,4-dioxane solvate may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 19C.
In some embodiments of the 1,4-dioxane solvate, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) 1,4-dioxane solvate has an XRPD pattern substantially as shown in FIG. 19A; (b) 1,4-dioxane solvate has a DSC thermogram substantially as shown in FIG. 19B; (c) 1,4-dioxane solvate has a TGA graph substantially as shown in FIG. 19C; and (d) 1,4-dioxane solvate has a melting temperature onset as determined by DSC at about 158° C.
In some embodiments, the 1,4-dioxane solvate has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 19A;
(b) a DSC thermogram substantially as shown in FIG. 19B;
In some embodiments, the 1,4-dioxane solvate has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 19A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for the 1,4-dioxane solvate, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, 21.1, 20.6, 21.7, 11.9, 24.5, and 14.7. Table 7 shows the full XRPD peak list for the 1,4-dioxane solvate.
TABLE 7
XRPD Peak List for 1,4-Dioxane Solvate Form
Angle (2-Theta °)
Intensity (%)
6.9
13.6
8.0
6.1
9.6
4.9
11.5
78.6
11.9
26.1
12.7
10.2
13.7
8.7
14.7
20.5
15.1
4.9
16.2
19.4
16.9
13.5
17.5
5.4
17.7
6.2
18.1
6.4
18.8
83.1
19.4
62.8
19.8
12.5
20.6
49.0
21.1
60.0
21.7
36.3
22.7
9.8
23.2
100.0
24.1
9.1
24.5
22.2
25.2
4.8
25.6
10.4
26.0
15.0
26.3
5.2
26.6
5.5
27.2
8.9
27.7
5.6
28.4
7.4
28.7
7.1
29.3
4.7
29.6
6.1
Toluene Solvate
In one aspect, provided is a toluene solvent form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 20.
In some embodiments of the toluene solvent form, the toluene solvent form has an XRPD pattern substantially as shown in FIG. 20.
In some embodiments, the toluene solvent form has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 20. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for the toluene solvent form, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, 24.0, 16.6, 22.5, 27.9, 12.7, and 27.5. Table 8 shows the full XRPD peak list for the toluene solvent form.
TABLE 8
XRPD Peak List for Toluene Solvent Form
Angle (2-Theta °)
Intensity (%)
6.9
15.9
8.4
75.1
9.7
16.1
10.3
10.7
11.5
13.9
11.9
13.3
12.7
36.6
13.6
17.4
15.8
15.9
16.6
46.2
17.1
31.0
18.0
19.8
19.3
25.8
19.9
29.2
21.5
22.6
22.5
44.8
23.1
51.3
23.3
56.7
24.0
48.5
25.5
100.0
26.3
31.3
27.5
32.2
27.9
39.7
29.6
24.7
Compositions Thereof
Provided are also compositions comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of polymorphs (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) as described herein. In a particular embodiment, a composition comprising one of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising two of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising three of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising four of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising five of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising six of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising seven of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising eight of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising nine of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising ten of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising eleven of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising twelve of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In other embodiments, the compositions described herein may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
In some embodiments, the term “substantially pure” or “substantially free” with respect to a particular polymorphic form of a compound means that the composition comprising the polymorphic form contains less than 95%, less than 90%, less than 80%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other polymorphic forms and/or impurities. In certain embodiments, “substantially pure” or “substantially free of” refers to a substance free of other substances, including other polymorphic forms and/or impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
Form I
In some embodiments, the composition comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form I as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form I. In particular embodiments of compositions comprising polymorphic Form I, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form I. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form I, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms II-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form I, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form I present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form I, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form II
In some embodiments, the composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form II as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form II. In particular embodiments of compositions comprising polymorphic Form II, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form II. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form II of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form II, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I, III-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form II, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form II present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form II, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form II, the compositions further comprise polymorphic Form X of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms II and X, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms II and X. It should be understood that the relative ratio of polymorphic Form II to polymorphic Form X present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form III
In some embodiments, the composition comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form III as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form III. In particular embodiments of compositions comprising polymorphic Form III, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form III. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form III of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form III, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-II, IV-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form III, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form III present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form III, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form III, the compositions further comprise polymorphic Form V of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms III and V, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms III and V. It should be understood that the relative ratio of polymorphic Form III to polymorphic Form V present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form III has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form III has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form IV
In some embodiments, the composition comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form IV as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form IV. In particular embodiments of compositions comprising polymorphic Form IV, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form IV. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form IV of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form IV, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-III, V-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form IV, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form IV present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form IV, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form IV, the compositions further comprise polymorphic Form IX of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms IV and IX, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms IV and IX. It should be understood that the relative ratio of polymorphic Form IV to polymorphic Form IX present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form IV has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form IV has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form V
In some embodiments, the composition comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form V as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form V. In particular embodiments of compositions comprising polymorphic Form V, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form V. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form V of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form V, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-IV, VI-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form V, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form V present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form V, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form V, the compositions further comprise polymorphic Form III of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms III and V, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms III and V. It should be understood that the relative ratio of polymorphic Form III to polymorphic Form V present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form V has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form V has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form VI
In some embodiments, the composition comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form VI as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form VI. In particular embodiments of compositions comprising polymorphic Form VI, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form VI. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form VI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form VI, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-V, VII-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form VI, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form VI present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form VI, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form VI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form VI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form VII
In some embodiments, the composition comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form VII as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form VII. In particular embodiments of compositions comprising polymorphic Form VII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form VII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form VII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form VII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-VI, VIII-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form VII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form VII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form VII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form VII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form VII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form VIII
In some embodiments, the composition comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form VIII as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form VIII. In particular embodiments of compositions comprising polymorphic Form VIII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form VIII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form VIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form VIII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-VII, IX-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form VIII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form VIII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form VIII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form VIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form VIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form IX
In some embodiments, the composition comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form IX as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form IX. In particular embodiments of compositions comprising polymorphic Form IX, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form IX. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form IX of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form IX, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-VIII, X-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form IX, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form IX present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form IX, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form IX, the compositions further comprise polymorphic Form IV of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms IV and IX, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms IV and IX. It should be understood that the relative ratio of polymorphic Form IV to polymorphic Form IX present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form IX has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form IX has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form X
In some embodiments, the composition comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form X as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form X. In particular embodiments of compositions comprising polymorphic Form X, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form X. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form X of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form X, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-IX, XI-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form X, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form X present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form X, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form X, the compositions further comprise polymorphic Form II of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms II and X, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms II and X. It should be understood that the relative ratio of polymorphic Form II to polymorphic Form X present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form X has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form X has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form XI
In some embodiments, the composition comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form XI as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form XI. In particular embodiments of compositions comprising polymorphic Form XI, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form XI. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form XI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form XI, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-X, XII-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form XI, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form XI present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form XI, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form XI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form XI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form XII
In some embodiments, the composition comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form XII as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form XII. In particular embodiments of compositions comprising polymorphic Form XII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form XII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form XII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form XII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-XI, XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form XII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form XII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form XII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form XII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form XII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form XIII
In some embodiments, the composition comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form XIII as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form XIII. In particular embodiments of compositions comprising polymorphic Form XIII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form XIII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form XIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form XIII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-XII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form XIII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form XIII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form XIII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form XIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form XIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Preparation of the Polymorphs
One method of synthesizing (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one has been previously described in U.S. Pat. No. 7,932,260. This reference is hereby incorporated herein by reference in its entirety, and specifically with respect to the synthesis of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. One or more polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be prepared from (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one or from its hydrochloride salt.
For example, in one aspect, provided is a method of producing a composition comprising one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a compound of Formula (I) with hydrochloric acid and a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the hydrochloride salt of the compound of Formula (I). In another aspect, provided is another method of producing a composition comprising one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a suitable solvent or a mixture of suitable solvents.
The choice of a particular solvent or combination of solvents affects the formation favoring one polymorphic form of a hydrochloride salt (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one over another. Solvents suitable for polymorph formation may include, for example, methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, and any mixtures thereof.
In another aspect, provided is also one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced according to any of the methods described herein.
It should be understood that the methods for preparing the polymorphs described herein (including any one or more of polymorphic Forms I to XIII) may yield quantity and quality differences compared to the methods for preparing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced on laboratory scale.
Form I
In one embodiment, provided is a method of producing a composition comprising polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
Provided is a polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
Provided is also a polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
In certain embodiments of the polymorphic Form I produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Forms II and X
In one embodiment, provided is a method of producing a composition comprising polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form II, Form X, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is acetone.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form II, Form X, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is acetone.
Provided is a polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is acetone.
Provided is also a polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is acetone.
In certain embodiments of the polymorphic Form II, Form X, or a mixture thereof, produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Forms III and V
In one embodiment, provided is a method of producing a composition comprising polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form III, Form V, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-methyltetrahydrofuran.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form III, Form V, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-methyltetrahydrofuran.
Provided is a polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 2-methyltetrahydrofuran.
Provided is also a polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 2-methyltetrahydrofuran.
In certain embodiments of the polymorphic Form III, Form V, or a mixture thereof, produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Forms IV and IX
In one embodiment, provided is a method of producing a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is tetrahydrofuran.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is tetrahydrofuran.
Provided is a polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is tetrahydrofuran.
Provided is a polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is tetrahydrofuran.
In certain embodiments of the polymorphic Form IV, Form IX, or a mixture thereof, produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form VI
In one embodiment, provided is a method of producing a composition comprising polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form VI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl isobutyl ketone.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form VI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl isobutyl ketone.
Provided is a polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is methyl isobutyl ketone.
Provided is also a polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to produce a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is methyl isobutyl ketone.
In certain embodiments of the polymorphic Form VI produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form VII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form VII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl ethyl ketone.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form VII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl ethyl ketone.
Provided is a polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is methyl ethyl ketone.
Provided is also a polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is methyl ethyl ketone.
In certain embodiments of the polymorphic Form VII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form VIII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form VIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is dichloromethane.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form VIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is dichloromethane.
Provided is a polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is dichloromethane.
Provided is also a polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is dichloromethane.
In certain embodiments of the polymorphic Form VIII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form XI
In one embodiment, provided is a method of producing a composition comprising polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form XI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-propanol.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form XI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-propanol.
Provided is a polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 2-propanol.
Provided is also a polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 2-propanol.
In certain embodiments of the polymorphic Form XI produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form XII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form XII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-propanol.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form XII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-propanol.
Provided is a polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 1-propanol.
Provided is also a polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 1-propanol.
In certain embodiments of the polymorphic Form XII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form XIII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form XIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-butanol.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form XIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-butanol.
Provided is a polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 1-butanol.
Provided is also a polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 1-butanol.
In certain embodiments of the polymorphic Form XIII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
The combination of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with one or more suitable solvents, as described above, yields a composition or mixture comprising the solvent and the one or more polymorphic forms produced. In some instances where only a portion of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is converted into one or more polymorphic forms, the composition further comprises the hydrochloride salt. In some embodiments of the methods described above to produce the one or more polymorphic forms, the method further comprises isolating the one or more polymorphic forms from the resulting composition. Any suitable techniques or methods known in the art to isolate the one or more polymorphic forms from the composition may be employed. For example, the solvent or mixture of solvents used in the methods described above may be removed by known methods, such as filtration and/or evaporation, to isolate the one or more polymorphic forms produced from the composition.
Pharmaceutical Compositions
The polymorphic forms described herein can be administered as the neat chemical, but it is typical, and preferable, to administer the compound in the form of a pharmaceutical composition or formulation. Accordingly, provided are pharmaceutical compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and any combinations thereof) and one or more pharmaceutically acceptable carriers, excipients, or other ingredients (including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants). In certain embodiments, pharmaceutical compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) and one or more pharmaceutically acceptable excipients is provided. In certain embodiments, pharmaceutical compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) also include one or more additional therapeutic agents, as well as one or more pharmaceutically acceptable excipients. The composition can include the polymorphic forms described herein either as the sole active agent or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones mixed with one or more pharmaceutically acceptable carriers, excipients, or other ingredients. Carriers, excipients, and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.
Provided herein is a pharmaceutical composition comprising one or more polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one described herein (e.g., one or more of polymorphic Forms I to XIII), and a pharmaceutical acceptable carrier or excipient.
Also provided herein is a pharmaceutical composition comprising one or more polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one described herein (e.g., one or more of polymorphic Forms I to XIII), and a pharmaceutical acceptable excipient.
In one embodiment, the pharmaceutical composition comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In a further embodiment, the pharmaceutical composition comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the pharmaceutical composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In another embodiment, the pharmaceutical composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the pharmaceutical composition comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In another embodiment, the pharmaceutical composition comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the pharmaceutical composition comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In another embodiment, the pharmaceutical composition comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
Techniques for formulation and administration of pharmaceutical compositions can be found in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co, Easton, Pa., 1990. The pharmaceutical compositions described herein can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Depending on the condition being treated, these pharmaceutical compositions can be formulated and administered systemically or locally.
The pharmaceutical compositions can be formulated to contain suitable pharmaceutically acceptable carriers, and optionally can comprise excipients and auxiliaries that facilitate processing of the polymorphic forms described herein into preparations that can be used pharmaceutically. The mode of administration generally determines the nature of the carrier. For example, formulations for parenteral administration can include aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration are physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For preparations including proteins, the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
Alternatively, formulations for parenteral use can include dispersions or suspensions of polymorphic forms described herein prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, dextran, and mixtures thereof. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT™ series available from Rohm America Inc. (Piscataway, N.J.). Emulsions, e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants). Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
Liposomes containing the polymorphic forms described herein also can be employed for parenteral administration. Liposomes generally are derived from phospholipids or other lipid substances. The compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, Academic Press, New York (1976).
In some embodiments, the polymorph or composition thereof disclosed herein is formulated for oral administration using pharmaceutically acceptable carriers, excipients or other ingredients well known in the art. Preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders. To illustrate, pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
In certain embodiments, the pharmaceutical compositions described herein are in the form of tablets, pills or capsules. In a particular embodiment, the pharmaceutical compositions described herein are in the form of a tablet. Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or more excipients, which include, without limitation:
a) diluents, such as microcrystalline cellulose and sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
b) binders, such as sodium starch glycolate, croscarmellose sodium, magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.;
c) cellulose materials, such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof, such as sodium alginate, or effervescent compositions;
e) lubricants, such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol;
f) flavorants and sweeteners;
g) colorants or pigments, e.g., to identify the product or to characterize the quantity (dosage) of active compound; and
h) other ingredients, such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
For example, provided is a tablet comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and any combinations thereof) and one or more pharmaceutically acceptable carriers or excipients. Also provided is a tablet comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and any combinations thereof) and one or more pharmaceutically acceptable excipients.
In one embodiment, the tablet comprises substantially pure polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the tablet comprises substantially pure polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutically acceptable excipient.
In another embodiment, the tablet comprises substantially pure polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the tablet comprises substantially pure polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the tablet comprises substantially pure polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In any of the foregoing tablets, in one variation, the tablet is substantially free of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, in any of the foregoing tablets, the tablet is free of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The polymorphs described herein are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the polymorph actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the subject receiving such treatment, the severity of the subject's symptoms, and the like.
The tablets or pills described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage element, the latter being in the form of an envelope over the former. The two elements can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner element to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymorphic acids and mixtures of polymorphic acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
For example, provided is a unit dosage comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, the unit dosage comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, the unit dosage comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, the unit dosage comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, the unit dosage comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In any of the foregoing unit dosage forms, in certain embodiments, the hydrochloride salt is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In any of the foregoing unit dosage forms, in one variation, the unit dosage form is substantially free of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In certain embodiments, in any of the foregoing unit dosage forms, the tablet further includes one or more excipients.
In certain embodiments, the unit dosage forms described herein include 75-300 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75-200 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75-150 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75 mg, 100 mg, 150 mg, or 200 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 100 mg or 150 mg 200 mg of the polymorphic forms described herein.
Modes of Administration and Dosages
Pharmaceutical compositions including the polymorphic forms described herein can be administered to the subject by any conventional method, including parenteral and enteral techniques. Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enteral administration modalities include, for example, oral, buccal, sublingual, and rectal administration. Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and buccal and sublingual administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Parenteral administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT™.
Moreover, the therapeutic index of the compound having the polymorphic forms described herein can be enhanced by modifying or derivatizing the compound for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compound can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described. See e.g., Pietersz et al., Immunol. Rev., 129:57 (1992); Trail et al., Science, 261:212 (1993); and Rowlinson-Busza et al., Curr. Opin. Oncol., 4:1142 (1992). Tumor-directed delivery of the compound can enhance the therapeutic benefit by, inter alia, minimizing potential nonspecific toxicities that can result from radiation treatment or chemotherapy. In some embodiments, the compound having a polymorphic form described herein, and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibody.
Pharmacokinetic and pharmacodynamic information about the polymorphic forms described herein and the formulation of the compound having a polymorphic form described herein can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for the compound having a polymorphic form described herein used in the methods described herein, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range that modulates PI3Kδ expression or activity. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the “therapeutic index”, which typically is expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantially higher than the effective dose, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity.
It should be understood that any effective administration regimen regulating the timing and sequence of doses can be used. A compound having a polymorphic form described herein and pharmaceutical compositions thereof may include those wherein the active ingredient is administered in an effective amount to achieve its intended purpose.
In some embodiments, a “therapeutically effective amount” means an amount sufficient to modulate PI3K expression or activity, including PI3Kδ expression or activity, and thereby treat a subject (e.g., a human) suffering an indication, or to alleviate the existing symptoms of the indication.
Exemplary dosage levels for a human subject may be of the order of from about 0.001 milligram of active agent per kilogram body weight (mg/kg) to about 1000 mg/kg. Dosage units of the active agent may comprise from about 0.01 mg to about 1000 mg, or from about 0.1 mg to about 100 mg, depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. For example, when administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. In certain embodiments, the total daily dosage for a human subject is about 150-300 mg/day. In certain embodiments, the total daily dosage for a human subject is about 200-300 mg/day. In certain embodiments, the total daily dosage for a human subject is 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg. In certain embodiments, the total daily dosage for a human subject is 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In certain embodiments, the total daily dosage for a human subject is 150 mg, 200 mg, or 300 mg. In certain embodiments, the total daily dosage for a human subject is 200 mg or 300 mg. In certain embodiments, the total daily dosage for a human subject is 100 mg or 150 mg. The final dosage regimen is determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the subject, the age, condition, body weight, sex, and diet of the subject, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
The frequency of dosing depends on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent. Short-acting pharmaceutical compositions (i.e., short half-life) can be administered once a day or more than once a day (e.g., two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks.
In certain embodiments, the pharmaceutical composition disclosed herein are administered once, twice, or three times daily. In certain embodiments, the pharmaceutical composition disclosed herein are administered once or twice daily. In certain embodiments, the pharmaceutical composition disclosed herein are administered once daily.
Bioequivalents of the Polymorphs
Also provided herein are polymorphs that are bioequivalent to any one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one described herein.
In certain embodiments, bioequivalence between two polymorphs refers to polymorphs having substantially similar bioavailability, substantially similar efficacy, substantially similar safety profiles, or a combination thereof.
In yet other embodiments, bioequivalence refers to polymorphs that exhibit substantially similar pharmacokinetic profiles or therapeutic effects. Bioequivalence may be demonstrated through several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies. In some embodiments, bioequivalence can be demonstrated using any suitable pharmacokinetic measures or combination of pharmacokinetic measures known in the art, including loading dose, steady-state dose, initial or steady-state concentration of drug, biological half-life, elimination rate, area under the curve (AUC), clearance, the peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency. In some embodiments, bioequivalence is achieved with similar dosing amounts. In alternative embodiments, bioequivalence is achieved with different dosing amounts.
Uses of the Polymorphs and Compositions Thereof
Therapeutic Uses
Provided are also a use of the polymorphs or compositions thereof described herein to selectively or specifically inhibit PI3Kδ activity therapeutically or prophylactically. The method comprises administering the polymorphs or compositions thereof to a subject (e.g., a human) in need thereof in an amount sufficient to inhibit PI3Kδ activity. The method can be employed to treat humans or animals suffering from, or subject to, a condition whose symptoms or pathology is mediated by PI3Kδ expression or activity.
“Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following:
(i) decreasing one more symptoms resulting from the disease;
(ii) diminishing the extent of the disease and/or stabilizing the disease (e.g., delaying the worsening of the disease);
(iii) delaying the spread (e.g., metastasis) of the disease;
(iv) delaying or slowing the recurrence of the disease and/or the progression of the disease;
(v) ameliorating the disease state and/or providing a remission (whether partial or total) of the disease and/or decreasing the dose of one or more other medications required to treat the disease;
(vi) increasing the quality of life; and/or
(vii) prolonging survival.
In some embodiments, “disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
The methods disclosed in the application embrace various modes of treating an animal subject, preferably a mammal, more preferably a primate, and still more preferably a human. Among the mammalian animals that can be treated are, for example, humans; companion animals (pets), including dogs and cats; farm animals, including cattle, horses, sheep, pigs, and goats; laboratory animals, including rats, mice, rabbits, guinea pigs, and nonhuman primates; and zoo specimens. Among the non-mammalian animals that can be treated include, for example, birds, fish, reptiles, and amphibians.
In one aspect, the polymorphs and compositions thereof described herein can be employed in methods of inhibiting the growth or proliferation of cancer cells of hematopoietic origin, such as cancer cells. In some embodiments, the cancer cells are of lymphoid origin, and in specific embodiments, the cancer cells are related to or derived from B lymphocytes or B lymphocyte progenitors. In another aspect, the polymorphs and compositions thereof described herein can be employed in methods of treating a human with a cancer.
Cancers amenable to treatment using the method disclosed in the application include, for example, lymphomas (e.g., malignant neoplasms of lymphoid and reticuloendothelial tissues, such as Burkitt's lymphoma, Hodgkins' lymphoma, non-Hodgkins' lymphomas, lymphocytic lymphomas); multiple myelomas; leukemias (e.g., lymphocytic leukemias, chronic myeloid (myelogenous) leukemias), and solid tumor (e.g., pancreatic). Other cancer cells, of hematopoietic origin or otherwise, that express p110δ also can be treated by administration of the polymorphs and compositions thereof described herein.
In other embodiments, the forms described herein may be used to treat cancers that are mediated by, dependent on or associated with PI3K activity, such as PI3Kδ activity. In certain embodiments, the cancer is a hematologic malignancy. In certain embodiments, the cancer is lymphoma, multiple myeloma, or leukemia. In certain embodiments, the cancer is a solid tumor cancer. In particular embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic lymphoma, marginal zone lymphoma, Burkitt lymphoma, or follicular B-cell non-Hodgkin lymphoma (FL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). In one embodiment, the cancer is indolent non-Hodgkin's lymphoma (iNHL). It should be understood that non-Hodgkin's lymphoma may, in certain embodiments, encompass the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In certain embodiments, the forms described herein may be used to treat chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL), or small lymphocytic lymphoma (SLL). In certain embodiments, the forms described herein may be used to treat relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), or relapsed small lymphocytic lymphoma (SLL). In certain embodiments, the forms described herein may be used to treat non-Hodgkin's lymphoma (NHL) or indolent non-Hodgkin's lymphoma (iNHL). In certain embodiments, the forms described herein may be used to treat relapsed non-Hodgkin's lymphoma (NHL) or relapsed indolent non-Hodgkin's lymphoma (iNHL).
In another aspect, the polymorphs and compositions thereof described herein can be employed in methods of treating an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD). In particular embodiments, the autoimmune disease is asthma, rheumatoid arthritis, multiple sclerosis, or lupus.
In yet another aspect, provided are methods of treating a human having a PI3K-mediated disorder by administering one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) to the human. In another aspect, provided are methods of treating a human having a PI3K-mediated disorder by administering one or more of the polymorphic forms described herein (e.g., one or more of the solvate forms corresponding to Pattern 1, 2, 3, 4, or the 2-methyl-1-propanol solvate, or the 1,4-dioxane solvate, or the toluene solvate) to the human. Provided are also methods of modulating PI3K an individual by administering one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one variation, the human has cancer, such as leukemia or lymphoma. In another variation, the human has an autoimmune disease, such as asthma, rheumatoid arthritis, multiple sclerosis, or lupus.
In any of the foregoing methods, one or more polymorphic forms may be administered to the individual as unit dosage, for example in the form of a tablet, as described herein. Exemplary unit dosage levels of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII, for a human subject may, in certain variations, be between about 0.01 mg to about 1000 mg, between about 1 mg to about 15 mg, or between about 50 mg to about 200 mg, or about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg, or about 175 mg, about 200 mg, or about 250 mg.
In another aspect, polymorphic forms described herein (e.g., polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) may be used in combination with one or more additional therapeutic agent that are being used and/or developed to treat cancers or inflammatory disorders. The one or more additional therapeutic agent may be an inhibitor to PI3K such as PI3Kγ, PI3Kβ, and/or PI3Kα, Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3, spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1, serine/threonine kinase TPL2, discoidin domain receptor (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), or monoclonal antibody (such as an anti-CD20 monoclonal antibody or an anti-CD39 monoclonal antibody) or any combination thereof.
One, two, three, or more of the therapeutic agents (e.g. a PI3K inhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4 inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDH inhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBK inhibitor, a HDAC inhibitor, a PKC inhibitor, or a monoclonal antibody) may be further used or combined with a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs (bendamustine, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.
As used herein the term “chemotherapeutic agent” or “chemotherapeutic” (or “chemotherapy”, in the case of treatment with a chemotherapeutic agent) may encompass any non-proteinaceous (e.g., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as bendamustine, thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL®, Bristol Meyers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent are used or included in the present application. For example, gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAK inhibitor and/or PI3Kδ inhibitor for treating hyperproliferative disorders.
Chemotherapeutic agents may also include, for example, anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston®); inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole (Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN, ENDOSTATIN, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor-1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide; angiostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors” (1999) Nature Medicine 5:1359-1364.
The anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct. 23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled “Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate,” relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled “Inhibitors of lysyl oxidase,” relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g., U.S. Pat. Nos. 5,021,456; 5,5059,714; 5,120,764; 5,182,297; 5,252,608 (relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent Application No. 2004/0248871, which are herein incorporated by reference in their entirety. Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate.
The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131.
The application also provides a method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.
In certain embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).
In certain embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.
Examples of immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-CD39 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient's tumor, such as lymphoma vaccine example is GTOP-99 (MyVax®).
Examples of chemotherapy agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin, Temsirolimus (CC1-779), Thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (R-MCP).
The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapies include, but are not limited to, Iodine-131 tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.
Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Uses in Manufacturing of Drug Product
Provided are also a use of the polymorphs described herein in the manufacture of a drug product. The one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) may be used as an intermediate in the manufacturing process to produce the drug product.
In certain embodiments, Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, the active pharmaceutical ingredient is Idelalisib.
Articles of Manufacture and Kits
Compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and formulated in one or more pharmaceutically acceptable carriers, excipients or other ingredients can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a label containing instructions for use of the compound(S).
In some embodiments, the article of manufacture is a container comprising a dosage form of one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers, excipients or other ingredients. In one embodiment of the articles of manufacture described herein, the dosage form is a tablet.
Kits also are contemplated. For example, a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. The instructions for use in the kit may be for treating a PI3K-mediated disorder, including, for example, a hematologic malignancy. In certain embodiments, the instructions for use in the kit may be for treating leukemia. In one embodiment, the instructions for use in the kit may be for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL).
In certain embodiments, conditions indicated on the label can include, for example, treatment of cancer. Conditions indicated on the label can include non-Hodgkin's lymphoma (NHL). In one embodiment, the condition may be indolent non-Hodgkin's lymphoma (iNHL). In another embodiment, the condition may be chronic lymphocytic leukemia (CLL). Other conditions that may be indicated on the label include, for example, follicular lymphoma (FL); lymphoplastic lymphoma (LPL); Waldenström macroglobulinemia (WM); marginal zone lymphoma (MZL); and small cell lymphocytic lymphoma (SLL).
In certain embodiments, the polymorphic and solvate forms described herein may potentially exhibit improved properties. For example, in certain embodiments, the polymorphic and solvate forms described herein may potentially exhibit improved stability. Such improved stability could have a potentially beneficial impact on the manufacture of the Compound of Formula I, such as for example offering the ability to store process intermediate for extended periods of time. Improved stability could also potentially benefit a composition or pharmaceutical composition of the Compound of Formula I. In certain embodiments, the polymorphic and solvate forms described herein may also potentially result in improved yield of the Compound of Formula I, or potentially result in an improvement of the quality of the Compound of Formula I. In certain embodiments, the polymorphic and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.
EXAMPLES
The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular materials and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof.
The polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one were characterized by various analytical techniques, including X-ray powder diffraction pattern (XPPD), differential scanning calorimetry (DSC), and thermographic analysis (TGA) using the procedures described below.
X-Ray Powder Diffraction:
XRPD patterns were collected at room temperature, using a PANalytical X'Pert MPD Pro Powder X-Ray Diffractometer configured with reflectance stage with spinning, data acquisition range: 2-40 degrees 2θ, Copper (Cu) anode; Kα1/Kα2 radiation; tube current 40 mA; tube tension 45 kV; automatic divergence and anti-scatter slits. Samples were prepared for analysis by distributing solid material as a thin layer on a silicon holder. Each holder was mounted on a reflectance/transmittance stage and rotated during data acquisition.
Differential Scanning Calorimetry:
DSC was performed using a TA Instruments Q2000 DSC instrument. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid, and then either crimped or hermetically sealed. The same cell was heated under a nitrogen purge at a rate of 10° C./min, up to a final temperature of 300° C. Indium was used as the calibration standard.
Thermogravimetric Analysis:
TGA was performed using a TA Instruments Q5000 TGA instrument. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was heated under nitrogen at a rate of 10° C./min, up to a final temperature of 300° C. The TGA furnace was calibrated using the magnetic Curie point method.
Example 1
Preparation of Form I of the HCl Salt of the Compound of Formula (I)
This Example demonstrates exemplary methods to synthesize a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (the compound of Formula (I)).
Method A
In a vessel was charged 10.0 grams (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and 50 mL absolute ethanol. In a separate vessel 1 mL of 12 M HCl (0.5 equiv.) was diluted in 20 mL absolute ethanol. The acidified ethanol was added to the vessel containing the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one suspension while stirring. After a few minutes the suspension was seeded with <1 mL of polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one suspension. The seeds were prepared by adding ethanol to amorphous solids, thereby allowing the conversion of amorphous solids to crystalline solid. The crystalline solids were then air dried. XRPD was used to monitor progress in converting to the HCl salt. Additional 1 mL of 12 M HCl (0.5 equiv.) was charged after about 24 hours. After 14 days, the XRPD confirmed full conversion to the HCl salt. The suspension was stored at ambient temperature for 30 days and solids were isolated by filtration. The solids were washed one time with about 50 mL water and allowed to air dry at room temperature.
KF of the resulting hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was observed to be about 13% and about 16% (avg. about 15%). DSC of the resulting hydrochloride salt (as seen in FIG. 1B) shows two broad endothermic events, one beginning at about 48° C. and the other at about 184° C. No exothermic events were observed to be present. TGA of the resulting hydrochloride salt (as seen in FIG. 1C) shows two mass loss events, one beginning at about 25° C. and ending at about 50° C., the other beginning at about 125° C. and ending (for the most part) at about 200° C. DVS of the resulting hydrochloride salt (as seen in FIGS. 1D and 1E) showed minor mass increase as a function of RH at 25° C. A single crystal X-ray of crystals grown from the resulting hydrochloride salt filtrate was taken, and the data is summarized in Table 9 below. The Single Crystal X-Ray Crystallography data showed that the crystals are a channel solvate and a mono-HCl salt. Data from further characterization of the crystals are summarized in Table 10 below.
TABLE 9
Single Crystal X-Ray Crystallography Data for the Compound of Formula (I)
Unit Cell Dimensions
Form and Composition
Distance (Å)
Angle (°)
Form
water
solvent
API:water:solvent
a
b
c
α
β
γ
Form I
N
Methanol
1:1:0.5
31.102
9.166
19.738
90
125.948
90
(15)
(5)
(10)
(17)
TABLE 10
Crystal Data and Structure Refinement
for the Compound of Formula (I)
Property
Value
Empirical formula
C22.50 H18 Cl F N7 O1.50
Formula weight
464.89
Temperature
100(2)
K
Wavelength
0.71073
Å
Crystal system
Monoclinic
Space group
C2
Volume
4555(4)
Å3
Z
8
Density (calculated)
1.356
g/cm3
To a slurry of 5-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)propyl)quinazolin-4(3H)-one (18 g contains about 30% TEA HCl) in ethanol (30 g), concentrated hydrochloric acid (5.0 g, 1.6 mole eq.) was added maintaining temperature ≤30° C. Immediately upon addition completion, high purity water (15.0 g) was added to the solution. After adjusting the contents to about 19 to 25° C. and checking the pH (targeting a value of ≤2.0, adding more concentrated hydrochloric acid if needed), the solution was agitated for about 1 h at about 19 to 25° C. To slightly increase the substrate concentration, (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (in free form) (0.4 g) was charged portion-wise at about 19 to 25° C. A cloudy mixture was observed, which turned into a suspension after 30 min. The resulting slurry was agitated at about 19 to 25° C. for about 5 h and filtered. The wet cake was washed with cold EtOH (8.0 g, about 9° C.) and dried under vacuum at about 50° C. (S)-2-(1-(9H-Purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one hydrochloride was obtained as a solid. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, 2H), 7.85 (m, 1H), 7.70-7.40 (m, 6H), 7.30 (m, 1H), 4.67 (br, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 0.85 (t, 3H).
Example 2
Hydrate Screen on the HCl Salt of the Compound of Formula (I)
This Example demonstrates the effect of water on the stability of polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I), prepared according to the protocols described in Example 1 above was mixed with ethanol and water. The amount of hydrochloride salt (Form I) and the ethanol/water ratio summarized in Table 11 below. XRPDs were taken on Days 5 and 21. Results from this Example are summarized in Table 11 below.
TABLE 11
Results from hydrate screen on the HCl salt of the Compound of Formula I
Form I HCl salt of
Ethanol/
Compound of
water
solubility
XRPD after
solubility
XRPD after
Formula (I) (mg)
aw
(mg/mL)
5 days
(mg/mL)
21 days
98
0.2
26
Form I
60
Form I
114
0.3
47
Form I
33
Form I
112
0.4
57
Form I
66
Form I
112
0.5
72
Form I
93
Form I
107
0.6
NA
Form I
183
Form I
127
0.7
NA
Form I
223
Form I
118
0.8
NA
Form I
174
Form I
113
0.9
NA
Form I &
44
Form I &
Form I of the
Form I of the
free form of
free form of
Compound
Compound
of Formula (I)
of Formula (I)
The hydrate screen in the water/ethanol system showed no changes in XRPD except in the case of water activity 0.9, which converted some of the hydrochloride salt to polymorphic Form I of the free form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I).
Example 3
Form Screen on the HCl Salt of the Compound of Formula (I)
This Example demonstrates the conversion of polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., the Compound of Formula (I), into other polymorphic forms based on particular solvents used.
Polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I), prepared according to the protocols described in Example 1 above was mixed with the solvent (as listed in Table 12 below) in a vial/flask, resulting in a suspension. The amount of hydrochloride salt (Form I) is also listed in Table 12 below.
After 7 days, a sample of the suspension was removed from the vial/flask, and the sample was centrifuged and filtered to separate the solids from the liquid in the sample. The isolated solids were characterized by XRPD (collected at room temperature). The filtrate was retained.
For several experiments, including the experiments involving THF, acetone and 2-MeTHF, crystals large enough for Single Crystal X-Ray Crystallography were observed in the vial/flask. A sample of the crystals taken in suspension was removed and analyzed by Single Crystal X-Ray Crystallography (data acquired at 100K).
After about 25 days, another sample was removed from the vial/flask, and the sample was centrifuged and filtered to separate the solids from the liquid in the sample. The isolated solids were characterized by XRPD (collected at room temperature). Results from this Example are summarized in Table 12 below.
TABLE 12
Results from form screen on the HCl salt of the Compound of Formula I
Single Crystal
Form I HCl salt
X-Ray of
of Compound of
XRPD after
XRPD after
crystals from
Formula (I)
Solvent
7 days
about 25
suspension
119
mg
water
Form I
Form I
NA
117
mg
isopropyl acetate
Form I
Form I
NA
(IPAc)
150
mg
methyl t-butyl ether
Form I
Form I
NA
(MTBE)
132
mg
2-propanol
Form I
mixture
NA
160
mg
dichloromethane
new
Form VIII
NA
(DCM)
163
mg
n-heptane
Form I
Form I
NA
114
mg
tetrahydrofuran (THF)
new
Form IX
IV
125
mg
acetone
new
Form X
II
155
mg
methanol
Form I
Form I
NA
120
mg
acetonitrile (ACN)
Form I
Form I
NA
157
mg
Ethanol
Form I
Form I
NA
140
mg
ethyl acetate (EtOAc)
Form I
Form I
NA
154
mg
2-
Form V
Form V
III
methyltetrahydrofuran
(2-MeTHF)
149
mg
methyl ethyl ketone
new
Form VII
NA
(MEK)
176
mg
methyl isobutyl ketone
Form I
Form VI
NA
(MIBK)
10
g
1-propanol
1-propanol
Form XII
NA
solvate
10
g
2-propanol
1-propanol
Form XI
NA
solvate
10
g
1-butanol
1-butanol
Form XIII
NA
solvate
The XRPDs taken for polymorphic Forms II-XIII are provided in FIGS. 2-13, respectively. Single Crystal X-Ray Crystallography data were collected from polymorphic Forms II-IV and XII prepared in this Example, and such data is summarized in Table 13 below.
TABLE 13
Single Crystal X-Ray Crystallography Data
Unit Cell Dimensions
Form and Composition
Distance (Å)
Angle (°)
Form
solvent
API:water:solvent
a
b
c
α
β
γ
II
acetone
1:0:3
13.266
13.858
31.012
90
90
90
(3)
(3)
(6)
III
2MeTHF
1:1:1.5
25.077
9.1485
14.2476
90
110.967
90
(3)
(10)
(14)
(3)
IV
THF
1:0:3
13.4685
13.8415
31.7543
90
90
90
(6)
(6)
(14)
XII
1-propanol
1:0:1
10.717
10.161
12.409
90
104.021
90
(3)
(3)
(4)
(4)
Example 4
Solvent Screen on Form I of the HCl Salt of the Compound of Formula (I)
This Example demonstrates the preparation of solvated forms of polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., the Compound of Formula (I).
Polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I) was prepared by suspending 5 g of the free base Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one in 25 mL absolute ethanol. The sample was agitated at 200 rpm and about 23° C. 1.05 mL of 12M HCl (1.1 eq.) was diluted in 10 mL absolute ethanol, then added to the suspension of the Compound of Formula (I) in ethanol, forming a slurry. The slurry suspension was stirred at about 23° C. for about 24 hours, filtered and washed with 10 mL absolute ethanol and dried under vacuum for three days. Formation of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was confirmed by x-ray powder diffraction.
50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) prepared according to the protocols described above was mixed with increasing amounts of each solvent listed in Table 14 below (10 vol, 20 vol, 30 vol, 40 vol, 50 vol, 60 vol, 70 vol, 70 vol (at about 50° C.)) until the material dissolved or reached the maximum amount of solvent. The mixtures were then evaluated for identification of the solid form using the following screening procedures:
Maturation: The suspensions were cycled in a platform shaker incubator between about 50° C. and room temperature (8 hours per cycle, for three days);
Slurry at 5° C.: 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was suspended in 40 vol of the solvent. The suspensions were left stirring at about 50° C. for about 7 days;
Slurry at 50° C.: 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was suspended in 40 vol of the solvent. The suspensions were left stirring at about 50° C. for about 2 days;
Salt formation: 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was dissolved or suspended in 10 vol of solvent and held at about 50° C. for 15 minutes, after which 1.1 eq of HCl (11.6 μL of 12M HCl) were added and the sample was slowly cooled to about 5° C. at about 0.1° C. per minute;
Solvent deposition: 25 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was transferred to a 2 mL vial, which was then placed into a larger sealed vial with 3 mL of the corresponding solvent, then held at about 40° C. for about 13 days.
Any solids obtained from the above screening procedures were analyzed wet/damp by XRPD as described below. The solids were isolated by decanting and/or filtration, then dried under vacuum. Solid form samples obtained after maturation experiments were dried under vacuum and analyzed by NMR to determine if the solvating ethanol was replaced by the suspending solvent. As shown in Table 14, the screening experiments identified new solvated forms of the HCl salt of the Compound of Formula I. For Patterns 1, 2, 3, and 4, each of the four of the identified solvated forms are a family of solvates, which are observed from more than one solvent.
TABLE 14
Results from solvent screen on Form I of
the HCl salt of the Compound of Formula I
Representative
Form
Solvent
XRPD
Pattern 1
Ethyl Acetate
FIG. 14A (damp)
Propyl acetate
FIG. 14B (dry)
Pattern 2
1-Methyl-1-propanol
FIG. 15A
Isopropyl acetate
Pattern 3
1,2-Dimethyoxyethane
FIG. 16A
1,4-Dioxane
Acetone
Acetone:Water
Acetonitrile
Chloroform
Dicholoromethane
Diethyl ether
Ethyl acetate
MEK
MIBK
Nitromethane
Propyl acetate
Tetrahydrofuran
Toluene
Pattern 4
1-Propanol
FIG. 17A
2-Propanol
IPA:Water (5%)
2-Methyl-1-propanol
2-Methyl-1-propanol
FIG. 18A
solvate
1,4-Dioxane solvate
1,4-Dioxane
FIG. 19A
Toluene solvate
Toluene
FIG. 20
Representative samples of the solvate forms listed in Table 14 obtained from the crystallization screening were dried under vacuum and further characterized. The data from these further characterization experiments is summarized in Table 15.
TABLE 15
Results from solvent screen on Form I of the HCl salt of the Compound of Formula I
Form
Solvent
NMR of dry
DSC
TGA
Pattern 1
Propylacetate
n/t
n/t
n/t
Pattern 2
Isopropyl
0.56eq iPrOAc
68° C.
(−42 J/g)
9.7%
acetate
153° C.
(−38 J/g)
(40° C.-130° C.)
179° C.
(−32 J/g)
4.7%
(130° C.-230° C.)
Pattern 3
1,2-
0.93eq DME
172° C.
(−92 J/g)
10.7%
Dimethyoxyethane
(110° C.-245° C.)
Pattern 4
Isopropyl
0.98eq IPA
170° C.
(−192 J/g)
13.4%
alcohol
(130° C.-215° C.)
2-Methyl-1-
2-Methyl-1-
1.34eq 2-
113° C.
(−134 J/g)
19.0%
propanol
propanol
Methyl-1-
(90° C.-225° C.)
solvate
propanol
1,4-Dioxane
1,4-Dioxane
0.65eq 1.4-
158° C.
(−96 J/g)
12.7%
solvate
Dioxane
(80° C.-225° C.)
Toluene solvate
Toluene
n/t
n/t
n/t
n/t: not tested
X-Ray Powder Diffraction (XRPD)
Two methods were used to collect XRPD on the samples described above.
Bruker AXS C2 GADDS
X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X-ray optics consists of a single Göbel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm. A θ-θ continuous scan mode was employed with a sample—detector distance of 20 cm which gives an effective 2θ range of 3.2°-29.7°. Typically the sample would be exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for XP/2000 4.1.43 and the data were analysed and presented using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0.
Ambient conditions: Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.
Non-ambient conditions: Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at 50° C./min and subsequently held isothermally for up to 4 minutes before data collection was initiated.
Bruker AXS D8 Advance
X-Ray Powder Diffraction patterns were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), θ-2θ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analysed and presented using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0.
Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was gently packed into a cavity cut into polished, zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis. The details of the data collection are: angular range: 2 to 42° 2θ, step size: 0.05° 2θ, collection time: 0.5 s/step.
Nuclear Magnetic Resonance (NMR)
1H-NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running with Topspin v1.3 using the standard Bruker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone.
Samples were prepared in DMSO-d6, unless otherwise stated. Off-line analysis was carried out using ACD Labs 2012 release (build 61851).
Differential Scanning Calorimetry (DSC)
DSC data were collected on a Mettler DSC 823E equipped with a 34 position auto-sampler. The instrument was calibrated for energy and temperature using certified indium. Typically 0.5-4 mg of each sample, in a pin-holed aluminium pan, was heated at 10° C./min from 25° C. to 350° C. A nitrogen purge at 50 ml/min was maintained over the sample.
The instrument control and data analysis software was STARe v9.20.
Thermo-Gravimetric Analysis (TGA)
TGA data were collected on a Mettler TGA/SDTA 851e equipped with a 34 position autosampler. The instrument was temperature calibrated using certified indium. Typically 2-13 mg of each sample was loaded onto a pre-weighed aluminium crucible and was heated at 10° C./min from ambient temperature to 350° C. A nitrogen purge at 50 ml/min was maintained over the sample.
The instrument control and data analysis software was STARe v9.20.
The XRPDs taken for the solvate forms identified in Table 14 are provided in FIGS. 14A, 14B, 15A, 16A, 17A, 18A, 19A, and 20 respectively.
For Pattern 1, shown in FIGS. 14A and 15B, 50 mg of the hydrochloride salt of the Compound Formula (I) was suspended in propyl acetate (3.5 mL, 70 vol) and held at 50° C. for 15 minutes, after which 1.1 eq of 12M HCl (11.6 μL) was added and the sample slowly cooled from 50° C. to 5° C. at 0.1° C. per minute. The XRPD pattern shown in FIG. 14A was observed while the sample was wet. On drying in a vacuum oven at about 25° C. for 6 days, the sample was converted to the XRPD pattern shown in FIG. 14B (Pattern 9). NMR data confirm the presence of propyl acetate in the crystallized from. FIG. 14C depicts the XRPD pattern after further heating at about 145° C. for about 16 hours (Pattern 9′). Table 16 lists the XRPD peaks for Pattern 9′
TABLE 16
XRPD Peak List for Pattern 9′ Form
Angle (2-Theta °)
Intensity (%)
7.5
11.1
9.2
100.0
11.8
16.8
12.0
12.4
14.1
19.5
16.8
31.3
17.1
18.8
18.5
32.6
19.4
8.2
20.1
9.0
20.8
12.4
21.5
11.2
22.9
20.7
23.4
32.5
24.7
12.2
25.9
28.7
28.0
17.7
28.6
10.9
29.2
5.9
29.5
5.6
For Pattern 2, shown in FIG. 15A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with isopropyl acetate (3.5 mL, 70 vols) producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. 1H NMR data confirm the presence of isopropyl acetate in the crystallized from.
For Pattern 3, shown in FIG. 16A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 1,2-dimethoxyethane (3.5 mL, 70 vols) producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. 1H NMR data confirm the presence of 1,2-dimethoxyethane in the crystallized from.
For Pattern 4, shown in FIG. 17A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 2-propanol (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. 1H NMR data confirm the presence of 2-propanol in the crystallized from.
For the 2-Methyl-1-propanol solvate, shown in FIG. 18A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 2-methyl-1-propanol (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. FIG. 18D depicts the same XRPD diffractogram, showing the entire Y axis (i.e., not truncated). 1H NMR data confirm the presence of 2-methyl-1-propanol in the crystallized from.
For the 1,4-Dioxane solvate, shown in FIG. 19A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 1,4-dioxane (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. The XRPD pattern is shown in FIG. 20. 1H NMR data confirm the presence of 1,4-dioxane in the crystallized from.
For the toluene solvate, shown in FIG. 20 (wet), 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with toluene (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. Upon drying, the XRPD of the toluene solvent is a mixture of Pattern 1 and Pattern 9′.
DSC plots for Pattern 9, Pattern 2, Pattern 3, Pattern 4, the 2-Methyl-1-propanol solvate form, and the 1,4-dioxane solvate form identified in Table 14 are provided in FIGS. 14D, 15B, 16B, 17B, 18B, and 19B respectively. TGA plots for Pattern 9, Pattern 2, Pattern 3, Pattern 4, the 2-Methyl-1-propanol solvate form, and the 1,4-dioxane solvate form identified in Table 14 are provided in FIGS. 14E, 15C, 16C, 17C, 18C, and 19C, respectively.
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15626048
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Jul 18th, 2017 12:00AM
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Dec 18th, 2014 12:00AM
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https://www.uspto.gov?id=US09708327-20170718
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Polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
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Polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are disclosed. Solvent forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are also disclosed.
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9708327
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1. A polymorph of a hydrochloride salt of a compound of Formula (I):
wherein the polymorph is selected from the group consisting of Form I, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; and wherein:
Form I has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.6, 16.6, 18.2, 23.2 and 25.1;
Form V has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.9, 24.0, 25.6 and 28.1;
Form VI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 17.0, 23.2 and 25.1;
Form VII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 17.8, 21.7 and 24.0;
Form VIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 19.9, 21.7 and 24.1;
Form IX has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 19.6, 21.8 and 24.0;
Form X has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 21.8, and 24.2;
Form XI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5;
Form XII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9 and 25.4; and
Form XIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 16.8, 18.5 and 23.9.
2. The polymorph of claim 1, wherein the polymorph is selected from the group consisting of Form I, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; and wherein:
Form I has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 8.9, 11.6, 13.8, 16.6, 18.2, 19.4, 22.5, 23.2 and 25.1;
Form V has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 8.0, 15.9, 18.9, 20.3, 24.0, 25.6, 28.1 and 36.3;
Form VI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1;
Form VII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.0, 9.8, 11.9, 15.3, 19.7, 20.1, 21.7, 24.0, 28.4 and 28.9;
Form VIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 12.4, 15.3, 19.0, 19.9, 20.3, 21.7, 24.1 and 28.9;
Form IX has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.5, 9.8, 12.5, 19.6, 20.8, 21.8, 24.0 and 29.0;
Form X has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 11.9, 15.5, 19.4, 19.8, 20.3, 21.8, 24.2, 28.6 and 29.0;
Form XI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.5, 15.0, 17.0, 19.3, 20.3, 22.0, 25.5 and 31.7;
Form XII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9, 19.1, 19.6, 23.3, 24.9, 25.4 and 29.4; and
Form XIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 8.0, 8.1, 9.7, 11.7, 13.6, 16.8, 18.5, 23.5, 23.9 and 25.7.
3. A polymorph of a hydrochloride salt of a compound of Formula (I):
wherein the polymorph is selected from the group consisting of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; and wherein:
Form I has an X-ray diffraction pattern as shown in FIG. 1;
Form II has a calculated X-ray diffraction pattern as shown in FIG. 2;
Form III has a calculated X-ray diffraction pattern as shown in FIG. 3;
Form IV has a calculated X-ray diffraction pattern as shown in FIG. 4;
Form V has an X-ray diffraction pattern as shown in FIG. 5;
Form VI has an X-ray diffraction pattern as shown in FIG. 6;
Form VII has an X-ray diffraction pattern as shown in FIG. 7;
Form VIII has an X-ray diffraction pattern as shown in FIG. 8;
Form IX has an X-ray diffraction pattern as shown in FIG. 9;
Form X has an X-ray diffraction pattern as shown in FIG. 10;
Form XI has an X-ray diffraction pattern as shown in FIG. 11;
Form XII has an X-ray diffraction pattern as shown in FIG. 12; and
Form XIII has an X-ray diffraction pattern as shown in FIG. 13.
4. A polymorph of a hydrochloride salt of a compound of Formula (I):
wherein the polymorph is selected from the group consisting of Form I, Form II, Form III, Form IV and Form XII; and wherein:
Form I has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948(17°); and γ=90°;
Form II has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°;
Form III has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3°); and γ=90°;
Form IV has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°; and
Form XII has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=10.717 (3); b=10.161 (3); c=12.409 (4); α=90; β=104.021 (4); and γ=90.
5. The polymorph of claim 1, wherein the polymorph is Form I.
6. The polymorph of claim 3, wherein the polymorph is Form II.
7. The polymorph of claim 3, wherein the polymorph is Form III.
8. The polymorph of claim 3, wherein the polymorph is Form IV.
9. The polymorph of claim 1, wherein the polymorph is Form V.
10. The polymorph of claim 1, wherein the polymorph is Form VI.
11. The polymorph of claim 1, wherein the polymorph is Form VII.
12. The polymorph of claim 1, wherein the polymorph is Form VIII.
13. The polymorph of claim 1, wherein the polymorph is Form IX.
14. The polymorph of claim 1, wherein the polymorph is Form X.
15. The polymorph of claim 1, wherein the polymorph is Form XI.
16. The polymorph of claim 1, wherein the polymorph is Form XII.
17. The polymorph of claim 1, wherein the polymorph is Form XIII.
18. A composition produced by:
combining a compound of Formula (I):
with hydrochloric acid and a solvent to produce the composition comprising one or more polymorphs of a hydrochloride salt of the compound of Formula (I); or
combining a hydrochloride salt of the compound of Formula (I) with a solvent to produce the composition comprising one or more polymorphs of a hydrochloride salt of the compound of Formula (I),
wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, and any mixtures thereof, and
wherein the one or more polymorphs are selected from the group consisting of Form I, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; and wherein:
Form I has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.6, 16.6, 18.2, 23.2 and 25.1;
Form V has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.9, 24.0, 25.6 and 28.1;
Form VI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 17.0, 23.2 and 25.1;
Form VII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 17.8, 21.7 and 24.0;
Form VIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 19.9, 21.7 and 24.1;
Form IX has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 19.6, 21.8 and 24.0;
Form X has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 21.8, and 24.2;
Form XI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5;
Form XII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9 and 25.4; and
Form XIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 16.8, 18.5 and 23.9.
19. The composition of claim 18, wherein:
the one or more polymorphs is Form I; and
the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
20. The composition of claim 18, wherein:
the one or more polymorphs is Form II or Form X, or a mixture thereof; and
the solvent is acetone.
21. The composition of claim 18, wherein:
the one or more polymorphs is Form III or Form V, or a mixture thereof; and
the solvent is 2-methyltetrahydrofuran.
22. The composition of claim 18, wherein:
the one or more polymorphs is Form IV or Form IX, or a mixture thereof; and
the solvent is tetrahydrofuran.
23. The composition of claim 18, wherein:
the one or more polymorphs is Form VI; and
the solvent is methyl isobutyl ketone.
24. The composition of claim 18, wherein:
the one or more polymorphs is Form VII; and
the solvent is methyl ethyl ketone.
25. The composition of claim 18, wherein:
the one or more polymorphs is Form VIII; and
the solvent is dichloromethane.
26. The composition of claim 18, wherein:
the one or more polymorphs is Form XI; and
the solvent is 2-propanol.
27. The composition of claim 18, wherein:
the one or more polymorphs is Form XII; and
the solvent is 1-propanol.
28. The composition of claim 18, wherein:
the one or more polymorphs is Form XIII; and
the solvent is 1-butanol.
29. The polymorph of claim 1, wherein the hydrochloride salt is a monohydrochloride salt.
30. A composition comprising one or more polymorphs of claim 1.
31. The composition of claim 30, wherein the one or more polymorphs are a mixture of at least two polymorphs.
32. The composition of claim 30, wherein the composition contains less than 95% by weight of substances other than the one or more polymorphs.
33. A pharmaceutical composition comprising the polymorph of claim 1, and one or more pharmaceutically acceptable carriers or excipients.
34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition is a tablet.
35. A method of treating a human in need of a treatment for cancer, comprising administering to the human a polymorph of claim 1, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL.
36. The method of claim 35, wherein the cancer is selected from small lymphocytic lymphoma (SLL), and follicular B-cell non-Hodgin Lymphoma (FL).
37. A method of producing a composition comprising one or more polymorphs of a hydrochloride salt of a compound of Formula (I):
comprising:
combining the compound of Formula (I) with hydrochloric acid and a solvent to produce the composition; or
combining a hydrochloride salt of the compound of Formula (I) with a solvent to produce the composition,
wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, and any mixtures thereof, and
wherein the one or more polymorphs are selected from the group consisting of Form I, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, and Form XIII; and wherein:
Form I has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.6, 16.6, 18.2, 23.2 and 25.1;
Form V has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.9, 24.0, 25.6 and 28.1;
Form VI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 11.8, 17.0, 23.2 and 25.1;
Form VII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 17.8, 21.7 and 24.0;
Form VIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 10.0, 19.9, 21.7 and 24.1;
Form IX has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.8, 19.6, 21.8 and 24.0;
Form X has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 9.9, 21.8, and 24.2;
Form XI has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5;
Form XII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.4, 12.4, 16.9 and 25.4; and
Form XIII has an X-ray diffraction pattern comprising degree 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.9, 16.8, 18.5 and 23.9.
38. The method of claim 37, wherein:
the one or more polymorphs is Form I; and
the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
39. The method of claim 37, wherein:
the one or more polymorphs is Form II or Form X, or a mixture thereof; and
the solvent is acetone.
40. The method of claim 37, wherein:
the one or more polymorphs is Form III or Form V, or a mixture thereof; and
the solvent is 2-methyltetrahydrofuran.
41. The method of claim 37, wherein:
the one or more polymorphs is Form IV or Form IX, or a mixture thereof; and
the solvent is tetrahydrofuran.
42. The method of claim 37, wherein:
the one or more polymorphs is Form VI; and
the solvent is methyl isobutyl ketone.
43. The method of claim 37, wherein:
the one or more polymorphs is Form VII; and
the solvent is methyl ethyl ketone.
44. The method of claim 37, wherein:
the one or more polymorphs is Form VIII; and
the solvent is dichloromethane.
45. The method of claim 37, wherein:
the one or more polymorphs is Form XI; and
the solvent is 2-propanol.
46. The method of claim 37, wherein:
the one or more polymorphs is Form XII; and
the solvent is 1-propanol.
47. The method of claim 37, wherein:
the one or more polymorphs is Form XIII; and
the solvent is 1-butanol.
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47
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CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/919,558, filed Dec. 20, 2013, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD
Provided are polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use. Also provided are solvate forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof; methods for their preparation, and methods for their use.
BACKGROUND
Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. See Rameh et al., J. Biol. Chem., 274:8347-8350 (1999) for a review. The enzyme responsible for generating these phosphorylated signaling products is phosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally was identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring. See Panayotou et al., Trends Cell Biol. 2:358-60 (1992).
Studies suggest that PI3K is involved in a range of cellular responses including cell growth, differentiation, and apoptosis. See Parker et al., Curr. Biol., 5:577-99 (1995); Yao et al., Science, 267:2003-05 (1995). PI3K also appears to be involved in a number of aspects of leukocyte activation. See e.g., Pages et al., Nature, 369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996); Fraser et al., Science, 251:313-16 (1991).
Several compounds have been identified as PI3K inhibitors. For example, compounds capable of inhibiting the biological activity of human PI3K, including (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and their uses are disclosed in U.S. Pat. No. 6,518,277, U.S. Pat. No. 6,667,300, and U.S. Pat. No. 7,932,260. Each of these references is hereby incorporated herein by reference in its entirety. In July 2014, ZYDELIG® (idelalisib), a first-in-class inhibitor of PI3K delta, was approved by the U.S. Food and Drug Administration for the treatment of three B-cell blood cancers. ZYDELIG® has also been approved by the European Commission for two blood cancers, chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).
BRIEF SUMMARY
The present application provides a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is substantially crystalline. In certain embodiments, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is crystalline. In certain embodiments, solvates of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are provided.
In one aspect, provided herein are polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and this compound has the following structure:
One or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are provided. In certain embodiments of the polymorphs provided herein, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt.
These polymorphs can be characterized by a variety of solid state analytical data, including for example X-ray powder diffraction pattern (XRPD), differential scanning calorimetry (DSC), thermographic analysis (TGA), and Single Crystal X-Ray Crystallography. One of skill in the art would recognize various techniques or methods that may be used to generate such characterization data. Unless otherwise stated, the XRPD patterns provided herein are generated by a powder X-ray diffractometer at room temperature. In certain instances, an XRPD pattern may also be calculated from the single crystal data acquired at 100K for that polymorphic form.
In another aspect, provided are compositions or pharmaceutical compositions comprising one or more polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) and one or more pharmaceutically acceptable carriers or excipients. Provided are also articles of manufacture and unit dosage forms comprising any one or more of the polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII). Provided are also kits comprising any one or more of the polymorphic forms (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one), and instructions for use (e.g., instructions for use in PI3K-mediated disorder, such as cancer). In one embodiment of the pharmaceutical compositions, articles of manufacture, unit dosage forms, and kits, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt.
Methods of using these polymorphic forms are provided. In another aspect, provided is a method of treating a human in need thereof, comprising administering to the human a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs. The human may be in need of a treatment for cancer or an autoimmune disease.
In one variation, provided is a method of treating a PI3K-mediated disorder in a human in need thereof, comprising administering to the human a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs. The PI3K-mediated disorder, in some embodiments, is cancer (e.g., leukemia or lymphoma) or an autoimmune disease.
Also provided is a method for increasing sensitivity of cancer cells to chemotherapy, comprising administering to a human undergoing chemotherapy with a chemotherapeutic agent an amount of a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs, sufficient to increase the sensitivity of cancer cells to the chemotherapeutic agent.
Also provided is a use of a polymorph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII), or a composition (including a pharmaceutical composition) comprising one or more such polymorphs, in the manufacture of a medicament for the treatment of a disease responsive to inhibition of PI3K activity, such as cancer (e.g., leukemia or lymphoma) or an autoimmune disease.
In one embodiment of the methods of using, and the use of the polymorphic forms described herein, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt.
Methods of making these polymorphic forms are provided. In yet other aspects, provided are methods of producing a composition comprising one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII). The methods comprise combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) with a suitable solvent or a suitable mixture of solvents. In one embodiment, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt. The solvent(S) may be selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, and any mixtures thereof. Also provided are polymorphic products obtained by the processes (e.g. methods of making) detailed herein.
In some embodiments, a solvate of a hydrochloride salt of a compound of Formula (I) is provided:
In some embodiments, the solvate is selected from the group consisting of ethyl acetate, propyl acetate, 1-methyl-1-propanol, isopropyl acetate, 1,2-dimethyoxyethane, 1,4-dioxane, acetone, acetone:water, acetonitrile, chloroform, dichloromethane, diethyl ether, ethyl acetate, MEK, MIBK, nitromethane, propyl acetate, tetrahydrofuran, toluene, 1-propanol, 2-propanol, IPA:water (5%), and 2-methyl-1-propanol. In some embodiments, the solvate is selected from the group consisting of propyl acetate, isopropyl acetate, 1,2-dimethyoxyethane, isopropyl alcohol, 2-methyl-1-propanol, 1,4-dioxane, and toluene.
In some embodiments, the polymorph is selected from the group consisting of Pattern 1, Pattern 2, Pattern 3, Pattern 4, 2-Methyl-1-propanol solvate, 1,4-Dioxane solvate, and Toluene solvate; and wherein:
Pattern 1 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8;
Pattern 2 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7;
Pattern 3 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7;
Pattern 4 has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2;
2-Methyl-1-propanol solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5;
1,4-Dioxane solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1; and
Toluene solvate has an X-ray diffraction pattern comprising degree 2θ-reflections (±0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0.
DESCRIPTION OF THE FIGURES
The present disclosure can be best understood by references to the following description taken in conjunction with the accompanying figures.
FIGS. 1A-1E show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, a thermographic analysis (TGA) graph, and two dynamic vapour sorption (DVS) graphs, respectively, of polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 2 shows XRPD patterns of polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 3 shows XRPD patterns of polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 4 shows XRPD patterns of polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 5 shows XRPD patterns of polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 6 shows XRPD patterns of polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 7 shows XRPD patterns of polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 8 shows XRPD patterns of polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 9 shows XRPD patterns of polymorphic Form IX of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 10 shows XRPD patterns of polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 11 shows XRPD patterns of polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 12 shows XRPD patterns of polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 13 shows XRPD patterns of polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 14A shows XRPD Pattern 1 of a solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (damp).
FIG. 14B shows XRPD Pattern 9 of a solvate form of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 14C shows XRPD Pattern 9′ of a solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 14D shows a differential scanning calorimetry (DSC) graph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one represented as Pattern 9.
FIG. 14E shows a thermographic analysis (TGA) graph of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one represented as Pattern 9.
FIGS. 15A-15C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of Pattern 2, a solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 16A-16C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of Pattern 3, a solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 17A-17C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of Pattern 4, a solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 18A-18D show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, a thermographic analysis (TGA) graph, and an X-ray powder diffraction pattern (XRPD) pattern of a 2-methyl-1-propanol solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIGS. 19A-19C show an X-ray powder diffraction pattern (XRPD) pattern, a differential scanning calorimetry (DSC) graph, and a thermographic analysis (TGA) graph of a 1,4-dioxane solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
FIG. 20 shows an X-ray powder diffraction pattern (XRPD) pattern of a toluene solvate of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
DETAILED DESCRIPTION
The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific compounds, methods, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.
Terms used in the singular will also include the plural and vice versa. The use of the term “about” includes and describes the value or parameter per se. For example, “about x” includes and describes “x” per se. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/−5%.
Polymorphs of a Hydrochloride Salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
A form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be present as an intermediate to the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, where a different polymorphic form or polymorphs may be beneficial for certain purposes, such as medical or pharmaceutical uses.
It is desirable to develop a crystalline form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof that is useful in the synthesis of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. A form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be an intermediate to the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. A polymorphic form or polymorph has properties such as bioavailability and stability at certain conditions that are suitable for medical or pharmaceutical uses. By way of example, a crystalline form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is an intermediate to an active agent or ingredient in a pharmaceutical composition.
A crystalline form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof; may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage form including tablets and capsules. Compared to other forms such as non-crystalline or amorphous forms, crystalline forms may provide desired or suitable hygroscopicity, particle size controls, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and/or process control. Thus, crystalline forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof, provides advantage of improving the manufacturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingredient, or having suitable bioavailability and/or stability as an active agent.
The use of certain solvents has been found to produce different polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, including any one or more of polymorphic Forms I to XIII, which may exhibit one or more favorable characteristics described above. The processes for the preparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.
One aspect of the application provides polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, a compound having the molecular structure shown below:
In certain embodiments, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, one or more of the polymorphic forms provided may be a channel solvate. The crystal lattice of such polymorphic forms may contain tunnels that penetrate the lattice, and the tunnels can be occupied by one or more molecules (e.g., solvent molecules) and ions (e.g., chloride ions).
The compound name provided above is named using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols. By way of example, the compound may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Accordingly, the compound structure provided above may also be named or identified as 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one under IUPAC and 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino) propyl]-4(3H)-quinazolinone under CAS.
Form I
In one aspect, provided is polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1A. Polymorphic Form I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 1B. Polymorphic Form I may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 1C. Polymorphic Form I may exhibit dynamic vapour sorption (DVS) graphs substantially as shown in FIGS. 1D and 1E.
The term “substantially as shown in” when referring, for example, to an XRPD pattern, a DSC thermogram, or a TGA graph includes a pattern, thermogram or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art.
Polymorphic Form I may have a unit cell as determined by crystal X-ray crystallography of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948 (17)°; and γ=90°.
In some embodiments of polymorphic Form I, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or all of the following (a)-(k) apply: (a) polymorphic Form I has an XRPD pattern substantially as shown in FIG. 1A; (b) polymorphic Form I has a DSC thermogram substantially as shown in FIG. 1B; (c) polymorphic Form I has a TGA graph substantially as shown in FIG. IC; (d) polymorphic Form I has DVS graphs substantially as shown in FIGS. 1D and 1E; (e) polymorphic Form I has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948 (17)°; and γ=90°; (f) polymorphic Form I has a melting temperature onset as determined by DSC at about 202° C.; (g) polymorphic Form I has a monoclinic crystal system; (h) polymorphic Form I has a C2 space group; (i) polymorphic Form I has a volume of 4555 (4) Å3; (j) polymorphic Form I has a Z value of 8; and (k) polymorphic Form I has a density of 1.356 g/cm3.
In some embodiments, polymorphic Form I has at least one, at least two, at least three, or all of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 1A;
(b) a DSC thermogram substantially as shown in FIG. 1B;
(c) DVS graphs substantially as shown in FIGS. 1D and/or 1E; and
(d) a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a=31.102 (15) Å; b=9.166 (5) Å; c=19.738 (10) Å; α=90°; β=125.948 (17)°; and γ=90°.
In some embodiments, polymorphic Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 1A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form I, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.6, 16.6, 18.2, 23.2 and 25.1 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 13.8, 19.4, and 22.5. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.9, 11.6, 13.8, 16.6, 18.2, 19.4, 22.5, 23.2 and 25.1.
In certain embodiments, the hydrochloride salt of polymorphic Form I is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form I may be a channel solvate. As commonly referred to by a person skilled in the art, the term “channel solvate”, or a variant thereof, refers to a crystal lattice containing tunnels that can be occupied by solvent molecules (e.g., channel solvents), and other molecules and ions. Examples of other molecules and ions that may be present in the channels of polymorphic Form I include water, ethanol and/or chloride ions.
Form II
In another aspect, provided is polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°.
Polymorphic Form II may have a calculated XRPD pattern substantially as shown in FIG. 2. It should be understood that the XRPD provided in FIG. 2 is a calculated XRPD from the single crystal data acquired at 100K for polymorphic Form II.
In some embodiments of polymorphic Form II, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply: (a) polymorphic Form II has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form II, substantially as shown in FIG. 2; (b) polymorphic Form II has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90β; and γ=90°; (c) polymorphic Form II has an orthorhombic crystal system; (d) polymorphic Form II has a C222 (1) space group; (e) polymorphic Form II has a volume of 5702 (2) Å3; (f) polymorphic Form II has a Z value of 8; and (g) polymorphic Form I has a density of 1.254 g/cm3.
In some embodiments, polymorphic Form II has at least one, or both of the following properties:
(a) an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form II, substantially as shown in FIG. 2; and
(b) a unit cell, as determined by Single Crystal X-ray Crystallography, of the following dimensions: a=13.266 (3) Å; b=13.858 (3) Å; c=31.012 (6) Å; α=90°; β=90°; and γ=90°.
In some embodiments, polymorphic Form II has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form II, displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 2. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments disclosed herein, including for polymorphic Form II, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the hydrochloride salt of polymorphic Form II is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form III
In another aspect, provided is polymorphic Form II of a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3)°; and γ=90°.
Polymorphic Form m may have a calculated XRPD pattern substantially as shown in FIG. 3. It should be understood that the XRPD provided in FIG. 3 is a calculated XRPD from the single crystal data acquired at 100K for polymorphic Form II.
In some embodiments of polymorphic Form III, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply: (a) polymorphic Form II has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form III, substantially as shown in FIG. 3; (b) polymorphic Form III has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3)°; and γ=90°; (c) polymorphic Form III has an monoclinic crystal system; (d) polymorphic Form III has a C2 space group; and (e) polymorphic Form III has a volume of 3052.2 (5) Å3.
In some embodiments, polymorphic Form III has at least one, or both of the following properties:
(a) an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form III, substantially as shown in FIG. 3; and
(b) a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=25.077 (3) Å; b=9.149 (10) Å; c=14.248 (14) Å; α=90°; β=110.967 (3)°; and γ=90°.
In some embodiments, polymorphic Form III has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 3. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments disclosed herein, including for polymorphic Form III, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the hydrochloride salt of polymorphic Form II is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form III may have one or more channels. Such channels may be occupied by certain molecules and/or ions, such as water and/or chloride ions.
Form IV
In another aspect, provided is polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°.
Polymorphic Form IV may have a calculated XRPD pattern substantially as shown in FIG. 4. It should be understood that the XRPD provided in FIG. 4 is a calculated XRPD from the single crystal data acquired at 100K for polymorphic Form IV.
In some embodiments of polymorphic Form IV, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(h) apply: (a) polymorphic Form IV has an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form IV, substantially as shown in FIG. 4; (b) polymorphic Form IV has a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°; (c) polymorphic Form IV has an orthorhombic crystal system; (d) polymorphic Form IV has a C222 (1) space group; (e) polymorphic Form IV has a volume of 5919.8 (5) Å3; (f) polymorphic Form IV has a Z value of 8; (g) polymorphic Form IV has a density of 1.405 g/cm3; and (h) polymorphic Form IV has an absorption coefficient of 0.184 mm−1.
In some embodiments, polymorphic Form IV has at least one, or both of the following properties:
(a) an XRPD pattern, calculated from the single crystal data acquired at 100K for polymorphic Form IV, substantially as shown in FIG. 4; and
(b) a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=13.469 (6) Å; b=13.842 (6) Å; c=31.754 (14) Å; α=90°; β=90°; and γ=90°.
In some embodiments, polymorphic Form IV has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 4. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments disclosed herein, including for polymorphic Form IV, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the hydrochloride salt of polymorphic Form IV is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form IV may have one or more channels. Such channels may be occupied by certain ions, such as chloride ions.
Form V
In another aspect, provided is polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 5.
In some embodiments, polymorphic Form V has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 5. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form V, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6 and 28.1. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 15.9, 24.0, 25.6, and 28.1 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 18.9, 20.3, and 36.3. In one embodiment, polymorphic Form V has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 15.9, 18.9, 20.3, 24.0, 25.6, 28.1 and 36.3.
Form VI
In another aspect, provided is polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 6.
In some embodiments, polymorphic Form VI has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 6. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form VI, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 17.0, 23.2 and 25.1. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 29) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 232 and 25.1 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 13.9, 16.7, 19.9, 22.3, and 22.5. In one embodiment, polymorphic Form VI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.8, 13.9, 16.7, 17.0, 19.9, 22.3, 22.5, 23.2 and 25.1.
Form VII
In another aspect, provided is polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 7.
In some embodiments, polymorphic Form VII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 7. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form VII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0. In certain embodiments, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 11.9, 15.3, 19.7, 20.1, 21.7 and 24.0. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7, and 24.0 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 153, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 17.8, 21.7 and 24.0 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 11.9, 15.3, 19.7, 20.1, 28.4 and 28.9. In one embodiment, polymorphic Form VII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.0, 9.8, 11.9, 15.3, 19.7, 20.1, 21.7, 24.0, 28.4 and 28.9.
Form VIII
In another aspect, provided is polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 8.
In some embodiments, polymorphic Form VIII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 8. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form VIII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1. In certain embodiments, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 12.4, 15.3, 20.3, 21.7 and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and one or more 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and one 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and two 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and three 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 19.9, 21.7 and 24.1 and four 2θ-reflections (+/−0.2 degrees 2θ) at 12.4, 15.3, 19.0, 20.3, and 28.9. In one embodiment, polymorphic Form VIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 10.0, 12.4, 15.3, 19.0, 19.9, 20.3, 21.7, 24.1 and 28.9.
Form IX
In another aspect, provided is polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 9.
In some embodiments, polymorphic Form IX has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 9. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form IX, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0. In certain embodiments, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8, 24.0 and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and one or more 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and one 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and two 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 19.6, 21.8 and 24.0 and three 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 12.5, 20.8, and 29.0. In one embodiment, polymorphic Form IX has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.5, 9.8, 12.5, 19.6, 20.8, 21.8, 24.0 and 29.0.
Form X
In another aspect, provided is polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 10.
In some embodiments, polymorphic Form X has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 10. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form X, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2. In certain embodiments, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 11.9, 15.5, 21.8, 24.2, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 21.8, and 24.2 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at 11.9, 15.5, 19.4, 19.8, 20.3, 28.6 and 29.0. In one embodiment, polymorphic Form X has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.9, 11.9, 15.5, 19.4, 19.8, 20.3, 21.8, 24.2, 28.6 and 29.0.
Form XI
In another aspect, provided is polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 11.
In some embodiments, polymorphic Form XI has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 11. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form XI, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.5, 17.0, 19.3, 20.3, 22.0 and 25.5 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 15.0, and 31.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.5, 15.0, 17.0, 19.3, 20.3, 22.0, 25.5 and 31.7.
Form XII
In another aspect, provided is polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 12.
Polymorphic Form XII may have a unit cell as determined by crystal X-ray crystallography of the following dimensions: a=10.717 Å (3); b=10.161 Å (3); c=12.409 Å (4); α=90°; β=104.021° (4); and γ=90°.
In some embodiments, polymorphic Form XII has at least one, or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 12; and
(b) a unit cell, as determined by Single Crystal X-Ray Crystallography, of the following dimensions: a=10.717 Å (3); b=10.161 Å (3); c=12.409 Å (4); α=90°; β=104.021° (4); and γ=90°.
In some embodiments, polymorphic Form XII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 12. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form XII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9 and 25.4 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 19.6, 23.3, 24.9, and 29.4. In one embodiment, polymorphic Form XII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.4, 12.4, 16.9, 19.1, 19.6, 23.3, 24.9, 25.4 and 29.4.
In certain embodiments, the hydrochloride salt of polymorphic Form XII is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, polymorphic Form XII may have one or more channels.
Form XIII
In another aspect, provided is polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an XRPD pattern substantially as shown in FIG. 13.
In some embodiments, polymorphic Form XIII has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 13. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for polymorphic Form XIII, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and one or more degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and one degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and two degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and three degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and four degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and five degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XI has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 16.8, 18.5 and 23.9 and six degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.0, 8.1, 9.7, 11.7, 13.6, 23.5, and 25.7. In one embodiment, polymorphic Form XIII has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 6.9, 8.0, 8.1, 9.7, 11.7, 13.6, 16.8, 18.5, 23.5, 23.9 and 25.7.
In further embodiments, additional patterns of solvate forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are provided.
Pattern 1
In one aspect, provided is Pattern 1 of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein Pattern 1 an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 14A.
In some embodiments, Pattern 1 has an XRPD pattern substantially as shown in FIG. 14A.
In some embodiments, Pattern 1 is a prepared in the presence of propylacetate. In some embodiments, Pattern 1 corresponds to a propylacetate solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments, Pattern 1 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 14A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 1, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.9, 11.7, 8.3, and 17.0. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, 25.8, 22.9, 11.7, 8.3, and 17.0. Table 1 shows the full XRPD peak list for Pattern 1.
TABLE 1
XRPD Peak List for Pattern 1
Angle (2-Theta °)
Intensity (%)
7.0
21.5
7.5
18.6
8.3
33.6
9.2
100.0
11.7
37.6
12.0
26.7
12.8
22.1
14.1
21.2
16.8
52.1
17.0
31.4
18.5
43.9
19.3
15.5
20.1
24.0
20.8
16.1
21.5
18.6
22.5
19.7
22.9
40.1
23.1
23.5
23.4
63.3
24.0
21.6
24.7
20.8
25.1
25.9
25.8
41.5
28.0
23.4
28.6
18.0
Pattern 9
In one aspect, provided is Pattern 9 of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein Pattern 9 an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 14B.
In some embodiments, Pattern 9 has an XRPD pattern substantially as shown in FIG. 14B.
In some embodiments, Pattern 9 is a prepared in the presence of propylacetate. In some embodiments, Pattern 9 corresponds to a propylacetate solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments, Pattern 9 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 14B. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 1, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4. In one embodiment, Pattern 1 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 23.4, 16.8, 18.5, and 25.8 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, and 23.4 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 27.9, 22.9, 14.0, and 17.0. In one embodiment, Pattern 9 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.2, 18.5, 25.8, 16.7, 23.4, 27.9, 22.9, 14.0, and 17.0. Table 2 shows the full XRPD peak list for Pattern 9.
TABLE 2
XRPD Peak List for Pattern 9
Angle (2-Theta °)
Intensity (%)
6.9
6.3
7.5
11.4
8.3
8.9
9.2
100.0
11.7
13.8
12.0
9.4
12.8
4.7
14.0
15.8
16.7
29.0
17.0
14.7
17.7
4.5
18.5
31.5
19.3
6.0
20.1
7.3
20.8
10.4
21.4
7.6
22.6
12.9
22.9
18.9
23.4
27.9
23.9
7.1
24.8
9.5
25.1
8.5
25.8
30.1
27.9
19.7
28.5
9.6
Pattern 2
In one aspect, provided is Pattern 2 of the polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. ISA. Pattern 2 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 15B. Pattern 2 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 15C.
In some embodiments, Pattern 2 is a prepared in the presence of isopropyl acetate. In some embodiments, Pattern 2 corresponds to an isopropyl acetate solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments of Pattern 2, at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply: (a) Pattern 2 has an XRPD pattern substantially as shown in FIG. 15A; (b) Pattern 2 has a DSC thermogram substantially as shown in FIG. 15B; (c) Pattern 2 has a TGA graph substantially as shown in FIG. 15C; (d) Form 2 has a melting temperature onset as determined by DSC at about 68° C.; (e) Pattern 2 has a second melting temperature onset as determined by DSC at about 153° C.; and (f) Pattern 2 has a third melting temperature onset as determined by DSC at about 179° C.
In some embodiments, Pattern 2 has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 15A;
(b) a DSC thermogram substantially as shown in FIG. 15B;
In some embodiments, Pattern 2 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 15A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 2, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 2 has an XRPD pattern comprising degree 26-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and one of the degree 2θ-reflections (+/−0.2 degrees 29) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, and 16.7 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 22.8, 25.0, 18.6, 13.3, and 28.1. In one embodiment, Pattern 2 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 7.8, 23.4, 9.2, 25.8, 16.7, 22.8, 25.0, 18.6, 13.3, and 28.1. Table 3 shows the full XRPD peak list for Pattern 2.
TABLE 3
XRPD Peak List for Pattern 2
Angle (2-Theta °)
Intensity (%)
6.8
5.2
7.8
100.0
9.2
31.0
11.6
8.2
13.3
10.5
14.1
5.4
15.6
4.7
16.7
18.4
18.1
9.9
18.6
12.4
20.1
8.3
21.1
7.5
22.8
18.3
23.4
52.1
25.0
17.8
25.8
20.6
28.1
10.2
Pattern 3
In one aspect, provided is Pattern 3 of the polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluo-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 16A. Pattern 3 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 16B. Pattern 3 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 16C.
In some embodiments, Pattern 3 is a prepared in the presence of 1,2-dimethoxyethane. In some embodiments, Pattern 3 corresponds to an 1,2-dimethoxyethane solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments of Pattern 3, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) Pattern 3 has an XRPD pattern substantially as shown in FIG. 16A; (b) Pattern 3 has a DSC thermogram substantially as shown in FIG. 16B; (c) Pattern 3 has a TGA graph substantially as shown in FIG. 16C; and (d) Pattern 3 has a melting temperature onset as determined by DSC at about 172° C.
In some embodiments, Pattern 3 has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 16A;
(b) a DSC thermogram substantially as shown in FIG. 16B;
In some embodiments, Pattern 3 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 16A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 3, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and two of the degree 29-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, and 19.7 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.0, 28.7, 15.1, 12.2, and 26.7. In one embodiment, Pattern 3 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 9.8, 21.5, 24.0, 11.7, 19.7, 20.0, 28.7, 15.1, 12.2, and 26.7. Table 4 shows the full XRPD peak list for Pattern 3.
TABLE 4
XRPD Peak List for Pattern 3
Angle (2-Theta °)
Intensity (%)
9.4
5.3
9.8
100.0
11.1
17.6
11.7
62.8
12.2
28.9
12.9
12.6
14.3
10.8
14.6
4.1
15.1
33.6
15.4
10.7
17.0
9.1
17.4
14.1
17.7
15.7
18.5
5.9
18.9
18.7
19.1
28.6
19.7
61.5
20.0
50.1
20.6
14.4
20.9
19.5
21.5
94.2
22.3
11.6
22.6
8.1
23.0
12.6
23.6
10.8
24.0
82.7
24.7
12.2
25.4
6.1
26.0
9.6
26.3
5.0
26.7
28.7
27.4
5.0
27.7
6.1
28.3
19.9
28.7
34.5
29.1
8.5
29.7
9.6
Pattern 4
In one aspect, provided is Pattern 4 of the polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 17A.
Pattern 4 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 17B. Pattern 4 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 17C.
In some embodiments, Pattern 4 is a prepared in the presence of isopropyl alcohol. In some embodiments, Pattern 4 corresponds to an isopropyl alcohol solvate of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In some embodiments of Pattern 4, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) Pattern 4 has an XRPD pattern substantially as shown in FIG. 17A; (b) Pattern 4 has a DSC thermogram substantially as shown in FIG. 17B; (c) Pattern 4 has a TGA graph substantially as shown in FIG. 17C; and (d) Pattern 4 has a melting temperature onset as determined by DSC at about 170° C.
In some embodiments, Pattern 4 has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 17A;
(b) a DSC thermogram substantially as shown in FIG. 17B;
In some embodiments, Pattern 4 has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 17A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for Pattern 4, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, and 20.2 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 19.1, 21.8, 7.2, 14.8, and 19.6. In one embodiment, Pattern 4 has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 12.3, 24.9, 16.8, 25.3, 20.2, 19.1, 21.8, 7.2, 14.8, and 19.6. Table 5 shows the full XRPD peak list for Pattern 4.
TABLE 5
XRPD Peak List for Pattern 4
Angle (2-Theta °)
Intensity (%)
7.2
13.8
8.4
3.1
11.4
7.0
12.3
100.0
13.0
5.1
14.5
3.4
14.8
11.3
15.2
2.6
16.8
58.7
17.3
1.8
17.7
7.9
18.5
3.2
18.8
4.4
19.1
18.9
19.6
11.3
19.9
9.1
20.2
24.2
20.5
9.7
21.3
7.7
21.8
18.5
23.0
11.3
23.5
6.0
24.0
6.3
24.5
2.8
24.9
70.9
25.3
42.0
25.7
4.2
26.4
3.6
26.8
6.1
27.4
1.8
27.8
4.7
28.0
10.3
28.3
2.2
29.1
4.2
29.5
6.6
2-Methyl-1-propanol Solvate
In one aspect, provided is the 2-methyl-1-propanol solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 18A. The 2-methyl-1-propanol solvate may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 18B. The 2-methyl-1-propanol solvate may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 18C.
In some embodiments of the 2-methyl-1-propanol solvate, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) 2-methyl-1-propanol solvate has an XRPD pattern substantially as shown in FIG. 18A; (b) 2-methyl-1-propanol solvate has a DSC thermogram substantially as shown in FIG. 18B; (c) 2-methyl-1-propanol solvate has a TGA graph substantially as shown in FIG. 18C; and (d) 2-methyl-1-propanol solvate has a melting temperature onset as determined by DSC at about 113° C.
In some embodiments, the 2-methyl-1-propanol solvate has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 18A;
(b) a DSC thermogram substantially as shown in FIG. 18B;
In some embodiments, the 2-methyl-1-propanol solvate has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 18A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for the 2-methyl-1-propanol solvate, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, and 24.5 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 24.3, 12.4, 22.5, 12.9, and 28.5. In one embodiment, the 2-methyl-1-propanol solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 8.6, 26.0, 17.3, 20.7, 24.5, 24.3, 12.4, 22.5, 12.9, and 28.5. Table 6 shows the full XRPD peak list for the 2-methyl-1-propanol solvate.
TABLE 6
XRPD Peak List for 2-Methyl-1-propanol Solvate Form
Angle (2-Theta °)
Intensity (%)
4.3
2.9
5.9
1.0
8.6
100.0
9.9
0.7
10.3
3.2
11.2
1.2
12.1
2.6
12.4
3.8
12.7
1.1
12.9
3.3
13.8
2.8
14.1
0.6
14.6
0.5
15.4
0.9
16.0
1.6
16.9
3.0
17.3
18.5
17.7
3.0
17.9
0.9
18.5
0.7
18.9
2.7
19.4
0.6
19.9
1.8
20.2
2.7
20.5
2.8
20.7
4.8
20.9
2.9
21.9
1.4
22.5
3.4
22.8
3.2
23.7
1.4
23.9
1.9
24.3
4.1
24.5
4.7
24.8
2.9
25.4
1.7
26.0
60.2
26.9
1.2
27.6
1.7
28.0
1.4
28.3
2.6
28.5
3.3
28.8
3.3
29.6
1.0
29.8
1.1
1,4-Dioxane Solvate
In one aspect, provided is the 1,4-dioxane solvate form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 19A. The 1,4-dioxane solvate may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 19B. The 1,4-dioxane solvate may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 19C.
In some embodiments of the 1,4-dioxane solvate, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) 1,4-dioxane solvate has an XRPD pattern substantially as shown in FIG. 19A; (b) 1,4-dioxane solvate has a DSC thermogram substantially as shown in FIG. 19B; (c) 1,4-dioxane solvate has a TGA graph substantially as shown in FIG. 19C; and (d) 1,4-dioxane solvate has a melting temperature onset as determined by DSC at about 158° C.
In some embodiments, the 1,4-dioxane solvate has at least one or both of the following properties:
(a) an XRPD pattern substantially as shown in FIG. 19A;
(b) a DSC thermogram substantially as shown in FIG. 19B;
In some embodiments, the 1,4-dioxane solvate has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 19A. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for the 1,4-dioxane solvate, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, and 21.1 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 20.6, 21.7, 11.9, 24.5, and 14.7. In one embodiment, the 1,4-dioxane solvate has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 23.2, 18.8, 11.5, 19.4, 21.1, 20.6, 21.7, 11.9, 24.5, and 14.7. Table 7 shows the full XRPD peak list for the 1,4-dioxane solvate.
TABLE 7
XRPD Peak List for 1,4-Dioxane Solvate Form
Angle (2-Theta °)
Intensity (%)
6.9
13.6
8.0
6.1
9.6
4.9
11.5
78.6
11.9
26.1
12.7
10.2
13.7
8.7
14.7
20.5
15.1
4.9
16.2
19.4
16.9
13.5
17.5
5.4
17.7
6.2
18.1
6.4
18.8
83.1
19.4
62.8
19.8
12.5
20.6
49.0
21.1
60.0
21.7
36.3
22.7
9.8
23.2
100.0
24.1
9.1
24.5
22.2
25.2
4.8
25.6
10.4
26.0
15.0
26.3
5.2
26.6
5.5
27.2
8.9
27.7
5.6
28.4
7.4
28.7
7.1
29.3
4.7
29.6
6.1
Toluene Solvate
In one aspect, provided is a toluene solvent form of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the polymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 20.
In some embodiments of the toluene solvent form, the toluene solvent form has an XRPD pattern substantially as shown in FIG. 20.
In some embodiments, the toluene solvent form has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2θ-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 20. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein, including for the toluene solvent form, are intended to encompass variations of +/−0.2 degrees 2θ.
In certain embodiments the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and one or more of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and one of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and two of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, and 24.0 and three of the degree 2θ-reflections (+/−0.2 degrees 2θ) at 16.6, 22.5, 27.9, 12.7, and 27.5. In one embodiment, the toluene solvent form has an XRPD pattern comprising degree 2θ-reflections (+/−0.2 degrees 2θ) at 25.5, 8.4, 23.3, 23.1, 24.0, 16.6, 22.5, 27.9, 12.7, and 27.5. Table 8 shows the full XRPD peak list for the toluene solvent form.
TABLE 8
XRPD Peak List for Toluene Solvent Form
Angle (2-Theta °)
Intensity (%)
6.9
15.9
8.4
75.1
9.7
16.1
10.3
10.7
11.5
13.9
11.9
13.3
12.7
36.6
13.6
17.4
15.8
15.9
16.6
46.2
17.1
31.0
18.0
19.8
19.3
25.8
19.9
29.2
21.5
22.6
22.5
44.8
23.1
51.3
23.3
56.7
24.0
48.5
25.5
100.0
26.3
31.3
27.5
32.2
27.9
39.7
29.6
24.7
Compositions Thereof
Provided are also compositions comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of polymorphs (e.g., any one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, XI, XII and XIII) as described herein. In a particular embodiment, a composition comprising one of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising two of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising three of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising four of polymorphic Forms I, II, m, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising five of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising six of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising seven of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising eight of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising nine of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising ten of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising eleven of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In a particular embodiment, a composition comprising twelve of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII described herein is provided. In other embodiments, the compositions described herein may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
In some embodiments, the term “substantially pure” or “substantially free” with respect to a particular polymorphic form of a compound means that the composition comprising the polymorphic form contains less than 95%, less than 90%, less than 80%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other polymorphic forms and/or impurities. In certain embodiments, “substantially pure” or “substantially free of” refers to a substance free of other substances, including other polymorphic forms and/or impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
Form I
In some embodiments, the composition comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form I as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form I. In particular embodiments of compositions comprising polymorphic Form I, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form I. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form I, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms II-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form I, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form I present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form I, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form II
In some embodiments, the composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form II as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form II. In particular embodiments of compositions comprising polymorphic Form II, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form II. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form II of the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form II, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I, III-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form II, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form II present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form II, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form II, the compositions further comprise polymorphic Form X of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms II and X, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms II and X. It should be understood that the relative ratio of polymorphic Form II to polymorphic Form X present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form III
In some embodiments, the composition comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form III as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form III. In particular embodiments of compositions comprising polymorphic Form III, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form III. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form III of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form III, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-II, IV-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form III, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form II present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form II, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form III, the compositions further comprise polymorphic Form V of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms III and V, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms III and V. It should be understood that the relative ratio of polymorphic Form III to polymorphic Form V present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form III has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form III has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form IV
In some embodiments, the composition comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form IV as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form IV. In particular embodiments of compositions comprising polymorphic Form IV, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form IV. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form IV of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form IV, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-III, V-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form IV, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form IV present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form IV, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form IV, the compositions further comprise polymorphic Form IX of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms IV and IX, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms IV and IX. It should be understood that the relative ratio of polymorphic Form IV to polymorphic Form IX present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form IV has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form IV has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form V
In some embodiments, the composition comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form V as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form V. In particular embodiments of compositions comprising polymorphic Form V, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form V. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form V of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form V, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-IV, VI-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form V, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form V present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form V, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form V, the compositions further comprise polymorphic Form II of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms III and V, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms III and V. It should be understood that the relative ratio of polymorphic Form III to polymorphic Form V present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form V has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form V has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form VI
In some embodiments, the composition comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form VI as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form VI. In particular embodiments of compositions comprising polymorphic Form VI, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form VI. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form VI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form VI, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-V, VII-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form VI, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form VI present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form VI, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form VI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form VI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form VII
In some embodiments, the composition comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form VII as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form VII. In particular embodiments of compositions comprising polymorphic Form VII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form VII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form VII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form VII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-VI, VIII-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form VII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form VII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form VII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form VII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form VII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form VIII
In some embodiments, the composition comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form VIII as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form VIII. In particular embodiments of compositions comprising polymorphic Form VIII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form VIII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form VIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form VIII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-VII, IX-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form VIII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form VIII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H) one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form VIII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form VIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form VIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form IX
In some embodiments, the composition comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form IX as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form IX. In particular embodiments of compositions comprising polymorphic Form IX, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form IX. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form IX of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form IX, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-VIII, X-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form IX, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form IX present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form IX, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form IX, the compositions further comprise polymorphic Form IV of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms IV and IX, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H) one present in the composition are polymorphic Forms IV and IX. It should be understood that the relative ratio of polymorphic Form IV to polymorphic Form IX present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form IX has less than about 5%, less than about 40, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form IX has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form X
In some embodiments, the composition comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form X as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form X. In particular embodiments of compositions comprising polymorphic Form X, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form X. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form X of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form X, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-IX, XI-XII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form X, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form X present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form X, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (8)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In certain embodiments of compositions comprising the polymorphic Form X, the compositions further comprise polymorphic Form II of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In other words, the compositions may comprise a mixture of polymorphic forms. In particular embodiments of compositions comprising a mixture of polymorphic Forms II and X, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are polymorphic Forms II and X. It should be understood that the relative ratio of polymorphic Form II to polymorphic Form X present in the composition may vary.
In yet other embodiments, the composition comprising the polymorphic Form X has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form X has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form XI
In some embodiments, the composition comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form XI as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form XI. In particular embodiments of compositions comprising polymorphic Form XI, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form XI. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form XI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H) one.
In other embodiments of compositions comprising the polymorphic Form XI, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-X, XII-XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form XI, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form XI present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form XI, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form XI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form XI has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form XII
In some embodiments, the composition comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form XII as described herein, wherein the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form XII. In particular embodiments of compositions comprising polymorphic Form XII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form XII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form XII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluo-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form XII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (including, for example, polymorphic Forms I-XI, XIII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form XII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form XII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form XII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form XII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form XII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Form XII
In some embodiments, the composition comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments are provided compositions comprising polymorphic Form XIII as described herein, wherein the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one within the composition is a substantially pure polymorphic Form XIII. In particular embodiments of compositions comprising polymorphic Form XIII, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition is polymorphic Form XIII. In certain embodiments, the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form XIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In other embodiments of compositions comprising the polymorphic Form XIII, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one present in the composition are other polymorphs of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-(3)-one (including, for example, polymorphic Forms I-XII) and/or impurities.
In yet other embodiments of compositions comprising the polymorphic Form XIII, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic Form XIII present. Impurities may, for example, include by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include contaminants from the process of synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include degradation products of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include other polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising the polymorphic Form XIII, impurities are selected from the group consisting of by-products from synthesizing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
In yet other embodiments, the composition comprising the polymorphic Form XIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In yet other embodiments, the composition comprising the polymorphic Form XIII has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (e.g., in its free form).
Preparation of the Polymorphs
One method of synthesizing (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one has been previously described in U.S. Pat. No. 7,932,260. This reference is hereby incorporated herein by reference in its entirety, and specifically with respect to the synthesis of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. One or more polymorphic forms of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one may be prepared from (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one or from its hydrochloride salt.
For example, in one aspect, provided is a method of producing a composition comprising one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a compound of Formula (I) with hydrochloric acid and a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the hydrochloride salt of the compound of Formula (I). In another aspect, provided is another method of producing a composition comprising one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a suitable solvent or a mixture of suitable solvents.
The choice of a particular solvent or combination of solvents affects the formation favoring one polymorphic form of a hydrochloride salt (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one over another. Solvents suitable for polymorph formation may include, for example, methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, 2-propanol, 1-propanol, 1-butanol, and any mixtures thereof.
In another aspect, provided is also one or more polymorphs of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced according to any of the methods described herein.
It should be understood that the methods for preparing the polymorphs described herein (including any one or more of polymorphic Forms I to XIII) may yield quantity and quality differences compared to the methods for preparing the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced on laboratory scale.
Form I
In one embodiment, provided is a method of producing a composition comprising polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
Provided is a polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
Provided is also a polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is selected from the group consisting of methanol, ethanol, water, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, n-heptane, acetonitrile, and any mixtures thereof.
In certain embodiments of the polymorphic Form I produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Forms II and X
In one embodiment, provided is a method of producing a composition comprising polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form II, Form X, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is acetone.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form II, Form X, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is acetone.
Provided is a polymorphic Form II, Form X, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is acetone.
Provided is also a polymorphic Form II, Form X, or a mixture thereof; of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is acetone.
In certain embodiments of the polymorphic Form II, Form X, or a mixture thereof produced according to the methods described above, the hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Forms I and V
In one embodiment, provided is a method of producing a composition comprising polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form III, Form V, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-methyltetrahydrofuran.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form III, Form V, or a mixture thereof; of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-methyltetrahydrofuran.
Provided is a polymorphic Form III, Form V, or a mixture thereof; of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 2-methyltetrahydrofuran.
Provided is also a polymorphic Form III, Form V, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 2-methyltetrahydrofuran.
In certain embodiments of the polymorphic Form III, Form V, or a mixture thereof, produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Forms IV and IX
In one embodiment, provided is a method of producing a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form IV, Form IX, or a mixture thereof of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is tetrahydrofuran.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form IV, Form IX, or a mixture thereof, of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is tetrahydrofuran.
Provided is a polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is tetrahydrofuran.
Provided is a polymorphic Form IV, Form IX, or a mixture thereof, of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is tetrahydrofuran.
In certain embodiments of the polymorphic Form IV, Form IX, or a mixture thereof; produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form VI
In one embodiment, provided is a method of producing a composition comprising polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form VI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl isobutyl ketone.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form VI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl isobutyl ketone.
Provided is a polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is methyl isobutyl ketone.
Provided is also a polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one to produce a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is methyl isobutyl ketone.
In certain embodiments of the polymorphic Form VI produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form VII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form VII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl ethyl ketone.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form VII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is methyl ethyl ketone.
Provided is a polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is methyl ethyl ketone.
Provided is also a polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is methyl ethyl ketone.
In certain embodiments of the polymorphic Form VII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form VIII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form VIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is dichloromethane.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form VIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is dichloromethane.
Provided is a polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is dichloromethane.
Provided is also a polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is dichloromethane.
In certain embodiments of the polymorphic Form VIII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form XI
In one embodiment, provided is a method of producing a composition comprising polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form XI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-propanol.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form XI of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 2-propanol.
Provided is a polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 2-propanol.
Provided is also a polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 2-propanol.
In certain embodiments of the polymorphic Form XI produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form XII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form XII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-propanol.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form XII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-propanol.
Provided is a polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 1-propanol.
Provided is also a polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 1-propanol.
In certain embodiments of the polymorphic Form XII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Form XIII
In one embodiment, provided is a method of producing a composition comprising polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent to produce a composition comprising polymorphic Form XIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-butanol.
In another embodiment, provided is a method of producing a composition comprising polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the method comprises combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent to produce a composition comprising polymorphic Form XIII of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, wherein the solvent is 1-butanol.
Provided is a polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with hydrochloric acid and a solvent, wherein the solvent is 1-butanol.
Provided is also a polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one produced by combining a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with a solvent, wherein the solvent is 1-butanol.
In certain embodiments of the polymorphic Form XIII produced according to the methods described above, the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
The combination of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one with one or more suitable solvents, as described above, yields a composition or mixture comprising the solvent and the one or more polymorphic forms produced. In some instances where only a portion of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is converted into one or more polymorphic forms, the composition further comprises the hydrochloride salt. In some embodiments of the methods described above to produce the one or more polymorphic forms, the method further comprises isolating the one or more polymorphic forms from the resulting composition. Any suitable techniques or methods known in the art to isolate the one or more polymorphic forms from the composition may be employed. For example, the solvent or mixture of solvents used in the methods described above may be removed by known methods, such as filtration and/or evaporation, to isolate the one or more polymorphic forms produced from the composition.
Pharmaceutical Compositions
The polymorphic forms described herein can be administered as the neat chemical, but it is typical, and preferable, to administer the compound in the form of a pharmaceutical composition or formulation. Accordingly, provided are pharmaceutical compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and any combinations thereof) and one or more pharmaceutically acceptable carriers, excipients, or other ingredients (including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants). In certain embodiments, pharmaceutical compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) and one or more pharmaceutically acceptable excipients is provided. In certain embodiments, pharmaceutical compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one) also include one or more additional therapeutic agents, as well as one or more pharmaceutically acceptable excipients. The composition can include the polymorphic forms described herein either as the sole active agent or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones mixed with one or more pharmaceutically acceptable carriers, excipients, or other ingredients. Carriers, excipients, and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.
Provided herein is a pharmaceutical composition comprising one or more polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one described herein (e.g., one or more of polymorphic Forms I to XIII), and a pharmaceutical acceptable carrier or excipient.
Also provided herein is a pharmaceutical composition comprising one or more polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one described herein (e.g., one or more of polymorphic Forms I to XIII), and a pharmaceutical acceptable excipient.
In one embodiment, the pharmaceutical composition comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In a further embodiment, the pharmaceutical composition comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the pharmaceutical composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In another embodiment, the pharmaceutical composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the pharmaceutical composition comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In another embodiment, the pharmaceutical composition comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the pharmaceutical composition comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In another embodiment, the pharmaceutical composition comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet another embodiment, the pharmaceutical composition comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
Techniques for formulation and administration of pharmaceutical compositions can be found in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co, Easton, Pa., 1990. The pharmaceutical compositions described herein can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Depending on the condition being treated, these pharmaceutical compositions can be formulated and administered systemically or locally.
The pharmaceutical compositions can be formulated to contain suitable pharmaceutically acceptable carriers, and optionally can comprise excipients and auxiliaries that facilitate processing of the polymorphic forms described herein into preparations that can be used pharmaceutically. The mode of administration generally determines the nature of the carrier. For example, formulations for parenteral administration can include aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration are physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For preparations including proteins, the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
Alternatively, formulations for parenteral use can include dispersions or suspensions of polymorphic forms described herein prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, dextran, and mixtures thereof. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT™ series available from Rohm America Inc. (Piscataway, N.J.). Emulsions, e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants). Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
Liposomes containing the polymorphic forms described herein also can be employed for parenteral administration. Liposomes generally are derived from phospholipids or other lipid substances. The compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, Academic Press, New York (1976).
In some embodiments, the polymorph or composition thereof disclosed herein is formulated for oral administration using pharmaceutically acceptable carriers, excipients or other ingredients well known in the art. Preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders. To illustrate, pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
In certain embodiments, the pharmaceutical compositions described herein are in the form of tablets, pills or capsules. In a particular embodiment, the pharmaceutical compositions described herein are in the form of a tablet. Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or more excipients, which include, without limitation:
a) diluents, such as microcrystalline cellulose and sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
b) binders, such as sodium starch glycolate, croscarmellose sodium, magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.;
c) cellulose materials, such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof, such as sodium alginate, or effervescent compositions;
e) lubricants, such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol;
f) flavorants and sweeteners;
g) colorants or pigments, e.g., to identify the product or to characterize the quantity (dosage) of active compound; and
h) other ingredients, such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
For example, provided is a tablet comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and any combinations thereof) and one or more pharmaceutically acceptable carriers or excipients. Also provided is a tablet comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and any combinations thereof) and one or more pharmaceutically acceptable excipients.
In one embodiment, the tablet comprises substantially pure polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the tablet comprises substantially pure polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutically acceptable excipient.
In another embodiment, the tablet comprises substantially pure polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the tablet comprises substantially pure polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In another embodiment, the tablet comprises substantially pure polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In yet another embodiment, the tablet comprises substantially pure polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In one embodiment, the tablet comprises substantially pure polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a pharmaceutical acceptable excipient.
In any of the foregoing tablets, in one variation, the tablet is substantially free of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, in any of the foregoing tablets, the tablet is free of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The polymorphs described herein are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the polymorph actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the subject receiving such treatment, the severity of the subject's symptoms, and the like.
The tablets or pills described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage element, the latter being in the form of an envelope over the former. The two elements can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner element to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymorphic acids and mixtures of polymorphic acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
For example, provided is a unit dosage comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one embodiment, the unit dosage comprises polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, the unit dosage comprises polymorphic Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, the unit dosage comprises polymorphic Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In another embodiment, the unit dosage comprises polymorphic Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In yet another embodiment, the unit dosage comprises polymorphic Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In any of the foregoing unit dosage forms, in certain embodiments, the hydrochloride salt is a monohydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In any of the foregoing unit dosage forms, in one variation, the unit dosage form is substantially free of amorphous or non-crystalline hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In certain embodiments, in any of the foregoing unit dosage forms, the tablet further includes one or more excipients.
In certain embodiments, the unit dosage forms described herein include 75-300 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75-200 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75-150 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 75 mg, 100 mg, 150 mg, or 200 mg of the polymorphic forms described herein. In certain embodiments, the unit dosage forms described herein include 100 mg or 150 mg 200 mg of the polymorphic forms described herein.
Modes of Administration and Dosages
Pharmaceutical compositions including the polymorphic forms described herein can be administered to the subject by any conventional method, including parenteral and enteral techniques. Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enteral administration modalities include, for example, oral, buccal, sublingual, and rectal administration. Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and buccal and sublingual administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Parenteral administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT™.
Moreover, the therapeutic index of the compound having the polymorphic forms described herein can be enhanced by modifying or derivatizing the compound for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compound can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described. See e.g., Pietersz et al., Immunol. Rev., 129:57 (1992); Trail et al., Science, 261:212 (1993); and Rowlinson-Busza et al., Curr. Opin. Oncol., 4:1142 (1992). Tumor-directed delivery of the compound can enhance the therapeutic benefit by, inter alia, minimizing potential nonspecific toxicities that can result from radiation treatment or chemotherapy. In some embodiments, the compound having a polymorphic form described herein, and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibody.
Pharmacokinetic and pharmacodynamic information about the polymorphic forms described herein and the formulation of the compound having a polymorphic form described herein can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for the compound having a polymorphic form described herein used in the methods described herein, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range that modulates PI3Kδ expression or activity. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the “therapeutic index”, which typically is expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantially higher than the effective dose, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity.
It should be understood that any effective administration regimen regulating the timing and sequence of doses can be used. A compound having a polymorphic form described herein and pharmaceutical compositions thereof may include those wherein the active ingredient is administered in an effective amount to achieve its intended purpose.
In some embodiments, a “therapeutically effective amount” means an amount sufficient to modulate PI3K expression or activity, including PI3Kδ expression or activity, and thereby treat a subject (e.g., a human) suffering an indication, or to alleviate the existing symptoms of the indication.
Exemplary dosage levels for a human subject may be of the order of from about 0.001 milligram of active agent per kilogram body weight (mg/kg) to about 1000 mg/kg. Dosage units of the active agent may comprise from about 0.01 mg to about 1000 mg, or from about 0.1 mg to about 100 mg, depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. For example, when administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. In certain embodiments, the total daily dosage for a human subject is about 150-300 mg/day. In certain embodiments, the total daily dosage for a human subject is about 200-300 mg/day. In certain embodiments, the total daily dosage for a human subject is 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg. In certain embodiments, the total daily dosage for a human subject is 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In certain embodiments, the total daily dosage for a human subject is 150 mg, 200 mg, or 300 mg. In certain embodiments, the total daily dosage for a human subject is 200 mg or 300 mg. In certain embodiments, the total daily dosage for a human subject is 100 mg or 150 mg. The final dosage regimen is determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the subject, the age, condition, body weight, sex, and diet of the subject, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
The frequency of dosing depends on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof; as required to maintain desired minimum level of the agent. Short-acting pharmaceutical compositions (i.e., short half-life) can be administered once a day or more than once a day (e.g., two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks.
In certain embodiments, the pharmaceutical composition disclosed herein are administered once, twice, or three times daily. In certain embodiments, the pharmaceutical composition disclosed herein are administered once or twice daily. In certain embodiments, the pharmaceutical composition disclosed herein are administered once daily.
Bioequivalents of the Polymorphs
Also provided herein are polymorphs that are bioequivalent to any one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one described herein.
In certain embodiments, bioequivalence between two polymorphs refers to polymorphs having substantially similar bioavailability, substantially similar efficacy, substantially similar safety profiles, or a combination thereof.
In yet other embodiments, bioequivalence refers to polymorphs that exhibit substantially similar pharmacokinetic profiles or therapeutic effects. Bioequivalence may be demonstrated through several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies. In some embodiments, bioequivalence can be demonstrated using any suitable pharmacokinetic measures or combination of pharmacokinetic measures known in the art, including loading dose, steady-state dose, initial or steady-state concentration of drug, biological half-life, elimination rate, area under the curve (AUC), clearance, the peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency. In some embodiments, bioequivalence is achieved with similar dosing amounts. In alternative embodiments, bioequivalence is achieved with different dosing amounts.
Uses of the Polymorphs and Compositions Thereof
Therapeutic Uses
Provided are also a use of the polymorphs or compositions thereof described herein to selectively or specifically inhibit PI3Kδ activity therapeutically or prophylactically. The method comprises administering the polymorphs or compositions thereof to a subject (e.g., a human) in need thereof in an amount sufficient to inhibit PI3Kδ activity. The method can be employed to treat humans or animals suffering from, or subject to, a condition whose symptoms or pathology is mediated by PI3Kδ expression or activity.
“Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following:
(i) decreasing one more symptoms resulting from the disease;
(ii) diminishing the extent of the disease and/or stabilizing the disease (e.g., delaying the worsening of the disease);
(iii) delaying the spread (e.g., metastasis) of the disease;
(iv) delaying or slowing the recurrence of the disease and/or the progression of the disease;
(v) ameliorating the disease state and/or providing a remission (whether partial or total) of the disease and/or decreasing the dose of one or more other medications required to treat the disease;
(vi) increasing the quality of life; and/or
(vii) prolonging survival.
In some embodiments, “disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
The methods disclosed in the application embrace various modes of treating an animal subject, preferably a mammal, more preferably a primate, and still more preferably a human. Among the mammalian animals that can be treated are, for example, humans; companion animals (pets), including dogs and cats; farm animals, including cattle, horses, sheep, pigs, and goats; laboratory animals, including rats, mice, rabbits, guinea pigs, and nonhuman primates; and zoo specimens. Among the non-mammalian animals that can be treated include, for example, birds, fish, reptiles, and amphibians.
In one aspect, the polymorphs and compositions thereof described herein can be employed in methods of inhibiting the growth or proliferation of cancer cells of hematopoietic origin, such as cancer cells. In some embodiments, the cancer cells are of lymphoid origin, and in specific embodiments, the cancer cells are related to or derived from B lymphocytes or B lymphocyte progenitors. In another aspect, the polymorphs and compositions thereof described herein can be employed in methods of treating a human with a cancer.
Cancers amenable to treatment using the method disclosed in the application include, for example, lymphomas (e.g., malignant neoplasms of lymphoid and reticuloendothelial tissues, such as Burkitt's lymphoma, Hodgkins' lymphoma, non-Hodgkins' lymphomas, lymphocytic lymphomas); multiple myelomas; leukemias (e.g., lymphocytic leukemias, chronic myeloid (myelogenous) leukemias), and solid tumor (e.g., pancreatic). Other cancer cells, of hematopoietic origin or otherwise, that express p110δ also can be treated by administration of the polymorphs and compositions thereof described herein.
In other embodiments, the forms described herein may be used to treat cancers that are mediated by, dependent on or associated with PI3K activity, such as PI3Kδ activity. In certain embodiments, the cancer is a hematologic malignancy. In certain embodiments, the cancer is lymphoma, multiple myeloma, or leukemia. In certain embodiments, the cancer is a solid tumor cancer. In particular embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic lymphoma, marginal zone lymphoma, Burkitt lymphoma, or follicular B-cell non-Hodgkin lymphoma (FL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). In one embodiment, the cancer is indolent non-Hodgkin's lymphoma (iNHL). It should be understood that non-Hodgkin's lymphoma may, in certain embodiments, encompass the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In certain embodiments, the forms described herein may be used to treat chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL), or small lymphocytic lymphoma (SLL). In certain embodiments, the forms described herein may be used to treat relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), or relapsed small lymphocytic lymphoma (SLL). In certain embodiments, the forms described herein may be used to treat non-Hodgkin's lymphoma (NHL) or indolent non-Hodgkin's lymphoma (iNHL). In certain embodiments, the forms described herein may be used to treat relapsed non-Hodgkin's lymphoma (NHL) or relapsed indolent non-Hodgkin's lymphoma (iNHL).
In another aspect, the polymorphs and compositions thereof described herein can be employed in methods of treating an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD). In particular embodiments, the autoimmune disease is asthma, rheumatoid arthritis, multiple sclerosis, or lupus.
In yet another aspect, provided are methods of treating a human having a PI3K-mediated disorder by administering one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) to the human. In another aspect, provided are methods of treating a human having a PI3K-mediated disorder by administering one or more of the polymorphic forms described herein (e.g., one or more of the solvate forms corresponding to Pattern 1, 2, 3, 4, or the 2-methyl-1-propanol solvate, or the 1,4-dioxane solvate, or the toluene solvate) to the human. Provided are also methods of modulating PI3K an individual by administering one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one. In one variation, the human has cancer, such as leukemia or lymphoma. In another variation, the human has an autoimmune disease, such as asthma, rheumatoid arthritis, multiple sclerosis, or lupus.
In any of the foregoing methods, one or more polymorphic forms may be administered to the individual as unit dosage, for example in the form of a tablet, as described herein. Exemplary unit dosage levels of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII, for a human subject may, in certain variations, be between about 0.01 mg to about 1000 mg, between about 1 mg to about 15 mg, or between about 50 mg to about 200 mg, or about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg, or about 175 mg, about 200 mg, or about 250 mg.
In another aspect, polymorphic forms described herein (e.g., polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) may be used in combination with one or more additional therapeutic agent that are being used and/or developed to treat cancers or inflammatory disorders. The one or more additional therapeutic agent may be an inhibitor to PI3K such as PI3Kγ, PI3Kβ, and/or PI3Kα, Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3, spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1, serine/threonine kinase TPL2, discoidin domain receptor (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), or monoclonal antibody (such as an anti-CD20 monoclonal antibody or an anti-CD39 monoclonal antibody) or any combination thereof.
One, two, three, or more of the therapeutic agents (e.g. a PI3K inhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4 inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDH inhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBK inhibitor, a HDAC inhibitor, a PKC inhibitor, or a monoclonal antibody) may be further used or combined with a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs (bendamustine, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.
As used herein the term “chemotherapeutic agent” or “chemotherapeutic” (or “chemotherapy”, in the case of treatment with a chemotherapeutic agent) may encompass any non-proteinaceous (e.g., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as bendamustine, thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubanimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL®, Bristol Meyers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-1; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent are used or included in the present application. For example, gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAK inhibitor and/or PI3Kδ inhibitor for treating hyperproliferative disorders.
Chemotherapeutic agents may also include, for example, anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston®); inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole (Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof; 2-methoxyestradiol, ANGIOSTATIN, ENDOSTATIN, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide; angiostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors” (1999) Nature Medicine 5:1359-1364.
The anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct. 23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled “Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate,” relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled “Inhibitors of lysyl oxidase,” relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g., U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat. No. 5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608 (relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent Application No. 2004/0248871, which are herein incorporated by reference in their entirety. Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate.
The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minrctumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131.
The application also provides a method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.
In certain embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).
In certain embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.
Examples of immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-CD39 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofaturmumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient's tumor, such as lymphoma vaccine example is GTOP-99 (MyVax®).
Examples of chemotherapy agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasnnse) Obatoclax (GXI 5-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin, Temsirolimus (CC1-779), Thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (R-MCP).
The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapies include, but are not limited to, Iodine-131 tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.
Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Uses in Manufacturing of Drug Product
Provided are also a use of the polymorphs described herein in the manufacture of a drug product. The one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII) may be used as an intermediate in the manufacturing process to produce the drug product.
In certain embodiments, Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one are used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form II of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form III of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form IV of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form V of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form VI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form VII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form VIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form IX of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form X of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form XI of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form XII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, Form XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is used in the manufacture of an active pharmaceutical ingredient. In certain embodiments, the active pharmaceutical ingredient is Idelalisib.
Articles of Manufacture and Kits
Compositions comprising one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and formulated in one or more pharmaceutically acceptable carriers, excipients or other ingredients can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and a label containing instructions for use of the compound(S).
In some embodiments, the article of manufacture is a container comprising a dosage form of one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to XIII of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, and one or more pharmaceutically acceptable carriers, excipients or other ingredients. In one embodiment of the articles of manufacture described herein, the dosage form is a tablet.
Kits also are contemplated. For example, a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. The instructions for use in the kit may be for treating a PI3K-mediated disorder, including, for example, a hematologic malignancy. In certain embodiments, the instructions for use in the kit may be for treating leukemia. In one embodiment, the instructions for use in the kit may be for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL).
In certain embodiments, conditions indicated on the label can include, for example, treatment of cancer. Conditions indicated on the label can include non-Hodgkin's lymphoma (NHL). In one embodiment, the condition may be indolent non-Hodgkin's lymphoma (iNHL). In another embodiment, the condition may be chronic lymphocytic leukemia (CLL). Other conditions that may be indicated on the label include, for example, follicular lymphoma (FL); lymphoplastic lymphoma (LPL); Waldenström macroglobulinemia (WM); marginal zone lymphoma (MZL); and small cell lymphocytic lymphoma (SLL).
In certain embodiments, the polymorphic and solvate forms described herein may potentially exhibit improved properties. For example, in certain embodiments, the polymorphic and solvate forms described herein may potentially exhibit improved stability. Such improved stability could have a potentially beneficial impact on the manufacture of the Compound of Formula I, such as for example offering the ability to store process intermediate for extended periods of time. Improved stability could also potentially benefit a composition or pharmaceutical composition of the Compound of Formula I. In certain embodiments, the polymorphic and solvate forms described herein may also potentially result in improved yield of the Compound of Formula I, or potentially result in an improvement of the quality of the Compound of Formula I. In certain embodiments, the polymorphic and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.
EXAMPLES
The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular materials and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof.
The polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one were characterized by various analytical techniques, including X-ray powder diffraction pattern (XPPD), differential scanning calorimetry (DSC), and thermographic analysis (TGA) using the procedures described below.
X-Ray Powder Diffraction:
XRPD patterns were collected at room temperature, using a PANalytical X'Pert MPD Pro Powder X-Ray Diffractometer configured with reflectance stage with spinning, data acquisition range: 2-40 degrees 2θ, Copper (Cu) anode; Kα1/Kα2 radiation; tube current 40 mA; tube tension 45 kV; automatic divergence and anti-scatter slits. Samples were prepared for analysis by distributing solid material as a thin layer on a silicon holder. Each holder was mounted on a reflectance/transmittance stage and rotated during data acquisition.
Differential Scanning Calorimetry:
DSC was performed using a TA Instruments Q2000 DSC instrument. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid, and then either crimped or hermetically sealed. The same cell was heated under a nitrogen purge at a rate of 10° C./min, up to a final temperature of 300° C. Indium was used as the calibration standard.
Thermogravimetric Analysis:
TGA was performed using a TA Instruments Q5000 TGA instrument. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was heated under nitrogen at a rate of 10° C./min, up to a final temperature of 300° C. The TGA furnace was calibrated using the magnetic Curie point method.
Example 1
Preparation of Form I of the HCl Salt of the Compound of Formula (I)
This Example demonstrates exemplary methods to synthesize a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (the compound of Formula (I)).
Method A
In a vessel was charged 10.0 grams (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and 50 mL absolute ethanol. In a separate vessel 1 mL of 12 M HCl (0.5 equiv.) was diluted in 20 mL absolute ethanol. The acidified ethanol was added to the vessel containing the (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one suspension while stirring. After a few minutes the suspension was seeded with <1 mL of polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one suspension. The seeds were prepared by adding ethanol to amorphous solids, thereby allowing the conversion of amorphous solids to crystalline solid. The crystalline solids were then air dried. XRPD was used to monitor progress in converting to the HCl salt. Additional 1 mL of 12 M HCl (0.5 equiv.) was charged after about 24 hours. After 14 days, the XRPD confirmed full conversion to the HCl salt. The suspension was stored at ambient temperature for 30 days and solids were isolated by filtration. The solids were washed one time with about 50 mL water and allowed to air dry at room temperature.
KF of the resulting hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one was observed to be about 13% and about 16% (avg. about 15%). DSC of the resulting hydrochloride salt (as seen in FIG. 1B) shows two broad endothermic events, one beginning at about 48° C. and the other at about 184° C. No exothermic events were observed to be present. TGA of the resulting hydrochloride salt (as seen in FIG. 1C) shows two mass loss events, one beginning at about 25° C. and ending at about 50° C., the other beginning at about 125° C. and ending (for the most part) at about 200° C. DVS of the resulting hydrochloride salt (as seen in FIGS. 1D and 1E) showed minor mass increase as a function of RH at 25° C. A single crystal X-ray of crystals grown from the resulting hydrochloride salt filtrate was taken, and the data is summarized in Table 9 below. The Single Crystal X-Ray Crystallography data showed that the crystals are a channel solvate and a mono-HCl salt. Data from further characterization of the crystals are summarized in Table 10 below.
TABLE 9
Single Crystal X-Ray Crystallography Data for the Compound of Formula (I)
Unit Cell Dimensions
Form and Composition
Distance (Å)
Angle (°)
Form
water
solvent
API:water:solvent
a
b
c
α
β
γ
Form I
N
Methanol
1:1:0.5
31.102 (15)
9.166 (5)
19.738 (10)
90
125.948 (17)
90
TABLE 10
Crystal Data and Structure Refinement
for the Compound of Formula (I)
Property
Value
Empirical formula
C22.50 H18 Cl F N7 O1.50
Formula weight
464.89
Temperature
100(2) K
Wavelength
0.71073 Å
Crystal system
Monoclinic
Space group
C2
Volume
4555(4) Å3
Z
8
Density (calculated)
1.356 g/cm3
Method B
To a slurry of 5-fluoro-3-phenyl-2-((1S)-1-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)propyl)quinazolin-4(3H)-one (18 g contains about 30% TEA HCl) in ethanol (30 g), concentrated hydrochloric acid (5.0 g, 1.6 mole eq.) was added maintaining temperature ≦30° C. Immediately upon addition completion, high purity water (15.0 g) was added to the solution. After adjusting the contents to about 19 to 25° C. and checking the pH (targeting a value of ≦2.0, adding more concentrated hydrochloric acid if needed), the solution was agitated for about 1 h at about 19 to 25° C. To slightly increase the substrate concentration, (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (in free form) (0.4 g) was charged portion-wise at about 19 to 25° C. A cloudy mixture was observed, which turned into a suspension after 30 min. The resulting slurry was agitated at about 19 to 25° C. for about 5 h and filtered. The wet cake was washed with cold EtOH (8.0 g, about 9° C.) and dried under vacuum at about 50° C. (S)-2-(1-(9H-Purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one hydrochloride was obtained as a solid. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, 2H), 7.85 (m, 1H), 7.70-7.40 (m, 6H), 7.30 (m, 1H), 4.67 (br, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 0.85 (t, 3H).
Example 2
Hydrate Screen on the HCl Salt of the Compound of Formula (I)
This Example demonstrates the effect of water on the stability of polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
Polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I), prepared according to the protocols described in Example 1 above was mixed with ethanol and water. The amount of hydrochloride salt (Form I) and the ethanol/water ratio summarized in Table 11 below. XRPDs were taken on Days 5 and 21. Results from this Example are summarized in Table 11 below.
TABLE 11
Results from hydrate screen on the HCl salt of the Compound of Formula I
Form I HCl salt of
Ethanol/
Compound of
water
solubility
XRPD after
solubility
XRPD after
Formula (I) (mg)
aw
(mg/mL)
5 days
(mg/mL)
21 days
98
0.2
26
Form I
60
Form I
114
0.3
47
Form I
33
Form I
112
0.4
57
Form I
66
Form I
112
0.5
72
Form I
93
Form I
107
0.6
NA
Form I
183
Form I
127
0.7
NA
Form I
223
Form I
118
0.8
NA
Form I
174
Form I
113
0.9
NA
Form I &
44
Form I &
Form I of the
Form I of the
free form of
free form of
Compound of
Compound of
Formula (I)
Formula (I)
The hydrate screen in the water/ethanol system showed no changes in XRPD except in the case of water activity 0.9, which converted some of the hydrochloride salt to polymorphic Form I of the free form of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I).
Example 3
Form Screen on the HCl Salt of the Compound of Formula (I)
This Example demonstrates the conversion of polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., the Compound of Formula (I), into other polymorphic forms based on particular solvents used.
Polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I), prepared according to the protocols described in Example 1 above was mixed with the solvent (as listed in Table 12 below) in a vial/flask, resulting in a suspension. The amount of hydrochloride salt (Form I) is also listed in Table 12 below.
After 7 days, a sample of the suspension was removed from the vial/flask, and the sample was centrifuged and filtered to separate the solids from the liquid in the sample. The isolated solids were characterized by XRPD (collected at room temperature). The filtrate was retained.
For several experiments, including the experiments involving THF, acetone and 2-MeTHF, crystals large enough for Single Crystal X-Ray Crystallography were observed in the vial/flask. A sample of the crystals taken in suspension was removed and analyzed by Single Crystal X-Ray Crystallography (data acquired at 100K).
After about 25 days, another sample was removed from the vial/flask, and the sample was centrifuged and filtered to separate the solids from the liquid in the sample. The isolated solids were characterized by XRPD (collected at room temperature). Results from this Example are summarized in Table 12 below.
TABLE 12
Results from form screen on the HCl salt of the Compound of Formula I
Single Crystal
Form I HCl salt
X-Ray of
of Compound of
XRPD after
XRPD after
crystals from
Formula (I)
Solvent
7 days
about 25
suspension
119 mg
water
Form I
Form I
NA
117 mg
isopropyl acetate (IPAc)
Form I
Form I
NA
150 mg
methyl t-butyl ether (MTBE)
Form I
Form I
NA
132 mg
2-propanol
Form I
mixture
NA
160 mg
dichloromethane (DCM)
new
Form VIII
NA
163 mg
n-heptane
Form I
Form I
NA
114 mg
tetrahydrofuran (THF)
new
Form IX
IV
125 mg
acetone
new
Form X
II
155 mg
methanol
Form I
Form I
NA
120 mg
acetonitrile (ACN)
Form I
Form I
NA
157 mg
Ethanol
Form I
Form I
NA
140 mg
ethyl acetate (EtOAc)
Form I
Form I
NA
154 mg
2-methyltetrahydrofuran (2-MeTHF)
Form V
Form V
III
149 mg
methyl ethyl ketone (MEK)
new
Form VII
NA
176 mg
methyl isobutyl ketone (MIBK)
Form I
Form VI
NA
10 g
1-propanol
1-propanol solvate
Form XII
NA
10 g
2-propanol
1-propanol solvate
Form XI
NA
10 g
1-butanol
1-butanol solvate
Form XIII
NA
The XRPDs taken for polymorphic Forms II-XIII are provided in FIGS. 2-13, respectively. Single Crystal X-Ray Crystallography data were collected from polymorphic Forms II-IV and XII prepared in this Example, and such data is summarized in Table 13 below.
TABLE 13
Single Crystal X-Ray Crystallography Data
Unit Cell Dimensions
Form and Composition
Distance (Å)
Angle (°)
Form
solvent
API:water:solvent
a
b
c
α
β
γ
II
acetone
1:0:3
13.266 (3)
13.858 (3)
31.012 (6)
90
90
90
III
2MeTHF
1:1:1.5
25.077 (3)
9.1485 (10)
14.2476 (14)
90
110.967 (3)
90
IV
THF
1:0:3
13.4685 (6)
13.8415 (6)
31.7543 (14)
90
90
90
XII
1-propanol
1:0:1
10.717 (3)
10.161 (3)
12.409 (4)
90
104.021 (4)
90
Example 4
Solvent Screen on Form I of the HCl Salt of the Compound of Formula (I)
This Example demonstrates the preparation of solvated forms of polymorphic Form I of the hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., the Compound of Formula (I).
Polymorphic Form I of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, i.e., Compound of Formula (I) was prepared by suspending 5 g of the free base Form I of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one in 25 mL absolute ethanol. The sample was agitated at 200 rpm and about 23° C. 1.05 mL of 12M HCl (1.1 eq.) was diluted in 10 mL absolute ethanol, then added to the suspension of the Compound of Formula (I) in ethanol, forming a slurry. The slurry suspension was stirred at about 23° C. for about 24 hours, filtered and washed with 10 mL absolute ethanol and dried under vacuum for three days. Formation of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was confirmed by x-ray powder diffraction.
50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) prepared according to the protocols described above was mixed with increasing amounts of each solvent listed in Table 14 below (10 vol, 20 vol, 30 vol, 40 vol, 50 vol, 60 vol, 70 vol, 70 vol (at about 50° C.)) until the material dissolved or reached the maximum amount of solvent. The mixtures were then evaluated for identification of the solid form using the following screening procedures:
Maturation: The suspensions were cycled in a platform shaker incubator between about 50° C. and room temperature (8 hours per cycle, for three days);
Slurry at 5° C.: 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was suspended in 40 vol of the solvent. The suspensions were left stirring at about 5° C. for about 7 days;
Slurry at 50° C.: 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was suspended in 40 vol of the solvent. The suspensions were left stirring at about 50° C. for about 2 days;
Salt formation: 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was dissolved or suspended in 10 vol of solvent and held at about 50° C. for 15 minutes, after which 1.1 eq of HCl (11.6 μL of 12M HCl) were added and the sample was slowly cooled to about 5° C. at about 0.1° C. per minute;
Solvent deposition: 25 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was transferred to a 2 mL vial, which was then placed into a larger sealed vial with 3 mL of the corresponding solvent, then held at about 40° C. for about 13 days.
Any solids obtained from the above screening procedures were analyzed wet/damp by XRPD as described below. The solids were isolated by decanting and/or filtration, then dried under vacuum. Solid form samples obtained after maturation experiments were dried under vacuum and analyzed by NMR to determine if the solvating ethanol was replaced by the suspending solvent. As shown in Table 14, the screening experiments identified new solvated forms of the HC salt of the Compound of Formula I. For Patterns 1, 2, 3, and 4, each of the four of the identified solvated forms are a family of solvates, which are observed from more than one solvent.
TABLE 14
Results from solvent screen on Form I of
the HCl salt of the Compound of Formula I
Form
Solvent
Represenative XRPD
Pattern 1
Ethyl Acetate
FIG. 14A (damp)
Propyl acetate
FIG. 14B (dry)
Pattern 2
1-Methyl-1-propanol
FIG. 15A
Isopropyl acetate
Pattern 3
1,2-Dimethyoxyethane
FIG. 16A
1,4-Dioxane
Acetone
Acetone:Water
Acetonitrile
Chloroform
Dicholoromethane
Diethyl ether
Ethyl acetate
MEK
MIBK
Nitromethane
Propyl acetate
Tetrahydrofuran
Toluene
Pattern 4
1-Propanol
FIG. 17A
2-Propanol
IPA:Water (5%)
2-Methyl-1-propanol
2-Methyl-1-propanol
FIG. 18A
solvate
1,4-Dioxane solvate
1,4-Dioxane
FIG. 19A
Toluene solvate
Toluene
FIG. 20
Representative samples of the solvate forms listed in Table 14 obtained from the crystallization screening were dried under vacuum and further characterized. The data from these further characterization experiments is summarized in Table 15.
TABLE 15
Results from solvent screen on Form I of the HCl salt of the Compound of Formula I
Form
Solvent
NMR of dry
DSC
TGA
Pattern 1
Propylacetate
n/t
n/t
n/t
Pattern 2
Isopropyl acetate
0.56eq iPrOAc
68° C. (−42 J/g)
9.7% (40° C.-130° C.)
153° C. (−38 J/g)
4.7% (130° C.-230° C.)
179° C. (−32 J/g)
Pattern 3
1,2-Dimethyoxyethane
0.93eq DME
172° C. (−92 J/g)
10.7% (110° C.-245°C.)
Pattern 4
Isopropyl alcohol
0.98eq IPA
170° C. (−192 J/g)
13.4% (130° C.-215° C.)
2-Methyl-1-propanol
2-Methyl-1-propanol
1.34eq 2-Methyl-1-
113° C. (−134 J/g)
19.0% (90° C.-225° C.)
solvate
propanol
1,4-Dioxane solvate
1,4-Dioxane
0.65eq 1.4-Dioxane
158° C. (−96 J/g)
12.7% (80° C.-225° C.)
Toluene solvate
Toluene
n/t
n/t
n/t
n/t: not tested
X-Ray Powder Diffraction (XRPD)
Two methods were used to collect XRPD on the samples described above.
Bruker AXS C2 GADDS
X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X-ray optics consists of a single Göbel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm. A θ-θ continuous scan mode was employed with a sample-detector distance of 20 cm which gives an effective 2θ range of 3.2°-29.7°. Typically the sample would be exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for XP/2000 4.1.43 and the data were analysed and presented using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0.
Ambient conditions: Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.
Non-ambient conditions: Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at 50° C./min and subsequently held isothermally for up to 4 minutes before data collection was initiated.
Bruker AXS D8 Advance
X-Ray Powder Diffraction patterns were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), 0-20 goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analysed and presented using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0.
Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was gently packed into a cavity cut into polished, zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis. The details of the data collection are: angular range: 2 to 42°2θ, step size: 0.05°2θ, collection time: 0.5 s/step.
Nuclear Magnetic Resonance (NMR)
1H-NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running with Topspin v1.3 using the standard Bruker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone.
Samples were prepared in DMSO-d6, unless otherwise stated. Off-line analysis was carried out using ACD Labs 2012 release (build 61851).
Differential Scanning Calorimetry (DSC)
DSC data were collected on a Mettler DSC 823E equipped with a 34 position auto-sampler. The instrument was calibrated for energy and temperature using certified indium. Typically 0.5-4 mg of each sample, in a pin-holed aluminium pan, was heated at 10° C./min from 25° C. to 350° C. A nitrogen purge at 50 ml/min was maintained over the sample.
The instrument control and data analysis software was STARe v9.20.
Thermo-Gravimetric Analysis (TGA) TGA data were collected on a Mettler TGA/SDTA 851e equipped with a 34 position autosampler. The instrument was temperature calibrated using certified indium. Typically 2-13 mg of each sample was loaded onto a pre-weighed aluminium crucible and was heated at 10° C./min from ambient temperature to 350° C. A nitrogen purge at 50 ml/min was maintained over the sample.
The instrument control and data analysis software was STARe v9.20.
The XRPDs taken for the solvate forms identified in Table 14 are provided in FIGS. 14A, 14B, 15A, 16A, 17A, 18A, 29A, and 20 respectively.
For Pattern 1, shown in FIGS. 14A and 15B, 50 mg of the hydrochloride salt of the Compound of Formula (I) was suspended in propyl acetate (3.5 mL, 70 vol) and held at 50° C. for 15 minutes, after which 1.1 eq of 12M HCl (11.6 μL) was added and the sample slowly cooled from 50° C. to 5° C. at 0.1° C. per minute. The XRPD pattern shown in FIG. 14A was observed while the sample was wet. On drying in a vacuum oven at about 25° C. for 6 days, the sample was converted to the XRPD pattern shown in FIG. 14B (Pattern 9). NMR data confirm the presence of propyl acetate in the crystallized from. FIG. 14C depicts the XRPD pattern after further heating at about 145° C. for about 16 hours (Pattern 9′). Table 16 lists the XRPD peaks for Pattern 9′
TABLE 16
XRPD Peak List for Pattern 9′ Form
Angle (2-Theta °)
Intensity (%)
7.5
11.1
9.2
100.0
11.8
16.8
12.0
12.4
14.1
19.5
16.8
31.3
17.1
18.8
18.5
32.6
19.4
8.2
20.1
9.0
20.8
12.4
21.5
11.2
22.9
20.7
23.4
32.5
24.7
12.2
25.9
28.7
28.0
17.7
28.6
10.9
29.2
5.9
29.5
5.6
For Pattern 2, shown in FIG. 15A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with isopropyl acetate (3.5 mL, 70 vols) producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. 1H NMR data confirm the presence of isopropyl acetate in the crystallized from.
For Pattern 3, shown in FIG. 16A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 1,2-dimethoxyethane (3.5 mL, 70 vols) producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. 1H NMR data confirm the presence of 1,2-dimethoxyethane in the crystallized from.
For Pattern 4, shown in FIG. 17A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 2-propanol (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. 1H NMR data confirm the presence of 2-propanol in the crystallized from.
For the 2-Methyl-1-propanol solvate, shown in FIG. 18A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 2-methyl-1-propanol (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. FIG. 18D depicts the same XRPD diffractogram, showing the entire Y axis (i.e., not truncated). 1H NMR data confirm the presence of 2-methyl-1-propanol in the crystallized from.
For the 1,4-Dioxane solvate, shown in FIG. 19A, 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with 1,4-dioxane (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. The XRPD pattern is shown in FIG. 20. 1H NMR data confirm the presence of 1,4-dioxane in the crystallized from.
For the toluene solvate, shown in FIG. 20 (wet), 50 mg of the polymorphic Form I of a hydrochloride salt of the Compound of Formula (I) was treated with toluene (3.5 mL, 70 vols), producing a suspension at 50° C. This suspension was matured between 50° C. and room temperature (8 hours per cycle) for three days. Upon drying, the XRPD of the toluene solvent is a mixture of Pattern 1 and Pattern 9′.
DSC plots for Pattern 9, Pattern 2, Pattern 3, Pattern 4, the 2-Methyl-1-propanol solvate form, and the 1,4-dioxane solvate form identified in Table 14 are provided in FIGS. 14D, 15B, 16B, 17B, 18B, and 19B respectively. TGA plots for Pattern 9, Pattern 2, Pattern 3, Pattern 4, the 2-Methyl-1-propanol solvate form, and the 1,4-dioxane solvate form identified in Table 14 are provided in FIGS. 14E, 15C, 16C, 17C, 18C, and 19C, respectively.
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14575857
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Dec 18th, 2018 12:00AM
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Sep 27th, 2016 12:00AM
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https://www.uspto.gov?id=US10154998-20181218
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Therapies for hematologic malignancies
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The invention provides methods that relate to a novel therapeutic strategy for the treatment of hematological malignancies and inflammatory diseases. In particular, the method comprises administering a compound of formula A,
wherein R is H, halo, or C1-C6 alkyl;
R′ is C1-C6 alkyl; or
a pharmaceutically acceptable salt thereof; and
optionally a pharmaceutically acceptable excipient;
and administering at least one additional therapeutic agent.
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10154998
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1. A method for treating a hematological malignancy in a subject in need thereof, comprising administering a compound of formula A,
wherein R is halo;
R′ is C1-C6 alkyl; or
a pharmaceutically acceptable salt thereof; and
optionally a pharmaceutically acceptable excipient;
and ofatumumab,
wherein said hematological malignancy is chronic lymphocytic leukemia (CLL) or acute lymphocytic leukemia (ALL).
2. The method according to claim 1, wherein the compound is predominantly the S-enantiomer.
3. The method according to claim 1, wherein R is fluoro (F) and is attached to position 5 or 6 of the quinazolinyl ring.
4. The method according to claim 1, wherein R is F; and R′ is methyl, ethyl or propyl.
5. The method according to claim 1, wherein the compound is a compound of formula I″
6. The method according to claim 1, further comprising administering at least one additional therapeutic agent.
7. The method according to claim 1, wherein the subject is refractory to chemotherapy treatment or is in relapse after treatment with chemotherapy.
8. The method according to claim 1, comprising administering to said subject a pharmaceutical composition comprising the compound of formula A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
9. A method for treating a hematological malignancy in a subject in need thereof, comprising administering a compound of formula I″
or a pharmaceutically acceptable salt thereof, and ofatumumab,
wherein said hematological malignancy is chronic lymphocytic leukemia (CLL) or acute lymphocytic leukemia (ALL).
10. The method according to claim 9, wherein the subject is refractory to chemotherapy treatment or is in relapse after treatment with chemotherapy.
11. The method according to claim 9, further comprising administering at least one additional therapeutic agent.
12. The method according to claim 9, comprising administering to said subject a pharmaceutical composition comprising the compound of formula I″ or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
13. The method according to claim 9, wherein said subject has at least one enlarged lymph node.
14. The method according to claim 10, wherein said subject is refractory to at least two standard or experimental chemotherapy treatments.
15. The method according to claim 9, wherein said compound of formula I″ or a pharmaceutically acceptable salt thereof is administered at a dose of 50-350 mg BID.
16. The method according to claim 15, wherein said compound of formula I″ or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg BID.
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16
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. patent application Ser. No. 13/417,185 filed Mar. 9, 2012, which is a continuation-in-part of U.S. patent application Ser. No. 12/618,612 filed Nov. 13, 2009, which claims priority from U.S. Provisional Patent Application Nos. 61/245,196 filed Sep. 23, 2009; 61/231,278 filed Aug. 4, 2009; 61/180,768 filed May 22, 2009; 61/155,057 filed Feb. 24, 2009; 61/142,845 filed Jan. 6, 2009; and 61/114,434 filed Nov. 13, 2008. The contents of these applications are incorporated by reference in their entirety.
TECHNICAL FIELD
The invention is in the field of therapeutics and medicinal chemistry. In particular, the invention concerns uses of certain quinazoline derivatives for the treatment of hematologic malignancies and certain other conditions.
BACKGROUND ART
Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring.
PI 3-kinase activation, is believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis.
The initial purification and molecular cloning of PI 3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits. Four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., p110α, p110β and p110δ, each interact with the same regulatory subunit, p85; whereas p110γ interacts with a distinct regulatory subunit, p101. The patterns of expression of each of these PI3Ks in human cells and tissues are also distinct.
Identification of the p110δ isoform of PI 3-kinase is described in Chantry et al., J Biol Chem, 272:19236-41 (1997). It was observed that the human p110δ isoform is expressed in a tissue-restricted fashion. It is expressed at high levels in lymphocytes and lymphoid tissues, suggesting that the protein might play a role in PI 3-kinase-mediated signaling in the immune system. The p110β isoform of PI3K may also play a role in PI3K-mediated signaling in certain cancers.
There is a need for a treatment relating to PI3K mediated disorders relating to cancers, inflammatory diseases, and autoimmune diseases.
SUMMARY
The present invention provides a class of quinazolinone type compounds and a method to use these compounds in the treatment of cancer, inflammatory, and autoimmune diseases. In particular, cancers that are hematologic malignancies, such as leukemia and lymphoma, are treated by the methods herein. Also provided are methods of using the quinazolinone compounds in combination with other therapeutic treatments in patients in need thereof.
In one aspect, the invention provides the use of a compound for the manufacture of a medicament for the treatment of a condition in a subject, wherein the condition is cancer or an autoimmune condition; wherein the compound is of formula A,
wherein R is H, halo, or C1-C6 alkyl; R′ is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable excipient.
In one embodiment, the compound is predominantly the S-enantiomer.
In some of the foregoing embodiments, R is fluoro (F) and is attached to position 5 or 6 of the quinazolinyl ring.
In some of the foregoing embodiments, R is H or F; and R′ is methyl, ethyl or propyl.
In some embodiments, the compound is
In some embodiments, compound is
In some of the foregoing embodiments, the autoimmune disease is allergic rhinitis, asthma, COPD, or rheumatoid arthritis.
In some of the foregoing embodiments, the condition is cancer.
In some of the foregoing embodiments, the cancer is a hematological malignancy.
In some of the foregoing embodiments, the hematological malignancy is leukemia.
In some of the foregoing embodiments, the hematological malignancy is lymphoma.
In some of the foregoing embodiments, the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM), B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL).
In some of the foregoing embodiments, the cancer is acute lymphocytic leukemia (ALL).
In some of the foregoing embodiments, the cancer is acute myeloid leukemia (AML).
In some of the foregoing embodiments, the cancer is chronic lymphocytic leukemia (CLL).
In some of the foregoing embodiments, the cancer is multiple myeloma (MM).
In some of the foregoing embodiments, the cancer is B-cell lymphoma.
In some of the foregoing embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).
In some of the foregoing embodiments, the cancer is B-cell or T-cell ALL.
In some of the foregoing embodiments, the cancer is Hodgkin's lymphoma.
In some of the foregoing embodiments, the cancer is breast, lung, colon, prostate or ovarian cancer.
In some of the foregoing embodiments, the subject is refractory to chemotherapy treatment, or in relapse after treatment with chemotherapy.
In some of the foregoing embodiments, the compound is prepared for administration with at least one additional therapeutic agent.
In some of the foregoing embodiments, the additional therapeutic agent is a proteasome inhibitor.
In some of the foregoing embodiments, the additional therapeutic agent is combined with the compound of Formula A.
In some of the foregoing embodiments, the additional therapeutic agent is selected from the group consisting of ofatumumab, bortezomib (Velcade®), carfilzomib (PR-171), PR-047, disulfiram, lactacystin, PS-519, eponemycin, epoxomycin, aclacinomycin, CEP-1612, MG-132, CVT 63417, PS-341, vinyl sulfone tripeptide inhibitors, ritonavir, PI-083, (+/−) 7 methylomuralide, (−)-7-methylomuralide.
In some of the foregoing embodiments, the additional therapeutic agent is bortezomib.
In some of the foregoing embodiments, the compound is prepared for administration with at least a group of at least two agents, wherein said group of agents is selected from the groups consisting of a-q,
a) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone);
b) R CHOP (rituximab CHOP);
c) hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine);
d) R-hyperCVAD (rituximab-hyperCVAD);
e) FCM (fludarabine, cyclophosphamide, mitoxantrone);
f) R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone);
g) bortezomib and rituximab;
h) temsirolimus and rituximab;
i) temsirolimus and Velcade®;
j) Iodine-131 tositumomab (Bexxar®) and CHOP;
k) CVP (cyclophosphamide, vincristine, prednisone);
l) R-CVP (rituximab-CVP);
m) ICE (iphosphamide, carboplatin, etoposide);
n) R-ICE (rituximab-ICE);
o) FCR (fludarabine, cyclophosphamide, rituximab);
p) FR (fludarabine, rituximab); and
q) D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
In some of the foregoing embodiments, the compound of formula A is present in a pharmaceutical composition comprising the compound of formula A and at least one pharmaceutically acceptable excipient.
In another aspect, the invention provides the use of a compound for the manufacture of a medicament for the treatment of a condition in a subject, wherein the condition is selected from the group consisting of multiple myeloma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), B cell ALL, T cell ALL, Hodgkin's lymphoma, breast, and ovarian cancer, wherein the compound is a compound of formula I′ or formula II′:
In some of the foregoing embodiments, the subject is refractory to chemotherapy treatment or in relapse after treatment with chemotherapy.
In some of the foregoing embodiments, the subject has a cancer that constitutively expresses Akt phosphorylation activity.
In some of the foregoing embodiments, the subject has a cancer with high p110δ activity and low p110α activity.
In some of the foregoing embodiments, the compound is used in combination with bortezomib.
In another aspect, the invention provides the use of a compound I″ or II″ in the manufacture of a medicament for treating a hematological cancer, wherein the medicament is prepared for administration with bortezomib or carfilzomib.
In some of the foregoing embodiments, the compound maintains an average blood concentration above the EC50 level for PI3Kδ activation and below the level for EC50 PI3Kγ activation in basophils over a period of at least 12 hours from compound administration.
In some of the foregoing embodiments, the compound maintains an average blood plasma concentration between 100 nM and 1100 nM over a period of at least 12 hours from compound administration.
In some of the foregoing embodiments, the subject is resistant to standard chemotherapeutic treatments.
In some of the foregoing embodiments, the subject has at least one enlarged lymph node.
In some of the foregoing embodiments, the subject is refractory to at least two standard or experimental chemotherapy treatments had at least two prior chemotherapy treatments.
In some of the foregoing embodiments, each chemotherapy treatment is selected from the group consisting of fludarabine, alkylating agents, rituximab, alemtuzumab, and the treatments a-q listed above.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a graphical summary of multiple myeloma (MM) cell growth as a function of varying concentrations of cytokines IGF-1 and IL-6 in combination with compound I, using LB cells.
FIG. 2 shows a graphical summary of cell growth of multiple myeloma (MM) cells as a function of varying concentrations of compound I and the presence or absence of bone marrow stromal cells (BMSC) after 48 hours.
FIG. 3 shows a graphical summary of apoptosis of Chronic Lymphocytic Leukemia (CLL) cells as a function of varying concentrations of compound of formula I.
FIG. 4 shows a summary chart of the effect of compound I on cell viability, reduction in Akt (Ser473) phosphorylation, and caspase 3 activation in several different Acute Lymphoblastic Leukemia (ALL) cell lines.
FIG. 5 shows a summary of the effect of compound I on the cell cycle of acute lymphoblastic leukemia (ALL) cell lines.
FIG. 6 shows a graphical summary of the effect of varying concentration of compound I on cellular growth in breast cancer T47D and HS-578T cell lines at 48 hrs and 72 hrs.
FIG. 7 shows a graphical summary of the effect of varying concentrations of compound I on cellular growth of ovarian IGROV-1 and OVCAR-3 cell lines at 48 hrs and 72 hrs.
FIG. 8 shows a summary of the effect of compound I on Akt phosphorylation in many leukemia and lymphoma cell lines.
FIG. 9 shows SDS-PAGE images and displays of Akt and pAkt in various hematopoietic cancer cell lines as a function of the presence or absence of compound I, showing compound I inhibits Akt phosphorylation.
FIG. 10 shows graphical summaries of apoptotic and viable cell populations in breast cancer cell lines as a function of varying concentrations of compound formula I, demonstrating that the compound induces apoptosis.
FIG. 11 shows the concentration of compound I in the blood of a healthy human subject over 12 hours after oral administration of 50, 100 and 200 mg doses of said compound.
FIG. 12 shows the comparison of lesion areas in a human patient diagnosed with mantle cell lymphoma after 28 days (1 cycle) of treatment with compound I and lesion areas prior to treatment.
FIG. 13 shows the ALC (absolute lymphocyte count) in the blood of a patient over a period of 4 weeks after 28 days (1 cycle) of treatment with the compound of formula I.
FIG. 14 shows the concentration of compound I in the blood of patients with and without mantle cell lymphoma (MCL) over 6 hours after administration (50 mg BID) at day 28, compared to the concentration in the blood of a normal healthy volunteer at day 7 (D7) using the same dosing schedule or dosing with 100 mg BID of Compound I.
FIG. 15 shows PI3K isoform expression in a panel of lymphoma and leukemia cell lines.
FIG. 16A shows cell viability and apoptosis data in leukemia cell lines exposed to Compound I. In FIG. 16B the Annexin staining indicates an increase in apoptosis in the treated cells.
FIG. 17A-D shows PAGE results of different PI3K isoform expression in CLL patient cells.
FIG. 18A shows the induction of caspase 3 cleavage in the presence of compound I and FIG. 18B shows the induction of PARP cleavage in the presence of compound I.
FIG. 19 shows increased apoptosis of Chronic Lymphocytic Leukemia (CLL) cells from poor prognosis patients caused by exposure to compound I, demonstrating that compound I is effective in drug resistant patients.
FIG. 20 shows increased apoptosis of Chronic Lymphocytic Leukemia (CLL) cells from refractory/relapsed patients caused by exposure to the compound of formula I.
FIG. 21 shows the results of Phospho-Akt production in the absence or presence of 0.1, 1.0, 10 μM of compound I.
FIG. 22A shows flow cytometry results relating to PI3K signaling in basophils with no stimulation, FIG. 22B-C shows flow cytometry results relating to PI3K signaling in basophils demonstrating that anti-FCϵR1 or fMLP increases CD63 expression compared to no stimulation.
FIG. 23 shows inhibition of PI3K inhibition by compound I in basophils, and demonstrates that Compound I is especially effective at inhibition of CD63 expression induced by a p110δ pathway, but also effective at micromolar concentration to inhibit expression induced by a p110γ pathway.
FIG. 24A shows pharmacokinetic data of single dose administration of compound I at different dose amounts in healthy volunteers, and FIG. 24B shows a pharmacokinetic profile that maintains an effective dosage over a 12 hour period.
FIG. 25A shows the effects of various doses of compound I on glucose levels and FIG. 25B shows the effects of various doses of compound I on insulin levels, exhibiting little off-target activity.
FIG. 26A shows the PI3K isoform expression in a panel of DLBCL cell lines.
FIG. 26 B shows an SDS-PAGE image of pAkt in DLBCL cell lines in the presence or absence of compound I.
FIG. 27 shows the effects of a 10 μM concentration of compound I on the phosphorylation of Akt and S6 in ALL cell lines in SDS-PAGE.
FIG. 28A-B shows a dose dependent reduction of phosphorylation of Akt, S6, and GSK-3β after treatment with a series of compound I dilutions.
FIG. 29 shows dose dependent effects of compound I on ALL cell lines in the downregulation of cFLIP, cleavage of Caspase 3, and cleavage of PARP.
FIG. 30A shows expression of p110 delta in MM cell lines and FIG. 30B shows expression of p110 delta in patient MM cells; and FIG. 30C shows expression of p110 delta in MM.1S and LB cells.
FIG. 31A shows expression of p110 delta from LB and INA-6 cells transfected with p110 delta siRNA (Si) or control siRNA (mock).
FIG. 31B shows a graph of INA-6 cell growth after transfection with p110 delta siRNA (Si) or control siRNA (mock).
FIG. 31C shows the % of viable cells cultured with or without compound I for 48 hours.
FIG. 31D shows the % of viable MM cells after being cultured with compound I at concentrations from 0 to 20 μM for 48 hours.
FIG. 31E shows the % of viable peripheral blood mononuclear cells from healthy donors after being cultured with compound I at various concentrations for 72 hours.
FIG. 31F shows immunoblotting results of lysates from INA-6 cells cultured with compound I (0-5 μM) for 120 hours.
FIG. 32A shows immunoblot AKT and ERK expression profiles after culturing of INA-6 cells with compound I or LY294002 for 12 hours; FIG. 32B shows INA-6 and MM.1S cells with compound I at various concentrations for 6 hours; FIG. 32C shows LB and INA-6 cells with compound I for 0-6 hours.
FIG. 33A shows fluorescent and transmission electron microscopic images of INA-6 and LB MM cells treated with compound I for 6 hours and LC3 accumulation; arrows indicate autophagosomes.
FIG. 33B shows fluorescence microscopy images of INA-6 cells treated with 5 μM of compound I or serum starvation for 6 hours.
FIG. 33C shows immunoblots of LC3 and beclin-1 protein levels from INA-6 cells treated with or without compound I and 3-MA (3-methyl adenine, a known inhibitor of autophagy).
FIG. 33D shows % growth of p110δ positive LB cells after treatment with up to 100 μM of 3-MA for 24 hours.
FIG. 34A-B shows the levels of growth inhibition of LB or INA-6 cells co-cultured with 0, 5, and 10 M of compound I in the presence or absence of varying amounts of IL-6 or IGF-1; Legend: control media (▪); compound I at 5.0 μM () or 10 μM (□).
FIG. 34C and FIG. 34D show MM cell growth inhibition in the presence of BMSC. Legend for FIG. 34C only: control media (□), Compound I 2.5 μM (), 5 μM (), and 10 μM (▪).
FIG. 34 E shows immunoblots of IL-6 in culture supernatants from BMSCs cultured with compound I or control media for 48 hours.
FIG. 34F shows immunoblots of AKT and ERK expression profiles in INA-6 cells treated with compound I cultured with our without BMSCs.
FIG. 34G shows % BMSC cell growth in two different patients after culturing with compound I for 48 hours.
FIG. 35A shows microscopic images of HuVECs (human umbilical vein endothelial cells) cultured with 0, 1 and 10 μM of compound I for 8 hours and microtubule formation assessed.
FIG. 35B shows a bar chart summarizing endothelial cell tube formation in HuVEC cells treated with compound I.
FIG. 35 C shows a graph charting % cell growth of HuVECs as a function of the increasing culture concentration of compound I.
FIG. 35 D shows decreasing Akt and ERK expression of HuVEC cell lysates after being cultured with compound I for 8 hours.
FIG. 36A charts the tumor volume in SCID mice with human MM xenografts treated with 0, 10 mg/kg or 30 mg/kg of compound II as a function of time, showing strong in vivo activity on the human xenograft tumor.
FIG. 36 B shows a photograph comparing the tumor from human MM xenografts on a mouse treated with compound II for 12 days to a control mouse.
FIG. 36C shows the survival rate of SCID mice with human MM xenografts treated with 0, 10, and 30 mg/kg compound II over time.
FIG. 36D shows images from immuno-histochemistric analysis of tumors harvested from a mouse treated with compound II in comparison to the control; wherein CD31 and P-AKT positive cells are dark brown.
FIG. 36E shows immunoblots detecting PDK-1 and AKT levels from tumor tissues harvested from mice treated with compound II in comparison to a control.
FIG. 36F shows a chart of sIL6R levels measured in mice treated with 0, 10 mg/kg or 30 mg/kg of compound II over a period of 4 weeks of treatment as determined by ELISA.
FIG. 37A show the % of viable LB or INA-6 MM cells after treatment with compound I with varying amounts of bortezomib (B); Legend: medium (▪), compound I 1.25 μM (), 2.5 μM (), or 5.0 μM (□).
FIG. 37B shows immunoblots comparing levels of phosphorylation of AKT in INA-6 cells treated for 6 hours with compound I and/or bortezomib.
FIG. 38A shows PI3K isoform expression in a panel of follicular lymphoma cell lines; FIG. 38B shows reduction in the expression of pAkt, Akt, pS6 and S6 after exposure to compound I; and FIG. 38C shows increase in PARP and caspase-3 cleavage after exposure to compound I in a dose-dependent manner.
FIG. 39A shows amounts of constitutive PI3K signaling in primary MCL cells in various amounts of compound I; FIG. 39B shows reduction in pAkt production in MCL cell lines containing a survival factor and varying amounts of compound I.
FIG. 40A-B show a computer tomography axillary image of a bulky lymphadenopathy in a patient with CLL before treatment with compound I and after 1 cycle of treatment with compound I.
FIG. 41A shows a graph quantifying mitochondrial depolarization induced by the BIM BH3 peptide at 0.03 μM final concentration in peripheral blood CLL cells that were BH3 profiled by FACS (n=30). FIG. 41B shows BH3 profiles from three individual patients showing pattern of predominant dependence on BCL2, Mcl-1, and Bcl-XL. FIG. 41C is a graph showing BIM depolarization in treatment-naïve patients achieving a partial response (PR) or complete response (CR) by 2008 IW-CLL criteria compared to patients with progressive disease (PD) during or within six months of completing frontline CLL therapy (p=0.024). FIG. 41D is a graph showing BIM depolarization in patients with unmutated IGHV status (n=7) compared to patients with mutated IGHV status (n=18) (p=0.0026). FIG. 41E is a graph showing the correlation between percentage of VH homology to germline with level of priming (p=0.0043).
FIG. 42A and FIG. 42B show graphs depicting CLL cell adherence quantified by whole well fluorimetry at 24 hours and 1 hour, respectively (one-tailed p=0.045 and 0.032, respectively). FIG. 42C shows a graph depicting CLL cell viability as assessed by Annexin V/PI of PB-derived CLL cells co-cultured in the presence or absence of StromaNKTert for 24 hours, with drug treatments as depicted in the graph. FIG. 42D shows dose response curves for CLL cells cultured in the presence of ABT-737 for 24 hours with or without StromaNKTert and with or without compound I. FIG. 42E shows dose response curves for CLL cells cultured in the presence of ABT-263 with or without StromaNKTert and with or without compound I.
FIG. 43A shows aggregate CLL cell % apoptosis as measured by AnnexinV/PI for all four patient samples. FIG. 43B shows a graph depicting mitochondrial depolarization in stroma-exposed CLL cells treated with compound I when compared to controls (one-tailed p=0.0749). FIG. 43C shows a graph depicting mitochondrial depolarization in stroma-exposed CLL cells treated with BAD BH3 peptide and ABT-737 with compound I when compared to controls (one-tailed p=0.0462 and 0.0468, respectively).
MODES OF CARRYING OUT THE INVENTION
Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted.
The discussion of the general methods given herein is intended for illustrative purposes only. Other alternative methods and embodiments will be apparent to those of skill in the art upon review of this disclosure.
A group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should also be read as “and/or” unless expressly stated otherwise. Although items, elements, or components of the invention may be described or claimed in the singular, the plural is contemplated to be within the scope thereof unless limitation to the singular is explicitly stated.
The invention provides methods that relate to a novel therapeutic strategy for the treatment of cancer and inflammatory diseases. In one aspect, the invention provides a method of treating cancer or an autoimmune disease in a subject comprising administering to said subject a compound of formula A
wherein R is H, halo, or C1-C6 alkyl; R′ is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable excipient.
In a particular embodiment, halo is F; and R′ is methyl, ethyl or propyl.
In a particular embodiment, R is attached to position 5 of the quinazolinyl ring, having the structure
In a particular embodiment, R is attached to position 6 of the quinazolinyl ring, having the structure
The term ‘compound’ used herein, unless otherwise specified, refers to a compound of formula A, such as compound I, compound II, or an enantiomer, such as I″ or II″, or an enantiomeric mixture.
The “compound of formula I” or “compound I” refers to the chemical compound 5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one, structure of formula I:
The S-enantiomer of compound I is shown here, designated I″:
The “compound of formula II” or “compound II” refers to the chemical compound 2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one, structure of formula II:
The S-enantiomer of compound II is shown here, designated II″:
In one embodiment, the compound of formula A is a compound of formula I. In another embodiment, the compound of formula A is a compound of formula II. In certain embodiments, the compound is a racemic mixture of R- and S-enantiomers. In certain embodiments, the compound is used as a mixture of enantiomers, and is often enriched with the S-enantiomer. In some embodiments, the compound is predominantly the S-enantiomer. In some embodiments, the compound of formula A, used in the methods described herein is at least 80% S-enantiomer. In certain embodiments, the compound is primarily composed of the S-enantiomer, wherein the compound comprises at least 66-95%, or 85-99% of the S-enantiomer. In some embodiments the compound has an enantiomeric excess (e.e.) of at least 90% or at least 95% of S-enantiomer. In some embodiments the compound has an S-enantiomeric excess (e.e.) of at least 98% or at least 99%. In certain embodiments, the compound comprises at least 95% of the S-enantiomer. In the cellular and patient experiments provided in the Example section, the sample of compound I used was over 95% S-enantiomer.
In specific embodiments, the compound of formula I or II, used in the methods described herein is at least 80% S-enantiomer. In certain embodiments, the compound of formula I or II is primarily composed of the S-enantiomer, wherein the compound comprises at least 66-95%, or 85-99% of the S-enantiomer. In some embodiments the compound of formula I or II has an enantiomeric excess (e.e.) of at least 90% or at least 95% of S-enantiomer. In some embodiments the compound of formula I or II has an S-enantiomeric excess (e.e.) of at least 98% or at least 99%. In certain embodiments, the compound of formula I or II comprises at least 95% of the S-enantiomer. In the cellular and patient experiments provided in the Example section, the sample of compound I used was over 95% S-enantiomer.
In a particular embodiment, the compound selectively inhibits PI3K p110δ compared to other PI3K isoforms.
In a particular embodiment, the autoimmune disease is allergic rhinitis, asthma, COPD, or rheumatoid arthritis.
In a particular embodiment, the cancer is a hematological malignancy and/or solid tumor. In another particular embodiment, the hematological malignancy is leukemia or lymphoma.
In some embodiments, lymphoma is a mature (peripheral) B-cell neoplasm. In specific embodiments, the mature B-cell neoplasm is selected from the group consisting of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; Lymphoplasmacytic lymphoma; Marginal zone lymphoma, such as Splenic marginal zone B-cell lymphoma (+/− villous lymphocytes), Nodal marginal zone lymphoma (+/− monocytoid B-cells), and Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type; Hairy cell leukemia; Plasma cell myeloma/plasmacytoma; Follicular lymphoma, follicle center; Mantle cell lymphoma; Diffuse large cell B-cell lymphoma (including Mediastinal large B-cell lymphoma, Intravascular large B-cell lymphoma, and Primary effusion lymphoma); and Burkitt's lymphoma/Burkitt's cell leukemia.
In some embodiments, lymphoma is selected from the group consisting of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM) or B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL).
In a further particular embodiment, leukemia is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL). Acute lymphocytic leukemia is also known as acute lymphoblastic leukemia and may be used interchangeably herein. Both terms describe a type of cancer that starts from the white blood cells, lymphocytes, in the bone marrow.
In some embodiments, Non-Hodgkin's Lymphoma (NHL) falls into one of two categories, aggressive NHL or indolent NHL. Aggressive NHL is fast growing and may lead to a patient's death relatively quickly. Untreated survival may be measured in months or even weeks. Examples of aggressive NHL includes B-cell neoplasms, diffuse large B-cell lymphoma, T/NK cell neoplasms, anaplastic large cell lymphoma, peripheral T-cell lymphomas, precursor B-lymphoblastic leukemia/lymphoma, precursor T-lymphoblastic leukemia/lymphoma, Burkitt's lymphoma, Adult T-cell lymphoma/leukemia (HTLV1+), primary CNS lymphoma, mantle cell lymphoma, polymorphic post-transplantation lymphoproliferative disorder (PTLD), AIDS-related lymphoma, true histiocytic lymphoma, and blastic NK-cell lymphoma. The most common type of aggressive NHL is diffuse large cell lymphoma.
Indolent NHL is slow growing and does not display obvious symptoms for most patients until the disease has progressed to an advanced stage. Untreated survival of patients with indolent NHL may be measured in years. Non-limiting examples include follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (such as extranodal marginal zone lymphoma (also called mucosa associated lymphoid tissue—MALT lymphoma), nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma), splenic marginal zone lymphoma), and lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia).
In some cases, histologic transformation may occur, e.g., indolent NHL in patients may convert to aggressive NHL.
In some embodiments, the invention provides methods of treating a patient with aggressive NHL or indolent NHL.
In some embodiments, the invention provides methods of treating a patient with a condition selected from the group consisting of mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), multiple myeloma (MM), and marginal zone lymphoma.
In some embodiments, the methods of the invention are administered to patients with relapsed or refractory conditions.
In another embodiment, the cancer is breast, lung, colon or prostate cancer.
In a particular embodiment, the cancer or autoimmune disease is associated with abnormal PI3K activity compared to PI3K activity in a subject without cancer or without an autoimmune disease.
In a particular embodiment, the preferred subject is refractory to chemotherapy treatment, or in relapse after treatment with chemotherapy. In an alternative embodiment, the subject is a de novo patient.
In a particular embodiment, the method comprises reducing the level of PI3Kδ activity in said patient.
In a particular embodiment, the subject is a human subject.
Subjects that undergo treatment with known therapeutic agents may experience resistance to treatment. For example, although bortezomib was FDA approved for relapsed/refractory, relapsed, and newly diagnosed MM, some patients do not respond and others acquire resistance to bortezomib. In some embodiments, the quinazolinone compound described herein synergistically augments efficacy of a known therapeutic agent. In some embodiments, the compounds described herein can augment any of the therapeutic agents described herein. In more specific embodiments, the compounds described herein synergistically augment proteasome inhibitors. In some of the foregoing embodiments, the subject is resistant to chemotherapeutic treatment. In some of the foregoing embodiments, the subject is resistant to proteasome inhibitors. In some of the foregoing embodiments, the subject is resistant bortezomib or carfilzomib. In one example, the compounds described herein synergistically augment bortezomib-induced MM cytotoxicity. Without being bound by theory, in some embodiments, the compounds discussed herein inhibit bortezomib-induced phosphorylation of AKT. In some embodiments, the methods described herein are used to overcome resistance to proteasome inhibitor treatment. In some embodiments, the invention provides a method to treat a subject that is resistant or has developed a resistance to therapeutic agents.
While not being bound by theory, the synergistic effects between a compound of formula A and conventional therapies may be attributed to the ability of the compound of the invention to induce tumor cell mobilization into peripheral circulation. Inducing the peripheral circulation of the tumor cells increases the ability of conventional therapy to act upon and more effectively neutralize the tumor. This synergy has been demonstrated in CLL patients.
Accordingly, the method comprises administering in addition to a compound of formula A to a patient, a therapeutically effective amount of at least one additional therapeutic agent and/or a therapeutic procedure selected to treat said cancer or autoimmune disease in said patient. “Therapeutic agent” may refer to one or more compounds, as used herein. The therapeutic agent may be a standard or experimental chemotherapy drug. The therapeutic agent may comprise a combination of more than one chemotherapy drug. Typical chemotherapy drug combinations are listed a-q herein. A particular therapeutic agent may be chosen depending on the type of disease being treated. Non-limiting examples of conventional chemotherapeutic treatments for particular hematologic disease are described in later sections. In a particular embodiment, the invention provides a method to treat a hematopoietic cancer patient, e.g., a CLL patient, with bortezomib and a compound of formula A (e.g., formula I, II, I″, or II″), wherein the combination provides a synergistic effect.
In a particular embodiment, said therapeutic agent is selected from the following group consisting of bortezomib (Velcade®), carfilzomib (PR-171), PR-047, disulfiram, lactacystin, PS-519, eponemycin, epoxomycin, aclacinomycin, CEP-1612, MG-132, CVT-63417, PS-341, vinyl sulfone tripeptide inhibitors, ritonavir, PI-083, (+/−)-7-methylomuralide, (−)-7-methylomuralide, perifosine, rituximab, sildenafil citrate (Viagra®), CC-5103, thalidomide, epratuzumab (hLL2-anti-CD22 humanized antibody), simvastatin, enzastaurin, Campath-1H®, dexamethasone, DT PACE, oblimersen, antineoplaston A10, antineoplaston AS2-1, alemtuzumab, beta alethine, cyclophosphamide, doxorubicin hydrochloride, PEGylated liposomal doxorubicin hydrochloride, prednisone, prednisolone, cladribine, vincristine sulfate, fludarabine, filgrastim, melphalan, recombinant interferon alfa, carmustine, cisplatin, cyclophosphamide, cytarabine, etoposide, melphalan, dolastatin 10, indium In 111 monoclonal antibody MN-14, yttrium Y 90 humanized epratuzumab, anti-thymocyte globulin, busulfan, cyclosporine, methotrexate, mycophenolate mofetil, therapeutic allogeneic lymphocytes, Yttrium Y 90 ibritumomab tiuxetan, sirolimus, tacrolimus, carboplatin, thiotepa, paclitaxel, aldesleukin, recombinant interferon alfa, docetaxel, ifosfamide, mesna, recombinant interleukin-12, recombinant interleukin-11, Bcl-2 family protein inhibitor ABT-263, denileukin diftitox, tanespimycin, everolimus, pegfilgrastim, vorinostat, alvocidib, recombinant flt3 ligand, recombinant human thrombopoietin, lymphokine-activated killer cells, amifostine trihydrate, aminocamptothecin, irinotecan hydrochloride, caspofungin acetate, clofarabine, epoetin alfa, nelarabine, pentostatin, sargramostim, vinorelbine ditartrate, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, fenretinide, ixabepilone, oxaliplatin, monoclonal antibody CD19, monoclonal antibody CD20, omega-3 fatty acids, mitoxantrone hydrochloride, octreotide acetate, tositumomab and iodine I 131 tositumomab, motexafin gadolinium, arsenic trioxide, tipifarnib, autologous human tumor-derived HSPPC-96, veltuzumab, bryostatin 1, anti-CD20 monoclonal antibodies, chlorambucil, pentostatin, lumiliximab, apolizumab, Anti-CD40, and ofatumumab, or a combination thereof. Combinations of therapeutic agents are used in current and experimental therapies such as those combinations a-q listed above.
In some embodiments, the therapeutic agent is preferably a proteasome inhibitor. In some embodiments, the methods comprise administering a compound with a proteasome inhibitor. Proteasome inhibitors include natural and synthetic compounds. Non-limiting examples of proteasome inhibitors include bortezomib, ([(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), which is marketed as ‘Velcade®’ by Millennium pharmaceuticals; carfilzomib (PR-171) and the oral analog, PR-047, both of which are developed by Proteolix, Inc. Other examples of proteasome inhibitors include disulfiram; lactacystin; synthetic compounds such as PS-519, eponemycin, epoxomycin, and aclacinomycin; calpain inhibitors, such as CEP-1612, MG-132, CVT-63417, PS-341; vinyl sulfone tripeptide inhibitors; ritonavir; PI-083; (+/−)-7-methylomuralide; and (−)-7-methylomuralide. In particular embodiments, the compound of formula A is administered in combination with bortezomib or carfilzomib. In more particular embodiments, the compound of formula I is administered in combination with bortezomib or carfilzomib. In other particular embodiments, the compound of formula II is administered in combination with bortezomib or carfilzomib. In particular embodiments, the compound of formula A is administered in combination with rituximab or ofatumumab. In more particular embodiments, the compound of formula I is administered in combination with rituximab or ofatumumab. In other particular embodiments, the compound of formula II is administered in combination with rituximab or ofatumumab.
In one aspect, the invention provides a pharmaceutical composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In one embodiment, the composition is enriched with the S-enantiomer.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula II:
or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In one embodiment, the composition is enriched with the S-enantiomer.
In one aspect, the invention provides a method of treating multiple myeloma (MM) in a patient comprising administering a combination of a compound of formula A and an additional therapeutic agent. In some embodiments, formula A is compound I or II. In specific embodiments, formula A is compound I″. In other embodiments, formula A is compound II″. In some of the foregoing embodiments the additional therapeutic agent is a proteasome inhibitor. In specific embodiments the additional therapeutic agent is bortezomib. In a specific embodiment, the method of treating multiple myeloma in a patient comprises administering compound I″ with bortezomib. In a specific embodiment, the method of treating multiple myeloma in a patient comprises administering compound II″ with bortezomib. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 60%. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 70%. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 80%. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 90%. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 95%. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 98%. In some of the foregoing embodiments, compound I″ or II″ has an enantiomeric excess of at least 99%.
In a particular embodiment, a combination of therapeutic agents is administered with a compound of Formula A, wherein said combination is selected from the group consisting of
a) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone);
b) R-CHOP (rituximab-CHOP);
c) hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine);
d) R-hyperCVAD (rituximab-hyperCVAD);
e) FCM (fludarabine, cyclophosphamide, mitoxantrone);
f) R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone);
g) bortezomib and rituximab;
h) temsirolimus and rituximab;
i) temsirolimus and Velcade®;
j) Iodine-131 tositumomab (Bexxar®) and CHOP;
k) CVP (cyclophosphamide, vincristine, prednisone);
l) R-CVP (rituximab-CVP);
m) ICE (iphosphamide, carboplatin, etoposide);
n) R-ICE (rituximab-ICE);
o) FCR (fludarabine, cyclophosphamide, rituximab);
p) FR (fludarabine, rituximab); and
q) D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
In alternative embodiments, the compound is used in combination with a therapeutic procedure. In a particular embodiment, the therapeutic procedure is selected from the group consisting of peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, immunohistochemistry staining method, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, high-dose chemotherapy and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
In a particular embodiment, the method further comprises obtaining a biological sample from said patient; and analyzing said biological sample with an analytical procedure selected from the group consisting of blood chemistry analysis, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, laboratory biomarker analysis, immunohistochemistry staining method, flow cytometry or a combination thereof.
For nomenclature purposes, the quinazolinyl and purinyl components of the compound are numbered accordingly:
As used herein, the term “alkyl,” includes straight-chain, branched-chain and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, and the like. The total number of carbon atoms in each such group is sometimes described herein, e.g., when the group can contain up to ten carbon atoms it can be represented as 1-10C or as C1-C10 or C1-10.
“Halo”, as used herein, includes fluoro, chloro, bromo and iodo. Fluoro and chloro are often preferred.
The term “selective PI3Kδ inhibitor” or “selective PI3Kβ inhibitor”, etc., as used herein, refers to a compound that inhibits the PI3Kδ or PI3Kβ isozyme, respectively, more effectively than at least one other isozymes of the PI3K family. The selective inhibitor may also be active against other isozymes of PI3K, but requires higher concentrations to achieve the same degree of inhibition of the other isozymes. “Selective” can also be used to describe a compound that inhibits a particular PI3-kinase more so than a comparable compound. A “selective PI3Kδ inhibitor” compound is understood to be more selective for PI3Kδ than compounds conventionally and generically designated PI3K inhibitors, e.g., wortmannin or LY294002. Concomitantly, wortmannin and LY294002 are deemed “nonselective PI3K inhibitors.” In certain embodiments, compounds of any type that selectively negatively regulate PI3Kδ expression or activity can be used as selective PI3Kδ inhibitors in the methods of the invention. Moreover, compounds of any type that selectively negatively regulate PI3Kδ expression or activity and that possess acceptable pharmacological properties can be used as selective PI3Kδ inhibitors in the therapeutic methods of the invention. Without being bound by theory, targeting p110 delta inhibition with a compound of the invention provides a novel approach for the treatment of hematological malignancies because this method inhibits constitutive signaling resulting in direct destruction of the tumor cell. In addition, without being bound by theory, p110 delta inhibition represses microenvironmental signals which are crucial for tumor cell homing, survival and proliferation.
In an alternative embodiment, compounds of any type that selectively negatively regulate PI3Kβ expression or activity can be used as selective PI3Kβ inhibitors in the methods of the invention. Moreover, compounds of any type that selectively negatively regulate PI3Kβ expression or activity and that possess acceptable pharmacological properties can be used as selective PI3Kβ inhibitors in the therapeutic methods of the invention.
“Treating” as used herein refers to inhibiting a disorder, i.e., arresting its development; relieving the disorder, i.e., causing its regression; or ameliorating the disorder, i.e., reducing the severity of at least one of the symptoms associated with the disorder. In some embodiments, “treating” refers to preventing a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it. “Disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
“Autoimmune disease” as used herein refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents.
In another aspect, the invention includes a method for suppressing a function of basophils and/or mast cells, and thereby enabling treatment of diseases or disorders characterized by excessive or undesirable basophil and/or mast cell activity. According to the method, a compound of the invention can be used that selectively inhibits the expression or activity of phosphatidylinositol 3-kinase delta (PI3Kδ) in the basophils and/or mast cells. Preferably, the method employs a PI3Kδ inhibitor in an amount sufficient to inhibit stimulated histamine release by the basophils and/or mast cells. Accordingly, the use of such compounds and other PI3Kδ selective inhibitors can be of value in treating diseases characterized by histamine release, i.e., allergic disorders, including disorders such as chronic obstructive pulmonary disease (COPD), asthma, ARDS, emphysema, and related disorders.
The present invention enables methods of treating such diseases as arthritic diseases, such as rheumatoid arthritis, psoriatic arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis; Behçet disease; sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, and toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated ophthalmopathy; eosinophilic granuloma; pulmonary or respiratory disorders such as asthma, chronic bronchitis, allergic rhinitis, ARDS, chronic pulmonary inflammatory disease (e.g., chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, and pulmonary oxygen toxicity; reperfusion injury of the myocardium, brain, or extremities; fibrosis such as cystic fibrosis; keloid formation or scar tissue formation; atherosclerosis; autoimmune diseases, such as systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, some forms of diabetes, and Reynaud's syndrome; and transplant rejection disorders such as graft-versus-host disease (GVHD) and allograft rejection; chronic glomerulonephritis; inflammatory bowel diseases such as chronic inflammatory bowel disease (CIBD), Crohn's disease, ulcerative colitis, and necrotizing enterocolitis; inflammatory dermatoses such as contact dermatitis, atopic dermatitis, psoriasis, or urticaria; fever and myalgias due to infection; central or peripheral nervous system inflammatory disorders such as meningitis, encephalitis, and brain or spinal cord injury due to minor trauma; Sjogren's syndrome; diseases involving leukocyte diapedesis; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex mediated diseases; hypovolemic shock; Type I diabetes mellitus; acute and delayed hypersensitivity; disease states due to leukocyte dyscrasia and metastasis; thermal injury; granulocyte transfusion-associated syndromes; and cytokine-induced toxicity.
The method can have utility in treating subjects who are or can be subject to reperfusion injury, i.e., injury resulting from situations in which a tissue or organ experiences a period of ischemia followed by reperfusion. The term “ischemia” refers to localized tissue anemia due to obstruction of the inflow of arterial blood. Transient ischemia followed by reperfusion characteristically results in neutrophil activation and transmigration through the endothelium of the blood vessels in the affected area. Accumulation of activated neutrophils in turn results in generation of reactive oxygen metabolites, which damage components of the involved tissue or organ. This phenomenon of “reperfusion injury” is commonly associated with conditions such as vascular stroke (including global and focal ischemia), hemorrhagic shock, myocardial ischemia or infarction, organ transplantation, and cerebral vasospasm. To illustrate, reperfusion injury occurs at the termination of cardiac bypass procedures or during cardiac arrest when the heart, once prevented from receiving blood, begins to reperfuse. It is expected that inhibition of PI3Kδ activity will result in reduced amounts of reperfusion injury in such situations.
In certain embodiments, the invention provides methods to treat a solid tumor. In specific embodiments, the cancer is breast, lung, colon, or prostate cancer. In certain embodiments, the invention provides methods to treat a solid tumor that is associated with abnormal or undesirable cellular signaling activity mediated by PI3Kβ. In certain embodiments, a solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma.
Genetic ablation of p110δ has been found to result in mild phenotype restricted to immune system. General observations include organisms that are fertile with no gross anatomical or behavioral abnormalities. A histological examination revealed major organs to appear normal. The total class I PI3K activity was reduced 30-50% in B and T cells. In addition, no increase in susceptibility to infections was observed. Furthermore, the effect on the hematopoietic system includes normal peripheral blood cell counts, the occurrence of lymphoid hypoplasia and the lack of germinal centers in spleen and lymph nodes, a reduced number of B220+IgM+B cell progenitors in bone marrow, a reduced level of serum immunoglobulin, and normal T cell development in the thymus.
Genetic ablation of p110δ affects myeloid and B cell signaling, which is important for oncogenesis. In particular, tyrosine kinase signaling, development, proliferation and survival are affected in myeloid cells. B cell function is most affected and includes proliferation, differentiation, apoptosis, and response to B cell survival factors (BCR, CD40, IL-4, chemokines). Thus, the invention includes methods of treating disease states in which one or more of these myeloid and B cell functions are abnormal or undesirable.
A pan PI3K inhibitor that targets on a molecular level p110α, p110β, p106δ, p110γ, (hvPS34, mTOR, DNA-PK, and others), in turn targets all tissues. The potential clinical indication includes cancer but clinical adverse events include hyperinsulinemia in cancer patients. The advantage of a p110δ selective inhibitor which targets cells mediating inflammation and cancer cells, wherein potential clinical indication include cancer, rheumatoid arthritis, asthma, allergies and COPD, is that treatment is well tolerated, and side effects like hyperinsulinemia are avoided. Thus in one aspect the invention provides a method to treat patients having insulin resistance, or type 2 diabetes, for cancer, rheumatoid arthritis, asthma, allergies, COPD, or other conditions treatable with the compounds of the invention. For patients needing such treatment who have excessive insulin conditions or tendencies, the compounds of the invention are particularly advantageous over pan-PI3K inhibitors. In certain embodiments, a compound of formula I or I″ is preferred because it provides therapeutic benefits to treating hematologic malignancies without adversely affecting insulin signaling.
In one embodiment, the invention relates to methods of inhibiting PI3K p110δ. In another embodiment, the invention relates to methods of inhibiting PI3K p110β or p110γ.
In certain embodiments, the method described herein has little or no off target activity. In particular, compound of formula I used in the method show little activity against over 300 protein kinases including those summarized in Table 3 of Example 16. In certain embodiments, the method described herein has no or minimal hyperinsulinemia effects in cancer patients compared to methods comprising the administration of pan-PI3K inhibitors. In certain embodiments, the method described herein is useful in targeting cells mediating Akt phosphorylation, because the compounds of Formula A inhibit Akt phosphorylation. Suitable patients for treatment with the compounds of the invention can thus be selected, in one embodiment, by selecting a patient exhibiting elevated Akt phosphorylation associated with a hematopoietic cancer such as lymphoma, leukemia or multiple myeloma.
The methods herein avoid off-target liabilities and are characterized by negative results in receptor gram screens, having no hERG inhibition and no significant P450 inhibition.
Another advantage of the inventive method is the absence of adverse cardiovascular, respiratory, or central nervous system effects as demonstrated in safety pharmacology studies. In addition, a 28-day toxicity study in rats and dogs demonstrated a high therapeutic index, e.g., a NOAEL (no observable adverse effect level)>>10 μM. This is the highest experimental dose of a chemical at which there is no statistically or biologically significant increase in frequency or severity of a toxicological effect between an exposed group and its appropriate control. Adverse effects are defined as any effects that result in functional impairment and/or pathological lesions that may affect the performance of the whole organism or that reduce an organism's ability to respond to an additional challenge.
In another embodiment, the inventive methods are non-genotoxic in a standard battery of tests.
Another advantage of the invention is that compound selectivity for one or two PI3K isoforms results in an improved safety profile over compounds having pan-PI3K inhibition. In yet another advantage, compound I has a favorable pharmacokinetic profile with good target coverage, and no adverse effects on glucose or insulin levels, and is well tolerated at doses above commonly used therapeutic doses by normal healthy volunteers. Another advantage of the invention includes the ability to treat a wide range of hematological malignancies as demonstrated by the examples herein.
In certain embodiments, the methods of the invention are directed towards treating a cancer or an autoimmune disease. In certain embodiments, the cancer is a hematological malignancy. In specific embodiments, the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL). In certain embodiments, the non-Hodgkin lymphoma is selected from the group consisting of large diffuse B-cell lymphoma (LDBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM) and lymphoplasmacytic lymphoma.
PI3K is implicated in many hematological malignancies and preclinical proof of concept relating to treatment with compound I has been established. The table below summarizes particular hematological malignancies and the method of action on the primary patient cell or disease cell line.
Indication
Effects of compounds of formula A
Chronic Lymphocytic Leukemia
Primary patient cells
(CLL)
Induces apoptosis
Blocks survival factors
Acute Myelogenous Leukemia
Primary patient cells
(AML)
Blocks PI3K signaling
Inhibits proliferation
Acute Lymphocytic Leukemia (ALL)
Cell Lines
Blocks PI3K signaling
Induces apoptosis
Non-Hodgkin's Lymphomas (NHL)
Cell Lines
(MCL, DLBCL, FL)
Blocks PI3K signaling
Induces apoptosis
Multiple Myeloma (MM)
Primary patient cells
P110 δ overexpressed in 24/24
samples Induces apoptosis
Data provided herein demonstrates that the compounds of the invention are useful to treat lymphomas and leukemias. Lymphomas and leukemias generally express the delta isoform of p110 selectively, e.g., FIG. 15 demonstrates that p110δ is prevalent in most lymphoma cell lines, while p110α is not generally observed. Moreover, data presented in FIG. 16A shows that cell cultures from six different leukemia cell lines were sensitive to Compound I, and were strongly affected by 5-10 micromolar concentrations of this compound. FIGS. 8 and 9 support compound I as reducing Akt(Ser473) production in several cell lines.
CLL, for example, produces mainly p110δ and to a lesser extent p110γ for signaling purposes, thus compounds that inhibit p110δ and/or p110γ are expected to exhibit selective cytotoxicity towards these cells. In Example 3, for example, shows dose-dependent cytotoxicity for compound I (FIG. 3), in CLL cells, including cells taken from poor prognosis patients (FIG. 19), and cells from patients shown to be resistant to other CLL treatments (FIG. 20). In addition, Example 13 and FIG. 13 demonstrate that compound I administered to a CLL patient at a rate of 50 mg BID for a 28-day cycle provides a significant therapeutic effect. An ALC concentration percent decrease in lymphocytes is observed. Thus in one aspect, the invention provides methods for treating CLL patients with drug-resistant CLL using compounds of Formula A. On the other hand, Example 17 suggests that a fibroblast cell line relying mainly on p110α for signaling was not sensitive to Compound I. Thus in one aspect, patient selection can include excluding patients having a cancer that relies mainly on p110α for signaling.
The compounds of Formula A are also useful to treat lymphoma, including both B-cell and T-cell lymphomas. Data in FIG. 4 demonstrates that six different ALL cell lines were sensitive to Compound I, which caused a significant reduction in cell viability in all six cell lines.
FIG. 12 and Example 12 demonstrate that mantle cell lymphoma patients treated with 50 mg BID of Compound I for 28 days experienced on average a 44% decrease in tumor burden. Moreover, FIG. 14 demonstrates that an MCL patient at the end of the 28 day cycle experienced similar plasma levels of Compound I following administration of a 50 mg dose to that observed in a normal healthy volunteer (NHV); thus the compound does not build up excessively over the course of a cycle of treatment, nor does the patient become tolerant by increased metabolism over the course of a treatment cycle.
In addition, the compounds of Formula A, or Formula I, are useful to treat hematopoietic cancers that constitutively express Akt phosphorylation activity. Example 8, and FIGS. 8 and 9 list cancer cell lines that demonstrate constitutive Akt phosphorylation, including B-cell lymphomas, T-cell lymphomas, ALL, malignant histiocytosis, DLBCL and AML. Exposure of the cell to compound I results in the reduction of Akt phosphorylation. See also Example 19, which shows that constitutive Akt phosphorylation was inhibited by Compound I in 13 of 13 cell lines.
In certain embodiments, the cancer is a solid tumor. In specific embodiments, the cancer is breast, ovarian, lung, colon, or prostate cancer. FIG. 6, for example, shows that Compound I reduces cellular proliferation of two breast cancer cell lines, and FIG. 10 illustrates cytotoxicity to three different breast cancer cell lines. Similarly, FIG. 7 demonstrates that Compound I is cytotoxic to two ovarian cancer cell lines.
For the treatment of a solid tumor, it is advantageous to use a compound of Formula A that expresses good activity (e.g., IC50 less than about 1 μM, and preferably less than about 250 nM—see Example 15) against p110β, since solid tumors often utilize this isozyme rather than or more than p110δ. Thus a compound of formula A that has an IC50 less than about 250 nM is preferred for treatment of a solid tumor; compound I, I″, II, or II″ is suitable for this use, as demonstrated herein.
In some embodiments, the subject for treatments described herein as one who has been diagnosed with at least one of the conditions described herein as treatable by the use of a compound of Formula A. In some embodiments, the subject has been diagnosed with a cancer named herein, and has proven refractory to treatment with at least one conventional chemotherapeutic agent. For instance, patients who have failed to respond to treatments such as proteasome inhibitors, autologous stem cell transplant, CHOP regimens, rituximab, fludarabine, alemtuzumab, conventional anticancer nucleoside analogues and alkylating agents frequently respond to the methods of treatment described herein. Thus, in one embodiment, the treatments of the invention are directed to patients who have received one or more than one such treatment.
In certain embodiments, the autoimmune disease is allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), or rheumatoid arthritis.
In certain embodiments, the methods of the invention are directed to B-cell, or B lymphocyte, related diseases. B-cells play a role in the pathogenesis of autoimmune diseases.
The compounds of Formula A (particularly Formulas I, I″, II and II″) are suitable for treating a variety of subjects having the conditions described herein, especially hematological cancers in humans. In some embodiments, the subject selected for treatment of a hematological malignancy that is a subject experiencing relapse after other treatments or is refractory to other treatments. In some embodiments, the subject is selected for treatment of a hematological malignancy that is resistant to other cancer drugs. In some embodiments, the subject is selected for treatment of a hematological malignancy that exhibits a high level of p110δ activity. In some embodiments, the subject is selected for treatment of a hematological malignancy that exhibits a relatively low level of p110α activity. In some embodiments, the subject is selected for treatment of a hematological malignancy that constitutively expresses Akt phosphorylation activity.
In one embodiment, the method described herein comprises administering to a subject a compound of formula A described herein, in combination with a therapy used to treat cancer or an autoimmune disease. “Therapy” or “treatment”, as used herein, is a treatment of cancer or an autoimmune disease by any well-known conventional or experimental form of treatment used to treat cancer or an autoimmune disease that does not include the use of a compound of formula A. In certain embodiments, the combination of a compound of formula A with a conventional or experimental therapy used to treat cancer or an autoimmune disease provides beneficial and/or desirable treatment results superior to results obtained by treatment without the combination. In certain embodiments, therapies used to treat cancer or an autoimmune disease are well-known to a person having ordinary skill in the art and are described in the literature. Therapies include, but are not limited to, chemotherapy, combinations of chemotherapy, biological therapies, immunotherapy, radioimmunotherapy, and the use of monoclonal antibodies, and vaccines.
In some of the foregoing embodiments, the combination method provides for a compound of formula A administered simultaneously with or during the period of administration of the therapy. In some of the foregoing embodiments the compound of formula A is administered simultaneously with the other chemotherapeutic treatment. In certain embodiments, the combination method provides for a compound of formula A administered prior to or after the administration of the therapy.
In some of the foregoing embodiments, the subject is refractory to at least one standard or experimental chemotherapy. In some of the foregoing embodiments, the subject is refractory to at least two standard or experimental chemotherapies. In some of the foregoing embodiments, the subject is refractory to at least three standard or experimental chemotherapies. In some of the foregoing embodiments, the subject is refractory to at least four standard or experimental chemotherapies.
In some of the foregoing embodiments, the subject is refractory to at least one standard or experimental chemotherapy selected from the group consisting of fludarabine, rituximab, alkylating agents, alemtuzumab and the chemotherapy treatments a-q listed above.
In some of the foregoing embodiments, the subject is refractory to at least two standard or experimental chemotherapies selected from the group consisting of fludarabine, rituximab, alkylating agents, alemtuzumab and the chemotherapy treatments a-q listed above.
In some of the foregoing embodiments, the subject is refractory to at least three standard or experimental chemotherapies selected from the group consisting of fludarabine, rituximab, alkylating agents, alemtuzumab and the chemotherapy treatments a-q listed above.
In some of the foregoing embodiments, the subject is refractory to at least four standard or experimental chemotherapies selected from the group consisting of fludarabine, rituximab, alkylating agents, alemtuzumab and the chemotherapy treatments a-q listed above.
The exact details regarding the administration of the combination may be determined experimentally. The refinement of sequence and timing of administering a compound of formula A with a selected therapy will be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.
Non-limiting examples of experimental or standard therapy are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.
Treatment of non-Hodgkin's lymphomas, especially of B cell origin, include, but are not limited to use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP, CVP, FCM, MCP, and the like), radioimmunotherapy, and combinations thereof, especially integration of an antibody therapy with chemotherapy.
Non-limiting examples of unconjugated monoclonal antibodies for Non-Hodgkin's lymphoma/B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TRAIL, bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74. Non-limiting examples of experimental antibody agents used in treatment of Non-Hodgkin's lymphoma/B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab. Any of the monoclonal antibodies can be combined with rituximab, fludarabine, or a chemotherapy agent/regimen.
Non-limiting examples of standard regimens of chemotherapy for Non-Hodgkin's lymphoma/B-cell cancers include CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), CVP (cyclophosphamide, vincristine and prednisone), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-FCM (rituximab plus FCM), R-CVP (rituximab plus CVP), and R-MCP (R-MCP).
Non-limiting examples of radioimmunotherapy for Non-Hodgkin's lymphoma/B-cell cancers include yttrium-90-labeled ibritumomab tiuxetan, and iodine-131-labeled tositumomab. These therapeutic agents are approved for use in subjects with relapsed or refractory follicular or low-grade lymphoma.
Therapeutic treatments for mantle cell lymphoma include combination chemotherapies such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) and FCM (fludarabine, cyclophosphamide, mitoxantrone). In addition, these regimens can be supplemented with the monoclonal antibody rituximab (Rituxan) to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Other approaches include combining any of the abovementioned therapies with stem cell transplantation or treatment with ICE (iphosphamide, carboplatin and etoposide).
Another approach to treating mantle cell lymphoma includes immunotherapy such as using monoclonal antibodies like Rituximab (Rituxan). Rituximab is also effective against other indolent B-cell cancers, including marginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. A combination of Rituximab and chemotherapy agents is especially effective. A modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as Iodine-131 tositumomab (Bexxar®) and Yttrium-90 ibritumomab tiuxetan (Zevalin®). In another example, Bexxar® is used in sequential treatment with CHOP. Another immunotherapy example includes using cancer vaccines, which is based upon the genetic makeup of an individual patient's tumor. A lymphoma vaccine example is GTOP-99 (MyVax®).
Another approach to treating mantle cell lymphoma includes autologous stem cell transplantation coupled with high-dose chemotherapy.
Another approach to treating mantle cell lymphoma includes administering proteasome inhibitors, such as Velcade® (bortezomib or PS-341), or antiangiogenesis agents, such as thalidomide, especially in combination with Rituxan. Another treatment approach is administering drugs that lead to the degradation of Bcl-2 protein and increase cancer cell sensitivity to chemotherapy, such as oblimersen (Genasense) in combination with other chemotherapeutic agents. Another treatment approach includes administering mTOR inhibitors, which can lead to inhibition of cell growth and even cell death; a non-limiting example is Temsirolimus (CCI-779), and Temsirolimus in combination with Rituxan®, Velcade® or other chemotherapeutic agents.
Other recent therapies for MCL have been disclosed (Nature Reviews; Jares, P. 2007). Non-limiting examples include Flavopiridol, PD0332991, R-roscovitine (Selicilib, CYC202), Styryl sulphones, Obatoclax (GX15-070), TRAIL, Anti-TRAIL DR4 and DR5 antibodies, Temsirolimus (CCl-779), Everolimus (RAD001), BMS-345541, Curcumin, Vorinostat (SAHA), Thalidomide, lenalidomide (Revlimid®, CC-5013), and Geldanamycin (17-AAG).
Non-limiting examples of other therapeutic agents used to treat Waldenstrom's Macroglobulinemia include perifosine, bortezomib (Velcade®), rituximab, sildenafil citrate (Viagra®), CC-5103, thalidomide, epratuzumab (hLL2-anti-CD22 humanized antibody), simvastatin, enzastaurin, campath-1H, dexamethasone, DT PACE, oblimersen, antineoplaston A10, antineoplaston AS2-1, alemtuzumab, beta alethine, cyclophosphamide, doxorubicin hydrochloride, prednisone, vincristine sulfate, fludarabine, filgrastim, melphalan, recombinant interferon alfa, carmustine, cisplatin, cyclophosphamide, cytarabine, etoposide, melphalan, dolastatin 10, indium In 111 monoclonal antibody MN-14, yttrium Y 90 humanized epratuzumab, anti-thymocyte globulin, busulfan, cyclosporine, methotrexate, mycophenolate mofetil, therapeutic allogeneic lymphocytes, Yttrium Y 90 ibritumomab tiuxetan, sirolimus, tacrolimus, carboplatin, thiotepa, paclitaxel, aldesleukin, recombinant interferon alfa, docetaxel, ifosfamide, mesna, recombinant interleukin-12, recombinant interleukin-11, Bcl-2 family protein inhibitor ABT-263, denileukin diftitox, tanespimycin, everolimus, pegfilgrastim, vorinostat, alvocidib, recombinant flt3 ligand, recombinant human thrombopoietin, lymphokine-activated killer cells, amifostine trihydrate, aminocamptothecin, irinotecan hydrochloride, caspofungin acetate, clofarabine, epoetin alfa, nelarabine, pentostatin, sargramostim, vinorelbine ditartrate, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, fenretinide, ixabepilone, oxaliplatin, monoclonal antibody CD19, monoclonal antibody CD20, omega-3 fatty acids, mitoxantrone hydrochloride, octreotide acetate, tositumomab and iodine I-131 tositumomab, motexafin gadolinium, arsenic trioxide, tipifarnib, autologous human tumor-derived HSPPC-96, veltuzumab, bryostatin 1, and PEGylated liposomal doxorubicin hydrochloride, and any combination thereof.
Non-limiting examples of other therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) drug therapies (Blood 2005 Abramson, J.) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for Waldenstrom's, and any combination thereof, such as ICE and R-ICE.
Non-limiting examples of therapeutic procedures used to treat Waldenstrom's Macroglobulinemia include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Non-limiting examples of other therapeutic agents used to treat Chronic Lymphocytic Leukemia (Spectrum, 2006, Fernandes, D.) include Chlorambucil (Leukeran), Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), Fludarabine (Fludara), Pentstatin (Nipent), Cladribine (Leustarin), Doxorubicin (Adriamycin®, Adriblastine), Vincristine (Oncovin), Prednisone, Prednisolone, Alemtuzumab (Campath, MabCampath), many of the agents listed for Waldenstrom's, and combination chemotherapy and chemoimmunotherapy, including the common combination regimen: CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); and FR (fludarabine, rituximab).
In certain embodiments, the method comprises administering in addition to a compound of I or II to said patient, a therapeutically effective amount of at least one therapeutic agent and/or therapeutic procedure selected to treat said cancer or autoimmune disease in said patient. In certain embodiments, the method comprises administering in addition to a compound of I or II to said patient, a therapeutically effective amount of a combination of therapeutic agents selected from the group consisting of a) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); b) R-CHOP (rituximab-CHOP); c) hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); d) R-hyperCVAD (rituximab-hyperCVAD); e) FCM (fludarabine, cyclophosphamide, mitoxantrone); f) R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); g) bortezomib and rituximab; h) temsirolimus and rituximab; i) temsirolimus and Velcade®; j) Iodine-131 tositumomab (Bexxar®) and CHOP; k) CVP (cyclophosphamide, vincristine, prednisone); 1) R-CVP (rituximab-CVP); m) ICE (iphosphamide, carboplatin, etoposide); n) R-ICE (rituximab-ICE); o) FCR (fludarabine, cyclophosphamide, rituximab); and p) FR (fludarabine, rituximab).
The compounds of the invention may be formulated for administration to animal subject using commonly understood formulation techniques well known in the art. Formulations which are suitable for particular modes of administration and for the compounds of formula A may be found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, Pa.
The compounds of the invention may be prepared in the form of prodrugs, i.e., protected forms which release the compounds of the invention after administration to the subject. Typically, the protecting groups are hydrolyzed in body fluids such as in the bloodstream thus releasing the active compound or are oxidized or reduced in vivo to release the active compound. A discussion of prodrugs is found in Smith and Williams Introduction to the Principles of Drug Design, Smith, H. J.; Wright, 2nd ed., London (1988).
A compound of the present invention can be administered as the neat chemical, but it is typically preferable to administer the compound in the form of a pharmaceutical composition or formulation. Accordingly, the present invention also provides pharmaceutical compositions that comprise a compound of formula A and a biocompatible pharmaceutical carrier, adjuvant, or vehicle. The composition can include the compound of Formula A as the only active moiety or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones mixed with excipient(s) or other pharmaceutically acceptable carriers. Carriers and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions are formulated to contain suitable pharmaceutically acceptable carriers, and can optionally comprise excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The administration modality will generally determine the nature of the carrier. For example, formulations for parenteral administration can comprise aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration are physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For preparations comprising proteins, the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
Alternatively, formulations for parenteral use can comprise dispersions or suspensions of the active compounds prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxy-methylcellulose, sorbitol, or dextran. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the Eudragit® series available from Rohm America Inc. (Piscataway, N.J.). Emulsions, e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants). Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
Liposomes containing the active compound of Formula A also can be employed for parenteral administration. Liposomes generally are derived from phospholipids or other lipid substances. The compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, Academic Press, New York (1976).
The pharmaceutical compositions comprising the compound of Formula A in dosages suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art. The preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders. To illustrate, pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or drage cores. Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or excipients, which include, without limitation:
a) diluents, such as sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
b) binders, such as magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.;
c) cellulose materials, such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof, such as sodium alginate, or effervescent compositions;
e) lubricants, such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol;
f) flavorants and sweeteners;
g) colorants or pigments, e.g., to identify the product or to characterize the quantity (dosage) of active compound; and
h) other ingredients, such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
In some preferred oral formulations, the pharmaceutical composition comprises at least one of the materials from group (a) above, or at least one material from group (b) above, or at least one material from group (c) above, or at least one material from group (d) above, or at least one material from group (e) above. Preferably, the composition comprises at least one material from each of two groups selected from groups (a)-(e) above.
Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
Dragée cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
The pharmaceutical composition can be provided as a salt of the active compound. Salts tend to be more soluble in aqueous or other protonic solvents than the corresponding free acid or base forms. Pharmaceutically acceptable salts are well known in the art. Compounds that contain acidic moieties can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include, for example, alkali metal (e.g., sodium or potassium) and alkaline earth (e.g., calcium or magnesium) cations.
Compounds of structural formula (A) that contain basic moieties can form pharmaceutically acceptable acid addition salts with suitable acids. For example, Berge, et al., describe pharmaceutically acceptable salts in detail in J Pharm Sci, 66:1 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorolsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate or sulfate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate or hydrogen phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include, without limitation, such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid.
Basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain alkyl halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides; and others. Products having modified solubility or dispersibility are thereby obtained.
Compositions comprising a compound of the invention formulated in a pharmaceutical acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of a compound of the invention and a label containing instructions for use of the compound. Kits are also contemplated under the invention. For example, the kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. In either case, conditions indicated on the label can include treatment of inflammatory disorders, cancer, etc.
Methods of Administration
Pharmaceutical compositions comprising a compound of formula A can be administered to the subject by any conventional method, including parenteral and enteral techniques. Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullarly, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enteral administration modalities include, for example, oral (including buccal and sublingual) and rectal administration. Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and rectal administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Parenteral administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT™.
Surgical techniques include implantation of depot (reservoir) compositions, osmotic pumps, and the like. A preferred route of administration for treatment of inflammation can be local or topical delivery for localized disorders such as arthritis, or systemic delivery for distributed disorders, e.g., intravenous delivery for reperfusion injury or for systemic conditions such as septicemia. For other diseases, including those involving the respiratory tract, e.g., chronic obstructive pulmonary disease, asthma, and emphysema, administration can be accomplished by inhalation or deep lung administration of sprays, aerosols, powders, and the like.
In some foregoing embodiments, the compound of formula A is administered before, during, or after administration of chemotherapy, radiotherapy, and/or surgery. The formulation and route of administration chosen will be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.
The therapeutic index of the compound of formula A can be enhanced by modifying or derivatizing the compounds for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compounds can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described (see for example, Pietersz, et al., Immunol Rev, 129:57 (1992); Trail, et al., Science, 261:212 (1993); and Rowlinson-Busza, et al., Curr Opin Oncol, 4:1142 (1992)). Tumor-directed delivery of these compounds enhances the therapeutic benefit by, inter alia, minimizing potential nonspecific toxicities that can result from radiation treatment or chemotherapy. In another aspect, the compound of formula A and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibody.
The characteristics of the agent itself and the formulation of the agent can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Such pharmacokinetic and pharmacodynamic information can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for any compound used in the method of the invention, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range that modulates expression or activity of a particular PI3K isoform or combination of isoforms. As human studies are conducted, further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
Although compounds of the invention are well tolerated, an example of a limit to the treatment dosage is elevated liver function tests (LFT). LFT involve standard clinical biochemistry tests on the patient's serum or plasma to provide information about the state of a patient's liver. Levels, such as alanine transaminase, aspartate transaminase, alkaline phosphatase, bilirubin, and gamma glutamyl transpeptidase, that are outside the normal range can signal possible liver toxicity. Dosing of the therapeutic compound can be adjusted to avoid or reduce elevated liver function test values and subsequent potential for liver toxicity. For instance, a subject may be administered escalating doses of a compound. At a certain dose amount, the subject begins to develop elevated LFT levels outside a normal range, signaling potential liver toxicity at that dosage. In response, the dosage may be reduced to an amount such that LFT levels are reduced to an acceptable range as judged by the treating physician, e.g. a level that is in the range normal for the subject being treated, or within about 25% to 50% of normal. Therefore, liver function tests can be used to titrate the administration dosage of a compound.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the “therapeutic index,” which typically is expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantially higher than the effective dose, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
Dosage may be limited by treatment-related toxicity symptoms. Such symptoms besides elevated liver function tests include anemia, vision blurring, diarrhea, vomiting, fatigue, mucositis, peripheral edema, pyrexia, peripheral neuropathy, pleural effusion, night sweats, and orthopnea, or a combination thereof. At a certain dose amount, if the subject develops intolerable levels of such symptoms, the dosage may be reduced such that the adverse event is eliminated and no longer adverse or reduced to an acceptable level as judged by a treating physician.
Another consideration in determining the appropriate dose of compound for a patient is the desired concentration circulating in the blood plasma. In a particular embodiment, the concentration of compound in the blood is between 40-3,000 ng/mL over a 12 hour period from the time of administration. In another particular embodiment, the concentration of compound in the blood is between 75-2,000 ng/mL over a 12 hour period from the time of administration. In another particular embodiment, the concentration of compound in the blood is between 500-2,000 ng/mL over a 12 hour period from the time of administration. In a preferred embodiment, the concentration of compound in the blood is between 40-3,000 ng/mL over a 12 hour period from the time of administration, wherein the compound is a formula of I, I″, II, or II″ and is orally administered in an amount of about 50 mg, 100 mg, 150 mg, or 200 mg. In a preferred embodiment, the concentration of compound in the blood is between 40-3,000 ng/mL over a 12 hour period from the time of administration, wherein the compound is a formula of I and is orally administered in an amount of about 50 mg, 100 mg, 150 mg, or 200 mg. In a preferred embodiment, the concentration of compound in the blood is between 40-3,000 ng/mL over a 12 hour period from the time of administration, wherein the compound is a formula of II and is orally administered in an amount of about 50 mg, 100 mg, 150 mg, or 200 mg. In some of the foregoing embodiments, the maximum concentration in the blood plasma is achieved within two hours of administration.
In certain embodiments, the dosage of the compound of Formula I or II is selected to produce a plasma concentration of drug of about 10 nM or higher over a period of 8 to 12 hours, on average, and to provide a peak plasma concentration of about 500 nM or higher, preferably about 1000 nM or higher. In certain embodiments, the dosage of the compound of Formula I or II is selected to produce a plasma concentration of drug of about 100 nM or higher over a period of 8 to 12 hours, on average, and to provide a peak plasma concentration of about 500 nM or higher, preferably about 1000 nM or higher. In certain embodiments, the dosage of the compound of Formula I or II is selected to produce a plasma concentration of drug of about 200 nM or higher over a period of 8 to 12 hours, on average, and to provide a peak plasma concentration of about 500 nM or higher, preferably about 1000 nM or higher.
In certain embodiments, the dosage of the compound of formula I or II is selected to produce a plasma concentration wherein the trough concentration of the compound is in the range where a therapeutic effect, such as apoptosis of cancer cells, is observed. In certain embodiments, the dosage of the compound of formula I or II is selected to produce a trough plasma concentration at or higher than the EC50 PI3Kδ isoform activation in blood plasma. In certain embodiments, the dosage of the compound of formula I or II is selected to produce an trough blood concentration above the EC50 level for PI3Kδ activation and below the level for EC50 PI3Kγ activation in a cell during a period of at least 12 hours from compound administration. For instance, if the EC50 value for PI3K δ basophil activation is 65 nM and the EC50 value for PI3K γ basophil activation is 1100 nM in whole blood plasma, then the dosage of the compound selected provides a trough plasma concentration of the compound between 60 nM and 1100 nM during a period of 8-12 hours from compound administration. Similarly, a dosage can be selected to produce an trough blood concentration above the EC50 level for PI3Kδ basophil activation and below the EC50 level for PI3K-α, -β or -γ basophil activation. The EC50 values for the PI3K isoform activation or inhibition in vivo can be determined by a person having ordinary skill in the art. In alternative embodiments, the upper range of the trough concentration of the drug may exceed and is not limited by the EC50 value of the PI3K-γ, -α, or -β isoform in blood plasma. Moreover, the blood concentration range of the drug is at a level which is therapeutically beneficial in treating the hematologic malignancy, while minimizing undesirable side effects.
For instance, while being delta-selective, the compounds can exhibit sufficient activity on p110γ to be clinically useful, i.e., to be effective on a cancer that relies upon p110γ for signaling, because a plasma level above the effective dosage for inhibition of p110γ can be achieved while still being selective relative to other isoforms, particularly the alpha isoform. Thus, in some embodiments, the dosage of the compound is selected to produce a blood concentration effective for selectively inhibiting p110δ and p110γ.
In some embodiments, the dosage of the compound provides a trough blood plasma concentration between 65 nM and 1100 nM during a period of 8 to 12 hours from compound administration. In some foregoing embodiments, the period is at least 12 hours from compound administration.
In a particular embodiment, the compound is administered in a therapeutically effective amount.
In a particular embodiment, the compound is administered at a dose of 20-500 mg/day. In a particular embodiment, the compound is administered at a dose of 50-250 mg/day.
In a particular embodiment, the compound is administered at a dose of 25 to 150 mg per dose, and two doses are administered per day (e.g., BID dosing with 25 to 150 mg doses). In a preferred embodiment, a subject is treated with 50 mg to 100 mg of a compound of formula A twice per day. In another preferred embodiment, a subject is treated with 50 mg to 150 mg of a compound of formula A twice per day.
In a particular embodiment, the method comprises administering to said patient an initial daily dose of 20-500 mg of the compound and increasing said dose by increments until clinical efficacy is achieved. Increments of about 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
In a particular embodiment, the method comprises continuing to treat said patient by administering the same dose of the compound at which clinical efficacy is achieved or reducing said dose by increments to a level at which efficacy can be maintained.
In a particular embodiment, the method comprises administering to said patient an initial daily dose of 20-500 mg of the compound and increasing said dose to a total dosage of 50-400 mg per day over at least 6 days. Optionally, the dosage can be further increased to about 750 mg/day.
In a particular embodiment, the compound is administered at least twice daily.
In a particular embodiment, the compound is administered orally, intravenously or by inhalation. Preferably, the compound is administered orally. In some embodiments, it is administered orally at a dosage of about 50 mg BID or at a dosage of about 100 mg BID. In other embodiments, it is administered orally at a dosage of about 150 mg BID.
For the methods of the invention, any effective administration regimen regulating the timing and sequence of doses can be used. Doses of the agent preferably include pharmaceutical dosage units comprising an effective amount of the agent. As used herein, “effective amount” refers to an amount sufficient to modulate PI3Kδ expression or activity and/or derive a measurable change in a physiological parameter of the subject through administration of one or more of the pharmaceutical dosage units. “Effective amount” can also refer to the amount required to ameliorate a disease or disorder in a subject.
Suitable dosage ranges for the compounds of formula A vary according to these considerations, but in general, the compounds are administered in the range of 10.0 μg/kg-15 mg/kg of body weight; 1.0 μg/kg-10 mg/kg of body weight, or 0.5 mg/kg-5 mg/kg of body weight. For a typical 70-kg human subject, thus, the dosage range is from 700 μg-1050 mg; 70 μg-700 mg; or 35 mg-350 mg per dose, and two or more doses may be administered per day. Dosages may be higher when the compounds are administered orally or transdermally as compared to, for example, i.v. administration. The reduced toxicity of a compound of formula A, permits the therapeutic administration of relatively high doses. In some of the foregoing embodiments, oral administration of up to 750 mg/day of a compound of the invention is suitable. In some of the foregoing embodiments, a compound of formula A is administered at a dose of 50 mg BID. In some of the foregoing embodiments, a compound of formula A is administered at a dose of 100 mg BID. In some of the foregoing embodiments, a compound of formula A is administered at a dosage of 150 mg BID. In some of the foregoing embodiments, a compound of formula A is administered at a dose of 200 mg BID. In some of the foregoing embodiments, a compound of formula A is administered at a dose of 350 mg BID. In specific embodiments, for treatment of leukemias, lymphomas and multiple myeloma, a dosage of about 50-350 mg per dose, administered orally once or preferably twice per day, is often suitable.
In some of the foregoing embodiments, oral administration of up to 750 mg/day of compound I″ or II″ is suitable. In some of the foregoing embodiments, a compound of formula I″ or II″ is administered at a dose of 50 mg BID. In some of the foregoing embodiments, a compound of formula I″ or II″ is administered at a dose of 100 mg BID. In some of the foregoing embodiments, a compound of formula I″ or II″ is administered at a dose of 150 mg BID. In some of the foregoing embodiments, a compound of formula I″ or II″ is administered at a dose of 200 mg BID. I In some of the foregoing embodiments, a compound of formula I″ or II″ is administered at a dose of 350 mg BID. In some of the foregoing embodiments, for treatment of leukemias, lymphomas and multiple myeloma, a dosage of about 50-350 mg per dose of a compound of formula I″ or II″, administered orally once or preferably twice per day, is often suitable.
The compounds may be administered as a single bolus dose, a dose over time, as in i.v. or transdermal administration, or in multiple dosages.
Dosing may be continued for at least seven days. In some embodiments, daily dosing is continued for about 28 days. In some embodiments, dosing is continued for about 28 days and is then discontinued for at least 7 days. In some embodiments, a complete cycle is continuous daily dosing for 28 days. Evaluation of a clinical response in the patient can be measured after each cycle. The clinical results can be used to make a decision to increase, decrease, discontinue or maintain the dosage.
Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosage regimen will be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the agent's specific activity, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
The frequency of dosing will depend on the pharmacokinetic parameters of the compound of Formula A and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the compound. Short-acting pharmaceutical compositions (i.e., short half-life) can be administered once a day or more than once a day (e.g., two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks. Pumps, such as subcutaneous, intraperitoneal, or subdural pumps, can be preferred for continuous infusion.
Subjects that will respond favorably to the method of the invention include medical and veterinary subjects generally, including human patients. Among other subjects for whom the methods of the invention is useful are cats, dogs, large animals, avians such as chickens, and the like. In general, any subject who would benefit from a compound of formula A is appropriate for administration of the invention method. In some foregoing embodiments, the patient has a cytogenetic characteristic of del(17p) or del(11q). In some foregoing, embodiments, the patient has a lymphadenopathy. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy in a patient. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy after one cycle of treatment. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy by at least 10% after one cycle of treatment. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy by at least 25% after one cycle of treatment. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy by at least 30% after one cycle of treatment. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy by at least 40% after one cycle of treatment. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy by at least 50% after one cycle of treatment. In some foregoing embodiments, the use of compound I, I″, II, or II″ reduces the size of a lymphadenopathy by at least 75% after one cycle of treatment.
In one aspect, the invention provides a method of treating a condition, comprising administering a compound of formula I, II or a pharmaceutically acceptable salt thereof and one or more therapeutic agents to a subject in need of such treatment, wherein the condition is a cancer or an autoimmune condition. In preferred embodiments, the therapeutic agent is a proteasome inhibitor. In more specific embodiments, the therapeutic agent is bortezomib. In some of the foregoing embodiments, the condition is a hematologic malignancy. In preferred embodiments, the condition is selected from the group consisting of multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, B-cell lymphoma, diffuse large B-cell lymphoma, B-cell ALL, T-cell ALL and Hodgkin's lymphoma. In preferred embodiments, the compound is substantially comprised of the S-enantiomer. In specific embodiments, the compound comprises at least 95% of the S-enantiomer. In some of the foregoing embodiments, the administration of said compound and therapeutic agent provides a synergistic benefit superior to results obtained without the combination of the compound and therapeutic agent.
The following examples are offered to illustrate but not to limit the invention. In the examples below, references to the ‘compound of formula I’ or ‘compound I’ refer to the S-enantiomer shown here, and samples used for these Examples exhibited a 98.2% ee as measured by chiral HPLC methods:
In addition, an analysis of this compound reveals the following characteristics of the material:
Test
Test Result
Appearance
Slightly off-white powder
1H-NMR
Spectrum conforms to the
reference
HPLC Assay
98.1%
(Anhydrous, solvent-free
basis)
Chiral Purity
98.2% ee
(HPLC)
Residual on Ignition
0.11%
Infrared Spectroscopy
Spectrum in agreement
(FTIR)
with the reference
13C-NMR
Spectrum conforms to the
reference
Particle Size Analysis
Median diameter: 11.3 μm
Water (Coulometric
0.56%
Karl Fischer)
Test Result
Property or Test
Expected
Found
Elemental Analysis
% C
63.3
63.5
% C, H, F, N
% H
4.4
4.4
% N
23.5
23.1
% F
4.5
4.5
Example 1
Inhibition of Cell Growth in MM Cells
This example demonstrates the compound of formula I inhibits the cellular growth stimulatory effects of cytokines (IGF-1 and IL-6) in multiple myeloma (MM) cells. LB cells (Myelomonocytic myeloma cell line) were cultured for 48 h with control media; with the compound of formula I, in the presence or absence of either IL-6 or IGF-1. The inhibitory effect of the compound of formula I on MM cell growth was assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT; Chemicon International) dye absorbance. Cells were pulsed with 10 μL of 5 mg/mL MTT to each well for the last 4 hours of 48-hour cultures, followed by 100 μL isopropanol containing 0.04 N HCl. Absorbance was measured at 570/630 nm using a spectrophotometer (Molecular Devices). A summary of the results is shown in FIG. 1. Exposure of 0.625 μM-2.5 μM of Compound I inhibits MM cell growth even in the presence of cell growth stimulatory cytokines.
Example 2
Effect of BMSC on Cytotoxicity
This example demonstrates Bone Marrow Stromal Cells (BMSCs) do not protect against compound I-induced LB cell cytotoxicity. LB cells were cultured with control media, and with the compound of formula I for 48 hours, in the presence or absence of BMSCs. Cell proliferation was assessed using [3H]-thymidine uptake assay. All data represent mean (±SD) of triplicate experiment. A summary of the results is shown in FIG. 2. LB cell growth is reduced after exposure to 0.625 μM-10 μM of compound I even in the presence of BMSC.
Example 3
Effect of Compound on Apoptosis of CLL Cells
This example demonstrates the compound of formula I induces apoptosis in patient chronic lymphocytic leukemia (CLL) cells. Peripheral blood was obtained from patients with B-CLL through the CLL Research Consortium from Ohio State University. Primary CD19-positive cells were isolated using Rosette-Sep (StemCell Technologies). Cells were maintained in RPMI 1640 (Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum, 2 mmol/L L-glutamine, and penicillin (100 units/mL)/streptomycin (100 μg/mL; Invitrogen) at 37° C., 5% CO2, and high humidity. After incubation with the compound of formula I or medium for 96 hours, 5×105 cells were washed with PBS and then resuspended in binding buffer (10 mmol/L HEPES/NaOH, pH 7.4, 150 mmol/L NaCl 5 mmol/L KCl, 1 mmol/L MgCl2, 1.8 mmol/L CaCl2) containing 2 μL of Annexin V-FITC stock (BioWhittaker, Inc) and 10 μL of 20 μg/mL PI (Sigma). After incubation for 10 minutes at room temperature in a light-protected area, the specimens were quantified by flow cytometry on a FACScan™ (Becton Dickinson).
Treatment of CLL patient cells with compound I results in apoptosis and the result appears to be dose-dependent, as seen in FIG. 3.
Compound I induced apoptosis was seen in CLL cells from poor prognosis patients, as the data indicates in FIG. 19.
Compound I induced apoptosis was also seen to be effective in CLL cells from refractory/relapsed patients as shown in FIG. 20.
Example 4
Effect of Compound in ALL Cell Lines
This example demonstrates the compound of formula I results in a reduction of Akt phosphorylation and a decrease in cellular proliferation accompanied by cell death in both T-ALL and B-ALL (Acute Lymphoblastic Leukemia) leukemic cell lines. Viability assays of cell lines were performed using the AlamarBlue assay (Invitrogen). Cells (1×106 per well) in a volume of 100 μL were placed in a 96-well flat-bottom plate and the compound of formula I (100 μL per well at 2× final concentration) or medium alone was added to the plates. All were performed in quadruplicate. Cells were incubated for fixed times (48 hours). After the incubation, 10 μL AlamarBlue® was added to each well. Cells were incubated for 4 hours and the optical density at 530-560 nm was obtained using a SpectraMax® M5 plate reader 2001. Cell viability was expressed as a percentage of absorption between treated cells/control sample. These results are summarized in the table shown in FIG. 4. Exposure to compound I result in substantial reduction in cellular viability in a variety ALL cell lines as well as reduction in Akt phosphorylation.
Example 5
Effect of Compound on ALL Cell Cycle
This example demonstrates treatment of the acute lymphoblastic leukemia (ALL) cell line CCRF-SB with the compound of formula I results in G0/G1 cell cycle arrest. Representative fluorescence-activated cell sorting (FACS) analysis of propidium iodide-stained CCRF-SB cells under normal growth conditions, and growth in the presence of the compound of formula I. The average percentage of cells in G0-G1, S, and G2-M phases is calculated in the table below the histographs. Results are shown in FIG. 5.
Example 6
Inhibition of Proliferation of Breast Cancer Cells
This example demonstrates the compound of formula I inhibits proliferation of breast cancer cell lines. T47D and HS-578T cell lines were grown in the presence of serum plus the indicated concentrations of the compound of formula I. Proliferation was measured in triplicate wells by AlamarBlue® assay (Invitrogen) 96-well plates. Results of proliferation assays are expressed as the mean cellular percentage values and shown in FIG. 6.
Example 7
Inhibition of Proliferation of Ovarian Cancer Cell Lines
This example demonstrates the compound of formula I inhibits proliferation of ovarian cancer cell lines. IGROV-1 and OVCAR-3 cell lines were grown in the presence of serum plus the indicated concentrations of the compound of formula I. Proliferation was measured in triplicate wells by AlamarBlue assay (Invitrogen) 96-well plates. Results of proliferation assays are expressed as the mean cellular percentage values and are shown in FIG. 7.
Example 8
Reduction of Akt Phosphorylation
This example demonstrates the compound of formula I reduces constitutive Akt phosphorylation in hematopoietic tumor cell lines that exhibited constitutive Akt phosphorylation. A large panel of leukemia and lymphoma cell lines was assessed for constitutive Akt phosphorylation. These cell lines represent B-lymphoma, T-lymphoma, ALL, Malignant histiocytosis, DLBCL and AML. Cell lines that demonstrated serum independent Akt phosphorylation were treated with the compound of formula I for 2 hours. Thereafter, cell were lysed, size-fractioned and immunoblotted with antibodies directed against phospho-Akt(Ser473). Results are shown in FIG. 8. Reduction in Akt(Ser473) was achieved for all cell lines after exposure to compound I.
Example 9
Compound I Effective in DLBCL
This example provides evidence that compound I blocks PI3K signaling and induces apoptosis in diffuse large B-cell lymphoma cells. P110δ is expressed in DLBCL cell lines as shown in FIG. 26A. FIG. 26B shows that exposure to compound I reduces pAKT levels in several DLBCL cell lines.
Example 10
Inducement of Apoptosis in Breast Cancer Cells
This example demonstrates the compound of formula I induces apoptosis in breast cancer cell lines. HS-578T, T47D, and MCF7 cells were treated with the compound of formula I or corresponding DMSO concentrations for 24 h. The percentage of apoptotic cells was determined by Annexin V-FITC/7AAD staining. Bottom left, viable cells (Annexin V-FITC/PI negative); bottom right, early apoptotic cells (Annexin V-FITC positive only); top right, mid-late apoptotic cells (Annexin V-FITC/7AAD double-positive); and top left, late apoptotic/necrotic (7AAD positive only). Percentages of cells in each quadrant are indicated except for the bottom left quadrant (viable cells). One experiment representative of three different experiments that gave similar results is shown in FIG. 10.
Example 11
Steady State Blood Levels on Day 7 in Healthy Volunteers
This example provides data relating to the concentration of the compound of formula I in the blood of a healthy human subject on day 7. The concentration was monitored over a period of 12 hours, after oral administration of 50, 100, or 200 mg BID of the compound of formula I on day 7 of the study. FIG. 11 follows the plasma concentration of the drug over a period of 12 hours from administration. The maximum concentration of drug is achieved within two hours for all doses. Administration of 50, 100 or 200 mg BID of said compound results in a concentration level that exceeds the PI3Kδ EC50 concentration in basophil for at least 12 hours.
In addition, single dose studies wherein 17-400 mg of the compound of formula I was administered in healthy volunteers was carried out. Concentration of the compound in the blood was measured over 24 hours from administration and results are shown in FIG. 24A. At about 6 hours, the concentration of compound I in the blood for all administered doses is at least about 100 nM. At about 12 hours, the concentration of compound I in the blood for doses 50 mg and higher is over 50 nM. The maximum concentration of compound I in the blood is achieved within 2 hours of administration.
In another experiment, the mean compound I concentration was measured on the 7th day of 50 mg BID dosing in healthy volunteers (N=6). The mean trough concentration was higher than the EC50 for PI3Kδ and the mean peak concentration was lower than the EC50 for PI3Kγ as determined in the whole blood basophil activation assay, FIG. 24B. This example demonstrates the concentration range of compound I administered at 50 mg BID is at a level that is above the ED50 PI3Kδ basophil activation level but lower than the minimum ED50 PI3Kγ basophil level activation level in whole blood for at least 12 hours.
Table 1, below, provides an overview of the subjects in the study, wherein either a singe dose (SD) or multiple dose (MD) of the compound of formula I is administered to a subject at varying amounts. The “n” values refer to the number of subjects in each group.
TABLE 1
Cohort
Regimen
Compound I
Placebo
1 (n = 8)
SD
17 mg (n = 6)
Placebo (n = 2)
2 (n = 8)
SD
50 mg (n = 6)
Placebo (n = 2)
3 (n = 8)
SD
125 mg (n = 6)
Placebo (n = 2)
4 (n = 8)
SD
250 mg (n = 6)
Placebo (n = 2)
5 (n = 8)
SD
400 mg (n = 6)
Placebo (n = 2)
6 (n = 8)
MD
50 mg BID × 7 d
Placebo BID × 7 d (n = 2)
(n = 6)
7 (n = 8)
MD
100 mg BID × 7 d
Placebo BID × 7 d (n = 2)
(n = 6)
8 (n = 8)
MD
200 mg BID × 7 d
Placebo BID × 7 d (n = 2)
(n = 6)
Example 12
Effect on Lesions in a Patient with Mantle Cell Lymphoma
This example provides data relating to the area of lesions of a patient with mantle cell lymphoma after 1 cycle of treatment (28 days) with the compound of formula I. The area of 6 lesions was measured prior to treatment and after a cycle of treatment. The response to 28 days of oral administration of 50 mg BID of the compound of formula I, results in a decrease of lesion area compared to area prior to treatment and represents a 44% decrease in tumor burden. The results are summarized in a bar graph found in FIG. 12.
Example 13
Response of a Patient with CLL to Treatment
This example provides data relating to the concentration of absolute lymphocyte count (ALC) in the blood of a patient with CLL after 1 cycle (28 days) of treatment with oral administration of the compound of formula I. The blood ALC concentration was measured over a period of 4 weeks after completion of one cycle of treatment. A 55% decrease in lymphocytosis and a 38% decrease in lymphadenopathy as a result of treatment were observed. A marked decrease in ALC concentration is observed between week 1 and week 2, FIG. 13.
Example 14
Comparison of Lymphoma Patient to Healthy Volunteer
This example provides data comparing the concentration of the compound of formula I in a lymphoma patient to normal healthy volunteers. On the 28th day of oral administration of 50 mg BID of compound in a patient with mantle cell lymphoma, the concentration of the compound in the blood was measured over a period of 6 hours after administration. The concentration of 50 and 100 mg oral administration in normal healthy volunteers on day 7 of administration was also observed. The results are summarized in FIG. 14. Thus, the compound does not build up excessively over the course of a cycle of treatment, nor does the patient become tolerant by increased metabolism over the course of the treatment cycle.
Example 15
Activity of Compound I in Various Kinases
This example shows the IC50 profile of compound I across classes of kinases as summarized in Table 2. While especially active on p110δ, Compound I was also active on p110γ and even active enough to be therapeutically useful at non-toxic doses against p110β, due to the demonstrated high NOAEL level of the compound; while exhibiting little activity on Class II-V phosphoinositide kinases. Thus while being delta-selective, the compounds can exhibit sufficient activity on p110γ to be clinically useful, i.e., to be effective on a cancer that relies upon p110γ for signaling, because a plasma level above the effective dosage for inhibition of p110γ can be achieved while still being selective relative to other isoforms, particularly the alpha isoform.
TABLE 2
Class II
Class III
Other
PI3K,
PI3K,
Class IV
Phosphoinositide
Class I PI3Ks, IC50 (nM)
IC50 (nM)
IC50 (nM)
PI3K, IC50 (nM)
kinases
Compound
p110α
p110β
p110δ
p110γ
CIIbeta
hVPS34
DNA-PK
mTOR
PIP5Kα
PIP5Kβ
I
435
128
1
14
>103
978
6,729
>103
>103
>103
NVP-BEZ-
19
293
63
267
3
6
1
2
ND*
ND
235
Novartis
InvitroGen Adapta assay
*ND = not determined
Example 16
No Off-Target Activity of Compound I in Kinome-Wide Protein Kinase Screen
This example demonstrates that compound I has little or no off target activity in a kinome-wide protein kinase screen. Using Ambit KINOMEscan™ a genome wide screen of over 350 protein kinases failed to detect any activity at 10 μM. Examples of some kinases in the screen are shown below in Table 3.
TABLE 3
Examples of Relevant Kinases in Screen
ABL
FGFR1
JAK1
P38MAPK
S6K
AKT
VEGFR1
JAK2
PDGFR
SLK
ALK
FLT3
JNK1
PIM
SRC
BLK
FRK
KIT
PKA
SYK
BRAF
FYN
LCK
PKC
TAK
BTK
HCK
LYN
PLK
TIE
CDK
HER2
MAPK
RAF
TRK
CSF1R
ICK
MEK
RET
TYK
EGFR
IGF1-R
MET
ROCK
YES
EPH
ITK
MLK
ROS
ZAP70
Example 17
Selectivity of Compound I for p110δ
This example demonstrates that compound I is selective for p110δ as measured in isoform specific cell-based assays.
Swiss-3T3 fibroblasts and RAW-264 were seeded on a 96-well tissue culture plate and allowed to reach at least 90% confluency. Cells were starved and treated with either vehicle or serial dilutions of compound I for 2 hrs and stimulated with PDGF or C5a respectively. Akt phosphorylation and total AKT was detected by ELISA. Purified B-cells were treated with either vehicle or serial dilutions of compound I for 30 minutes at room temperature before the addition of purified goat anti-human IgM. Results are expressed as relative [3H] thymidine incorporation induced by IgM crosslinking.
TABLE 4
PI3Kα
PI3Kδ
PI3Kγ
EC50 (nM)
EC50 (nM)
EC50 (nM)
Fibroblast Cell Line
Primary B Cell
Monocyte Cell Line
PDGF induced pAKT
BCR mediated
C5a induced pAKT
proliferaton
>20,000
6
3,894
(n = 12)
(n = 6)
(n = 11)
Example 18
Expression of p110δ in Leukemia and Lymphoma Cell Lines
This example demonstrates that PI3K p110δ is highly expressed in a broad range of leukemia and lymphoma cell lines.
PI3K p110δ promotes proliferation and survival in a wide range of leukemia and lymphoma cell lines. Among the cell types investigated are MCL, DLBCL, AML, ALL, and CML.
Expression of PI3K p110α, β, γ and δ in a panel of lymphoma and leukemia cell lines is demonstrated in FIG. 15. Proteins from 106 cells were separated by SDS-PAGE and analyzed by Western blot using antibodies specific for the α, β, γ and δ isoforms. Purified recombinant p110 proteins were used as controls. Anti-actin antibodies were used to assess equal loading of the samples. p110δ was consistently expressed at a high level while other p110 isoforms were highly variable. PI3K p110δ is known to be uniformly expressed in patient AML cells as discussed by Sujobert, et al., Blood 2005 106(3), 1063-1066.
Example 19
Inhibitory Effect of Compound I on p110δ
Example 19 shows compound I inhibition of p110δ blocks PI3K signaling in leukemia and lymphoma cell lines with constitutive pathway activation.
The PI3K pathway is frequently deregulated in leukemia and lymphoma cell lines. 48% of cell lines, or 13 out of 27, were found to have constitutive p-AKT. In addition, PI3K pathway activation is dependent on p110δ. Compound I was found to inhibit constitutive AKT phosphorylation in 13 out of 13 cell lines.
PAGE results of FIG. 9 demonstrates that constitutive AKT phosphorylation was inhibited by the presence of compound I in each of 11 cell lines, including B-cell and T-cell lymphomas. Cells were incubated for 2 hrs with 10 M compound I. Cell lysates were run on SDS-PAGE and transferred onto PDVF membrane and probed with appropriate antibodies. Compound I was found to inhibit constitutive AKT phosphorylation in 11 out of 11 cell lines. Additional cell line data for T-ALL and B-ALL cell lines is shown in FIG. 27. A decrease in Akt and S6 phosphorylation after exposure to a range concentrations of compound I (0.1 μM to 10 μM), was quantitated by densitometry, expressed as the percent change, FIG. 28A-B.
Example 20
Compound I Inhibits Proliferation and Apoptosis in Leukemia Cell Lines
Example 20 demonstrates that compound I inhibits proliferation and induces apoptosis in leukemia cell lines. FIG. 16A-B show that treatment with compound I for 24 hours reduces cellular viability in a dose dependent manner.
Proliferation assays (AlamarBlue®) on ALL cell lines grown in the presence of 10% FBS serum and measurements were taken at 24 hrs. Proliferation was measured in triplicate wells in 96-well plates. The inhibition of PI3K signaling by compound I resulted in a block of cell cycle progression, and/or cell death. In each of six leukemia cell lines, viability was reduced by 40-50% with 10 micromolar concentrations of Compound I, FIG. 16A.
Induction of apoptosis by compound I. Cells were treated with DMSO (vehicle), 1 μM or 10 μM compound I for 24 hrs. The percentage of apoptotic cells was determined by Annexin V-FITC/7AAD staining. One experiment representative of different experiments that gave similar results is shown in FIG. 16B.
Example 21
Expression of p110 Delta in CLL Cells
This example demonstrates PI3K p110δ and p110 δ isoform expression in patient CLL cells.
PI3K mediated signaling pathways have been implicated in CLL. These pathways have a role in cell proliferation, prevention of apoptosis and cell migration. Efforts were made to determine PI3K isoform expression in patient CLL cells.
CLL patient demographics are summarized below in Table 5.
TABLE 5
CLL Patient Demographics
(Total (N = 24)
I) Cytogenetic abnormalities
13q14.3
58%
11q22.3
33%
17p13.1
20%
Trisomy 12
12%
II) Treatment History
Fludarabine refractory
29%
Unknown
54%
II) IgVH Status
Mutated
33%
Unmutated
33%
Unknown
33%
The PAGE images of FIG. 17A-D compare the expression of p110α, p110δ, p110β, and p110γ in CLL cells of patients A-E. p110δ and p110γ is expressed in each patient compared to the other PI3K isoforms.
Example 22
Compound I Induces Cleavage of Caspase 3 and PARP
This example demonstrates that compound I induced the cleavage of caspase 3 and PARP. FIG. 18A-B show results of caspase 3 and PARP (Poly(ADP) Ribose Polymerase) cleavage in the presence of 1, 10 μM of compound I or 25 μM of LY294002.
Further experiments provide evidence of compound I inducing caspase 2 and PARP cleavage. Cells were cultured with compound I or vehicle alone for 24 hrs. Thereafter, cells were lysed and sized-fractionated and immunoblotted with antibody directed against FLIP, FIG. 29. Additionally, whole cell lysates were added to MDS (Meso Scale Diagnostics) multi-spot 96-well 4 spot plates coated with Total caspase-3, cleaved caspase-3, cleaved PARP, and BSA. Proteins were detected with antibodies labeled with SULFO-TAG reagent and quantified. A dose dependent response in the cleavage of caspase 3 and PARP was achieved upon exposure to 5 or 10 μM of compound I.
Example 23
Compound I Blocks PI3K Signaling
This example demonstrates that compound I blocks PI3K signaling in patient AML cells. PI3Kδ is implicated in signaling in AML patient cells. FIG. 21 shows the results of Phospho-Akt production in the absence or presence of 0.1, 1.0, 10 μM of Compound I. This provides evidence that compound I reduces phopsho-Akt production in patient AML cells.
Example 24
Measurement of PI3K Signaling in Basophils Founding Whole-Blood
This example demonstrates a whole-blood assay for measurement of PI3K signaling in basophils using flow cytometry by the induction of CD63 surface expression.
Inhibition of PI3K signaling in basophils permits compound I to be a useful pharmacodynamic marker. PI3K signaling is monitored by CD63 surface expression. In particular, p110δ mediates FCϵR1 signaling and p110γ mediates fMLP receptor signaling. The flow cytometry analysis of PI3K mediated CD63 expression on basophils comprises the following sequential steps:
1. Collect peripheral blood
2. Basophil stimulation (fMLP or Anti-FCϵR1 Mab)
3. Label basophils (Anti-CCR3-FITC and Anti-CD63-PE)
4. Lyse and fix cells
5. Analysis by flow cytometry
FIG. 22A-C compares the results of A) no stimulation, B) stimulation with Anti-FCER1, or C) stimulation with fMLP.
FIG. 23 shows that Compound I is especially active where p110δ mediated signaling is most important, but is also relatively active where p110γ is utilized: it achieved 50% reduction in SD63 expression at <<1 M for the p110δ test, and ca. 10 μM for the p110γ test. Basophil activation was measured in human whole blood using the Flow2 CAST® kit. Whole blood samples were treated with either vehicle or serial dilutions of compound I prior to activation of basophils either with anti-FcϵRI mAb or fMLP. Cells were stained with the combination of anti-human CD63-FITC and anti-human CCR3-PE mAbs. The percent CD63 positive cells within the gated basophil population were determined in different treatment groups and normalized to the vehicle control.
Example 25
Compound I Reduces Lymphadenopathy in CLL Patient
Example 26
This example provides evidence of the reduction in size of a bulky lymphadenopathy in a CLL patient with a del[17p]. A patient with del(17p) had an axillary lymphadenopathy, which was imaged by computed tomography (CT) to provide a baseline measurement of 5.9 cm×4.1 cm, FIG. 40A. After one cycle of treatment with compound I, the lymphadenopathy was reduced to a dimension of 3.8×1.8 cm, FIG. 40B. A cycle treatment was 28 days of continuous oral dosing at either 200 mg BID or 350 mg BID of compound I.
Limited Effect of Compound I on Glucose and Insulin Levels of a Subject
This example demonstrates that treatment with compound I has little or no effect on glucose and insulin levels. Compound I was administered at 50-200 mg amounts BID to a subject over a period of up to 10 days. Blood glucose and insulin concentrations were measured over time and compared to placebo results as shown in FIG. 25A-B.
Blood glucose concentration remained steady after 10 days of treatment with even the highest dosage amount of compound I. Insulin levels remained within the normal range after 7 days of treatment with compound I. This provides evidence that compound I has little or no effect on glucose and insulin levels.
Example 27
Materials and Methods
This example provides information on materials and methods of carrying out the experiments described in Examples 28-35 which relate to the use of compound I in the treatment of multiple myeloma.
Materials
p110δ inhibitor compound I and compound II were provided by Calistoga Pharmaceuticals, (Seattle, Wash.). The sample of compound I and II used was over 95% the S enantiomer. Compound I was dissolved in Dimethyl sulphoxide at 10 mM and stored at −20° C. for in vitro study. Compound II was dissolved in 1% carboxyl methylcellulose (CMC)/0.5% Tween 80 and stored at 4° C. for in vivo study. Recombinant human P110α, β, γ, and δ were reconstituted with sterile phosphate-buffered saline (PBS) containing 0.1% BSA. bortezomib was provided by Millennium Pharmaceuticals (Cambridge, Mass.). 3-Methyladenine was purchased from Sigma-Aldrich (St. Louis, Mo.).
Cell Culture
Dex-sensitive (MM.1S) and resistant (MM.1R) human MM cell lines were kindly provided by Dr. Steven Rosen (Northwestern University, Chicago, Ill.). H929, RPMI8226, and U266 human MM cell lines were obtained from American Type Culture Collection (Manassas, Va.). Melphalan-resistant RPMI-LR5 and Doxorubicin (Dox)-resistant RPMI-Dox40 cell lines were kindly provided by Dr. William Dalton (Lee Moffitt Cancer Center, Tampa, Fla.). OPM1 plasma cell leukemia cells were provided by Dr. Edward Thompson (University of Texas Medical Branch, Galveston). IL-6-dependent human MM cell line INA-6 was provided by Dr. Renate Burger (University of Kiel, Kiel, Germany). LB human MM cell line was established in the laboratory. Phenotypic analysis revealed no cytogenetic abnormalities. Phenotypic analysis is shown in table 6. CD expression profile of LB cell line, defined by flow-cytometric analysis.
TABLE 6
LB expression
CD marker
% expression
CD3
5.5%
CD19
61.7%
CD20
97.2%
CD38
54.1%
CD40
96.8%
CD49e
5.9%
CD70
98.0%
CD138
96.3%
All MM cell lines were cultured in RPMI1640 medium. Bone marrow stromal cells (BMSCs) were cultured in Dulbecco's modification of Eagle's medium (DMEM) (Sigma) containing 15% fetal bovine serum, 2 mM L-glutamine (Life Technologies), 100 U/mL penicillin, and 100 μg/mL streptomycin (Life Technologies). Blood samples collected from healthy volunteers were processed by Ficoll-Paque™ gradient to obtain peripheral blood mononuclear cells (PBMNCs). Patient MM and BM cells were obtained from BM samples after informed consent was obtained per the Declaration of Helsinki and approval by the Institutional Review Board of the Dana-Farber Cancer Institute (Boston, Mass.). BM mononuclear cells were separated using Ficoll-Paque™ density sedimentation, and plasma cells were purified (>95% CD138+) by positive selection with anti-CD138 magnetic activated cell separation micro beads (Miltenyi Biotec, Auburn, Calif.). Tumor cells were also purified from the BM of MM patients using the RosetteSep negative selection system (StemCell Technologies, Vancouver, BC, Canada).
Growth Inhibition Assay
The growth inhibitory effect of compound I on growth of MM cell lines, PBMCs, and BMSCs was assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra-sodium bromide (MTT; Chemicon International, Temecula, Calif.) dye absorbance.
Effect of Compound I on Paracrine MM Cell Growth in the BM
MM cells (2×104 cells/well) were cultured for 48 h in BMSC coated 96-well plates (Costar, Cambridge, Mass.), in the presence or absence of drug. DNA synthesis was measured by [3H]-thymidine (Perkin-Elmer, Boston, Mass.) uptake, with [3H]-thymidine (0.5μ Ci/well) added during the last 8 h of 48 h cultures. All experiments were performed in quadruplicate.
Transient Knockdown of P110δ Expression
INA-6 cells and LB cells were transiently transfected with siRNA ON-TARGET plus SMART pool P110δ or nonspecific control duplex (Dharmacon Lafayette, Co) using Cell Line Nucleofector Kit V (Amaxa Blosystems Gaitherburg, Md.).
Immunofluorescence
Viable MM cells (2.5×104) were pelleted on glass slides by centrifugation at 500 rpm for 5 minutes using a cytospin system (Thermo Shandon, Pittsburgh, Pa.). Cells were fixed in cold absolute acetone and methanol for 10 min. Following fixation, cells were washed in phosphate-buffered saline (PBS) and then blocked for 60 min with 5% FBS in PBS. Slides were then incubated with anti-CD138 antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.) at 4° C. for 24 h, washed in PBS, incubated with goat anti-mouse IgG for 1 h at 4° C., and analyzed using Nikon E800 fluorescence microscopy.
Detection and Quantification of Acidic Vesicular Organelles (AVO) with Acridine Orange Staining.
Autophagy was characterized by sequestration of cytoplasmic proteins and development of AVOs. To detect and quantify AVOs in compound I or 3MA-treated cells, vital staining was performed for 15 min with acridine orange at a final concentration of 1 μg/ml. Samples were examined under a fluorescence microscope.
Angiogenesis Assay
The anti-angiogenic activity of compound I was determined using an in vitro Angiogenesis Assay Kit (Chemicon, Temecula, Calif.). HUVEC and endothelial growth media were obtained from Lonza (Walkersville, Md., USA). HUVEC were cultured with compound I on polymerized matrix gel at 37° C. After 8 h, tube formation was evaluated using Leika DM IL microscopy (Leica Microsystems, Wetzlar, Germany) and analyzed with IM50 software (Leica Microsystems Imaging Solutions, Cambridge, UK). HUVEC cell migration and rearrangement was visualized, and the number of branching points counted.
Western Blotting
MM cells were cultured with or without compound I; harvested; washed; and lysed using radioimmuno precipitation assay (RIPA) buffer, 2 mM Na3VO4, 5 m M NaF, 1 mM phenylmethylsulfonyl fluoride (5 mg/ml). Whole-cell lysates were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation, transferred to Pure Nitrocellulose membranes (Bio-Rad Laboratories, Hercules, Calif.), and immunoblotted with anti-AKT, phospho(p)-AKT (Ser473, Thr 308), ERK1/2, P-ERK1/2, P-PDK1, STAT, P-STAT, P-FKRHL, P-70S6K, LC3, and PI3K/p110 α Abs (Cell Signaling Danvers, Mass.); anti-p110β, PI3K/p110δ, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), α-tubulin, and actin Abs (Santa Cruz Biotechnology, CA); and anti-p110γ Ab (Alexis, San Diego, Calif.): and anti-LC3 Ab (Abgent, San Diego, Calif.).
ELISA
Cytokine secretion by human BMSCs cocultured with MM cells was assessed by ELISA. BMSCs were cultured in 96-well plates with varying concentrations of compound I, with or without INA-6 cells. After 48 h, supernatants were harvested and stored at −80° C. Cytokines were measured using Duo set ELISA Development Kits (R&D Systems, Minneapolis, Minn.). All measurements were carried out in triplicate.
Human Cytokine Array
The cytokine levels in culture supernatants were assessed using Proteome Profiler Antibody Arrays Panel A (R&D Systems, Minneapolis, Minn.), Supernatants from co-cultures with BMSCs were incubated for 4 hours with membranes arrayed with Abs against 37 cytokines, according to manufacturer's instructions.
Murine Xenograft Models of Human MM
CB17 SCID mice (48-54 days old) were purchased from Charles River Laboratories (Wilmington, Mass.). All animal studies were conducted according to protocols approved by the Animal Ethics Committee of the Dana-Farber Cancer Institute. Mice were inoculated subcutaneously in the right flank with 3×106 LB cells in 100 μL RPMI-1640. When tumors were palpable, mice were assigned into the treatment groups receiving 10 mg/kg or 30 mg/kg gavages twice daily; and 7 mice in the control group receiving vehicle alone. Caliper measurements of the longest perpendicular tumor diameters were performed every alternate day to estimate the tumor volume using the following formula representing the 3D volume of an ellipse: 4/3×(width/2)2×(length/2). Animals were sacrificed when tumors reached 2 cm or the mice appeared moribund. Survival was evaluated from the first day of treatment until death. Tumor growth was evaluated using caliper measurements from the first day of treatment until day of first sacrifice, which was day 12 for the control group and days 17 and 19 for the treatment groups. The images were captured with a canon IXY digital 700 camera. Ex vivo analysis of tumor images was captured with a LEICA DM IL microscope and LEICA DFC300 FX camera at 40 u/0.60 (Leica, Heidelberg, Germany).
Human fetal bone grafts were implanted into CB17 SCID-mice (SCID-hu). Four weeks following bone implantation, 2.5×106 INA-6 cells were injected directly into the human BM cavity in the graft in a final volume of 100 μl of RPMI-1640 medium. An increase in the levels of soluble human IL-6 receptor (shuIL-6R) from INA-6 cells was used as an indicator of MM cell growth and burden of disease in SCID-hu mice. Mice developed measurable serum shuIL-6R approximately 4 weeks following INA-6 cell injection, and then received either 10 or 30 mg/kg drug or vehicle alone daily for 7 weeks. Blood samples were collected and assessed for shuIL-6R levels using an enzyme-linked immunosorbent assay (ELISA, R&D Systems. Minneapolis Minn.).
Statistical Analysis
Statistical significance was determined by Dunn's multiple comparison tests. The minimal level of significance was p<0.05. Survival was assessed using Kaplan-Meier curves and log-rank analysis. The combined effect of compound I and bortezomib was analyzed by isobologram analysis using the CalcuSyn software program (Biosoft, Ferguson, Mo.); a combination index (CI) <0.7 indicates a synergistic effect.
Example 28
Expression of p110 Delta in MM Cells
This example demonstrates that p110 delta is highly expressed in patient MM cells. To assess PI3K/p110 expression, Abs was used against recombinant human PI3K/p110α, β, γ, and δ proteins with specific immunoreactivity against these isoforms. The expression of p110δ in 11 MM cell lines (MM.1S, OPM1, OPM2, RPMI8226, DOX40, LR5, MM.1R, U266, INA-6, H929, and LB), as well as 24 patient MM samples were evaluated and immunoblots shown in FIG. 30A and FIG. 30B. FIG. 30A shows expression of p110-α, -β, -γ, and -δ in MM cell lines detected by immunoblotting using specific antibodies. Anti-α-Tubulin MAb served as a loading control. p110δ in patient MM cells was detected by immunoblotting using anti-P110δ Ab (FIG. 30B).
Anti-GAPDH MAb served as a loading control. INA-6 and LB cells strongly expressed p1106, whereas MM.1S, OPM1, MM.1R, Dox40, U266 or H929 lacked p110δ expression (FIG. 30A).
p110δ expression in MM.1S and LB cells was confirmed by immunofluorescence analysis (FIG. 30C). Human recombinant P110-α, -β, -γ, -δ proteins in SDS sample buffer were heated for 3 min prior to loading on gel. (10-20 μg per lane.) Recombinant human P110-α, -β, -γ, -δ proteins were detected by Immunoblot analysis. Levels of P110δ were measured in MM1S and LB cells using P110 δ specific FITC conjugated secondary antibodies. P110δ stained green, and nucleic acids (DAPI) stained blue.
Western blotting revealed no correlation of between p110δ expression and expression of the other isoforms (α, β and γ). Importantly, all patient MM cells also expressed p110δ, (FIG. 30B).
Example 29
Cytotoxicity of Compound I on MM Cells
This example demonstrates that compound I has selective cytotoxicity against cells with p110δ. Specifically, compound I potently induced cytotoxicity in p110 delta positive MM cells as well as in primary patient MM cells without cytotoxicity in peripheral blood mononuclear cells from healthy donors, suggesting a favorable therapeutic index.
The growth inhibitory effect of p110δ knockdown in MM cells was evaluated. LB and INA-6 cells were transfected with P110δ siRNA (Si) or control siRNA (Mock). After 24 h, expression of P110δ was determined by western blot analysis, see FIG. 31A. INA-6 cells were transfected with p110δ siRNA or control siRNA, and then cultured for 72 hours. Cell growth was assessed by MTT assay, see FIG. 31 B. Data indicates mean±SD of triplicate cultures, expressed as fold of control. Transfection with p110δ siRNA, but not mock siRNA, down-regulated p110δ and inhibited MM cell growth at 72 h (FIG. 31A and FIG. 31B). The growth inhibitory effect of p110δ specific small molecule inhibitor compound I in MM cell lines, PBMCs, and patient MM cells was evaluated.
Compound I induced cytotoxicity against LB and INA-6 MM cells (p110δ-positive) in a dose- and time-dependent fashion; in contrast, minimal cytotoxicity was noted in p110δ-negative cell lines (FIG. 31C). The legend for FIG. 31C: LB (□), INA-6 (Δ), RPMI 8226 (∘), OPM2 (⋄), H929 (●), U266 (♦), RPMI-LR5 (▴) and OPM1 (▪) MM cells were cultured with or without compound I for 48 h.
Importantly, compound I also induced cytotoxicity against patient MM cells (FIG. 31D), without cytotoxicity in PBMCs from 4 healthy volunteers at concentrations up to 20 μM (FIG. 31E). Patients MM cells isolated from BM by negative selection were cultured with compound I for 48 h. Peripheral blood mononuclear cells isolated from healthy donors were cultured with compound I for 72 h. Data represent mean±SD viability, assessed by MTT assay of triplicate cultures, expressed as percentage of untreated controls. These results strongly suggest that sensitivity to compound I is associated with P110δ expression, and suggest a favorable therapeutic window.
To determine whether the cytotoxicity induced by compound I is via apoptosis, the cleavage of caspases and PARP by western blot analysis was examined. INA-6 cells were cultured with compound I (0-5 μM) for 120 h. Total cell lysates were subjected to immunoblotting using anti-caspase-3, -8, -9, PARP, and α-tubulin Abs. FL indicates full-length protein, and CL indicates cleaved protein. Significantly increased cleavage of caspase-8, caspase-9, caspase-3, and PARP was observed in INA-6 MM cells treated with compound I for 120 h (FIG. 31F). These results indicate that cytotoxicity triggered by compound I is mediated, at least in part, via caspase-dependent (both intrinsic and extrinsic) apoptosis.
Example 30
Inhibition of AKT and ERK Phosphorylation by Compound I
This example demonstrates the Inhibition of AKT and ERK phosphorylation by compound I.
An important downstream effector of PI3K is the serine/threonine protein kinase AKT, which is activated by phosphorylation of Thr308 in the activation loop of the kinase domain and Ser473 in the C-terminal tail. Phosphorylation of both sites requires an interaction between the N-terminal pleckstrin homology domain of AKT and membrane phosphoinositide generated by PI3K. It was shown that compound I inhibits both domains, suggesting that P110δ is the predominant isoform responsible for PI3K signaling in MM cell lines.
Inhibition of AKT and ERK pathways in INA-6 cells by compound I was examined. INA-6 cells were cultured with Compound I or LY294002 for 12 h, FIG. 32A. Actin Ab was used as a loading control. INA-6 and MM.1S cells were cultured with Compound I (0, 0.25, 1.0, 5.0 μM) for 6 hours, FIG. 32B. LB and INA-6 cells were cultured with compound I for 0-6 hours, FIG. 32C. Whole cell lysates were subjected to immunoblotting using AKT, P-AKT (Ser473 and Thr308), ERK1/2, P-ERK1/2, P-PDK1, and P-FKRHL antibodies. α-tubulin is used as a loading control.
Compound I significantly blocked phosphorylation of AKT and ERK1/2 in p110δ positive INA-6 cells (FIG. 32A), but did not affect phosphorylation of AKT or ERK in MM.1S cells with low expression of P110δ (FIG. 32B). Compound I also significantly inhibited phosphorylation of upstream PDK-1 and downstream FKHRL in INA-6 and LB MM cells in a time- and dose-dependent fashion (FIG. 32C), further confirming inhibition of a both PI3K/AKT and ERK pathways in these cells.
Example 31
Compound I Induces AVO Development and Autophagy
This example demonstrates the ability of compound I to trigger both apoptosis and autophagy.
AKT regulates autophagy, thus investigation of compound I in inducing autophagy in LB and INA-6 MM cells was carried out.
INA-6 and LB MM cells were treated with 5 μM Compound I for 6 h. Compound I treatment induced LC3 accumulation in LB and INA-6 cells, evidenced by fluorescence microscopy or transmission electron microscopy. Autophagosome formation was defined by the accumulation of LC3; arrows indicate autophagosomes, FIG. 33A.
INA-6 cells were treated with 5 μM Compound I or serum starvation for 6 h, stained with 1 μg/mL acridine orange for 15 min, and analyzed by fluorescence microscopy, FIG. 33B.
LC3 and beclin-1 protein levels were determined by western blotting using LC3 and beclin-1 antibodies of lysates from INA-6 cells treated with Compound I, with or without 3-MA, FIG. 33C. GAPDH served as a loading control.
Immunofluorescence analysis showed markedly increased LC 3 staining in INA-6 and LB cells triggered by compound I (5 μM, 6 h) treatment (FIG. 33A). Electron microscopic analysis also showed increased autophagic vacuoles (arrows) in MM cells treated with compound I. Since autophagy is characterized as acidic vesicular organelle (AVO) development, acridine orange staining was carried out. As shown in FIG. 33B, vital staining with acridine orange revealed development of AVOs in compound I-treated LB and INA-6 cells. Moreover, markedly increased LC3-II and Beclin1 protein were detected in INA-6 MM cells after 6 h treatment with compound I, which was blocked by 3-MA autophagic inhibitor (FIG. 33C).
No cytotoxicity in INA-6 and LB cells was induced by 3-MA at concentrations up to 100 μM, FIG. 33D. P110 δ positive LB cells (♦) were treated with 3-MA (0-100 μM) for 24 h. Data represent means (±SD) of triplicate cultures.
These results indicate that compound I induces development of AVOs and autophagy at earlier time points than induction of caspase/PARP cleavage.
Autophagy degrades cellular components, recycles cellular constituents, and responds to various cellular stress. In this example, LC3-II, a hallmark of autophagy, is induced by compound I treatment in p110 δ positive MM cell lines. Importantly, compound I treatment resulted in a marked increase in autophagy, evidenced by the presence of autophagic vacuoles in the cytoplasm, formation of AVOs, membrane association of microtubule-associated protein I of LC3 with autophagosomes, and a marked induction of LC3-II protein. Electron microscopic analysis confirmed that compound I induced autophagosomes. LC3-II was expressed through LC3-I conversion. Conversely, autophagy induced by compound I was suppressed by 3-MA, a specific inhibitor of autophagy. These studies suggest that early cytotoxic effects of compound I are associated with autophagy.
Example 32
Compound I Inhibits Cell Growth in the Presence of BMSC
This example demonstrates the ability of compound I to inhibit paracrine MM cell growth with BMSCs.
Since IL-6 and IGF-1 induces growth and anti-apoptosis in MM cells, compound I was examined in overcoming the effects of these cytokines in INA-6 and LB MM cells. LB and INA-6 cells were cultured for 48 h with control media (▪); or with compound I at 5.0 μM () or 10 μM (□), in the presence or absence of IL-6 (1 and 10 ng/ml), FIG. 34A, or IGF-1 (10 and 100 ng/mL), FIG. 34B. DNA synthesis was determined by measuring [3H]-thymidine incorporation during the last 8 h of 72 h cultures. Data represent means (±SD) of triplicate cultures. Neither IL-6 nor IGF-1 protected against the growth inhibition induced by compound I (FIGS. 34A and B).
The BM microenvironment confers proliferation and drug-resistance in MM, thus MM cell growth inhibitory effect of compound I in the presence of BMSCs was examined.
LB and INA-6 MM cells were cultured for 48 h with control media (□), and with 2.5 μM (), 5 μM (), and 10 μM (▪) of Compound I, in the presence or absence of BMSCs, FIG. 34C. DNA synthesis was determined by [3H]-thymidine incorporation. Data represent means (±SD) of triplicate cultures.
IL-6 in culture supernatants from BMSCs treated with compound I (0-2.5 μM) was measured by ELISA, FIG. 34D. Error bars indicate SD (±).
BMSCs were cultured with 1.0 μM compound I or control media for 48 h; cytokines in culture supernatants were detected using cytokine arrays, FIG. 34E.
INA-6 cells cultured with or without BMSCs were treated with compound for 48 h. Total cell lysates were subjected to immunoblotting using indicated antibodies, FIG. 34F. Actin was used as a loading control.
BMSCs from 2 different patients (□, ⋄) were cultured with compound I (0-20 μM) for 48 h. Cell viability was assessed by MTT assay, FIG. 34G. Values represent mean±SD of triplicate cultures.
Importantly, compound I inhibited growth and cytokine secretion (FIG. 34C-E), as well as phosphorylation of AKT and ERK (FIG. 34F), induced by BMSCs. In contrast, no significant growth inhibition in BMSCs was noted (FIG. 34G). These results indicate that compound I blocks paracrine MM cell growth in the context of the BM microenvironment.
Example 33
Compound I Inhibits Angiogenic HuVEC Tubule Formation
This example demonstrates the ability of Compound I to inhibit HuVEC tubule formation. The role of PI3K, specifically p110 isoform, in angiogenesis was investigated. Endothelial cells are an essential regulator of angiogenesis for tumor growth. Both Akt and ERK pathways are associated with endothelial cell growth and regulation of angiogenesis; and importantly, endothelial cells express p110δ. This example also demonstrates that compound I blocks in vitro capillary-like tube formation, associated with down regulation of Akt phosphorylation.
The effect of P110 δ inhibition on angiogenesis was investigated. HuVECs were treated with 0, 1.0, or 10 μM of compound I for 8 h, and tube formation by endothelial cells was evaluated (FIG. 35A). HuVEC cells were plated on Matrigel-coated surfaces and allowed to form tubules for 8 h, in the presence or absence of Compound I. Endothelial cell tube formation was measured by microscopic analysis, FIG. 35B. *P<0.005.
HuVECs were cultured with Compound I (0-20 μM) 48 h, and viability was assessed by MTT assay, FIG. 35C. Data shown are mean±SE of triplicate wells from a representative experiment. Thus, compound I inhibited capillary-like tube formation in a dose-dependent fashion (p<0.05) (FIG. 35B), without associated cytotoxicity (FIG. 35C).
Phosphorylation and expression of AKT and ERK1/2 was markedly down regulated in HuVEC cells by compound I treatment. HuVECs were cultured with compound I (0-200 μM) for 8 h, and cell lysates were analyzed by immunoblotting using the indicated antibodies, FIG. 35D. Actin was used as a loading control.
These findings suggest that compound I can inhibit angiogenesis, associated with down regulation of AKT and ERK activity.
Example 34
Compound II Inhibits MM Cell Growth In Vivo
This example demonstrates the ability of compound II to inhibit human MM cell growth in vivo.
The in vivo efficacy of P110δ inhibitor was evaluated in a xenograft model in which SCID mice are injected subcutaneously with human MM cells.
Mice injected with 5×106 LB cells were treated orally twice a day with control vehicle (●), and compound II 10 mg/kg (□) or 30 mg/kg (◯). Mean tumor volume was calculated as in Materials and Methods, FIG. 36A. Error bars represent SD (±).
Representative whole-body images from a mouse treated for 12 d with control vehicle (top panel) or Compound II (30 mg/kg) (bottom panel), FIG. 36B.
Tumors harvested from Compound II (30 mg/kg) treated mouse (right panel) and control mouse (left panel) were subjected to immuno-histochemistric analysis using CD31 and P-AKT Abs. CD31 and P-AKT positive cells are dark brown, FIG. 36D.
Mice were treated with Compound II 10 mg/kg (- -), 30 mg/kg ( . . . ) or Control vehicle (-). Survival was evaluated from the first day of treatment until sacrifice using Kaplan-Meier curves, FIG. 36C.
Tumor tissues were harvested from mice treated with control vehicle or Compound II (30 mg/kg). Protein levels of phosphorylated of PDK-1 and AKT (Ser473) were determined by western blotting of cell lysates, FIG. 36E. Actin was used as a loading control.
Growth of INA-6 cells engrafted in human bone chips in SCID mice was monitored by serial serum measurements of shuIL-6R. Mice were treated with Compound II 10 mg/kg (□), 30 mg/kg (Δ) or control vehicle (●), and shuIL-6R levels were determined weekly by ELISA, FIG. 36F. Error bars indicate SD (±).
Compound II (p110 δ inhibitor) significantly reduced MM tumor growth in the treatment group (n=7) compared with control mice (n=7). Comparison of tumor volumes showed statistically significant differences between control versus treatment groups (vs 10 mg/kg, P<0.05; vs 30 mg/kg, P<0.01) (FIG. 36A). Marked decrease in tumor growth in treated versus in control mice was observed at day 12. (FIG. 36B) Kaplan-Meier curves and log-rank analysis showed a mean Overall Survival (OS) of 15 days (95% confidence interval, 12-17 days) in control mice versus 23 days (95% CI, 15-34 days) and 32 days (95% CI, 27-49 days) in the 10 mg/kg and 30 mg/kg compound II treated groups, respectively. Statistically significant prolongation in mean OS compared with control mice was also observed in treatment groups (vs 10 mg/kg, P=0.086; vs 30 mg/kg, P=0.056) (FIG. 36C). Importantly, treatment with either the vehicle alone or compound II did not affect body weight. In addition, immunohistochemical (FIG. 36D) and immunoblot (FIG. 36E) analysis confirmed that compound II treatment (30 mg/kg) significantly inhibited p-Akt and p-PDK-1, as well as significantly decreased CD31 positive cells and microvessel density (p<0.01) (FIG. 36D). This suggests that compound II can inhibit angiogenesis in vivo via suppression of the Akt pathway.
In order to examine the activity of compound II on MM cell growth in the context of the human BM microenvironment in vivo, a SCID-hu model was used in which IL-6 dependent INA-6 cells are directly injected into a human bone chip implanted subcutaneously in SCID-mice. This model recapitulates the human BM microenvironment with human IL-6/BMSC-dependent growth of INA-6 human MM cells. These SCID-hu mice were treated with compound II or vehicle alone daily for 4 weeks, and serum shuIL-6R monitored as a marker tumor burden. As shown in FIG. 36F, compound II treatment significantly inhibited tumor growth compared with vehicle control. Significant tumor growth inhibition in this model was observed, evidenced by decreased serum shuIL-6R levels released by INA-6 cells, confirming that p110δ inhibition blocks the MM growth promoting activity of the BM microenvironment in vivo. Taken together, these data demonstrate that inhibition of p110δ by compound II significantly inhibits MM growth in vivo and prolongs survival.
Example 35
Compound I in Combination with Bortezomib Exhibits Synergistic Cytotoxicity
This example demonstrates the effect of Compound I in combination with bortezomib to mediate synergistic MM cytotoxicity.
The effects of combining compound I with bortezomib in inducing synergistic MM cytotoxicity was investigated. LB and INA-6 MM cells were cultured with medium (●) and with compound I, 1.25 μM (), 2.5 μM (), or 5.0 μM (□), in the presence or absence of bortezomib (0-5 nM). Cytotoxicity was assessed by MTT assay; data represent the mean±SD of quadruplicate-cultures, FIG. 37A.
INA-6 cells were treated with Compound I (5 μM) and/or bortezomib (5 nM) for 6 h. Phosphorylation of AKT was determined by western blotting of cell lysates using phospho-AKT (ser473) antibody, FIG. 37B. Actin served as a loading control.
Compound I enhances cytotoxicity of bortezomib. Increasing concentrations of compound I (1.5-5.0 μM) added to bortezomib (2.5, 5.0 nM) triggered synergistic cytotoxicity in LB and INA-6 MM cells (FIG. 37A and Table 7). Importantly, induction of phospho-Akt by bortezomib treatment was inhibited in the presence of compound I (FIG. 37B).
TABLE 7
Combination index (CI)
Bortezomib
Compound I
(nM)
(μM)
Fa
CI
LB
2.5
1.25
0.39
0.57
2.5
2.5
0.52
0.58
2.5
5
0.57
0.67
5
1.25
0.42
0.88
5
2.5
0.60
0.25
5
5
0.67
0.22
INA-6
2.5
1.25
0.49
0.31
2.5
2.5
0.58
0.48
2.5
5
0.69
0.54
5
1.25
0.56
0.73
5
2.5
0.66
0.42
5
5
0.75
0.31
Example 36
Compound I Effective in Follicular Lymphoma Cell Lines
This example provides evidence that compound I blocks PI3K signaling and induces apoptosis in follicular lymphoma cells. P110δ is expressed in FL cell lines as shown in FIG. 38A. Certain cell lines show reduction in the production of pAkt, Akt, pS6 and S6 when the cell is exposed to compound I, FIG. 38B. Cleavage of PARP and Caspase-3 is observed after exposure to compound I in a dose dependent fashion after 24 hours at 0.1 μM and 0.5 μM, FIG. 38C.
Example 37
Compound I Effective in Primary MCL Cells
This example demonstrates that compound I is effective against MCL. Compound I was found to block constitutive PI3K signaling in primary MCL cells of two patients in a dose dependent manner when exposed to 0.1 μM or 1 μM of compound I, FIG. 39A. Compound I is also observed to inhibit survival factor and chemokine signaling in MCL cell lines. FIG. 39B shows a significant reduction of pAkt in MCL lines exposed to different survival factors in the presence of compound I.
Example 38
Effect of Compound in Combination with Ofatumumab in CLL
This example summarizes the Phase 1-2 study of repeated cycles (28 days/cycle) of compound I in combination with ofatumumab for the treatment of patients who had previously been treated for CLL.
Compound I (150 mg 2 times per day [BID]) was co-administered continuously with 12 infusions of ofatumumab given over 24 weeks. Ofatumumab was administered with an initial dose of 300 mg on either Day 1 or Day 2 (relative to the first dose of compound I). One week later, ofatumumab was administered at 1,000 mg every week for 7 doses, then at 1,000 mg every 4 weeks for 4 doses. After completion of the ofatumumab treatment, each subject continued to receive compound I as a single agent at a dose of 150 mg BID as long as the subject was benefiting.
From the entire cohort of 21 patients, demographic and preliminary efficacy data from 11 patients were available. The median [range] age was 63 [54-76] years. The majority (9/11; 82%) of patients had bulky adenopathy (≥1 lymph node measuring ≥5 cm in longest dimension). The median [range] number of prior therapies was 3 [1-6], including prior exposure to alkylating agents (10/11; 90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab (3/11; 28%) and/or ofatumumab (2/11; 18%). At the data cutoff, the median [range] treatment duration was 5 [0-7] cycles. Almost all subjects (9/11; 82%) experienced marked and rapid reductions in lymphadenopathy within the first 2 cycles. Among the 11 patients, 10 were evaluable for response assessment at the end of Cycle 2 or later. Eight patients (80%) met criteria for a response as judged by the investigator based on the criteria published in Hallek M, et al. (Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun. 15; 111(12):5446-56). One patient had reduced lymphadenopathy meeting criteria for stable disease, and one patient had disease progression. The transient increase in the peripheral lymphocyte counts that was expected with single-agent PI3Kδ inhibition was reduced in magnitude and duration. The reduction of the transient lymphocytosis was induced by the combination of compound I and oftatumumab.
Preliminary safety data show that the combination treatment had a favorable safety profile and lacked myelosuppression. In addition, pharmacodynamic data revealed that elevated baseline levels of CLL-associated chemokines and cytokines (CCL3, CCL4, CXCL13, and TNFα) were reduced after 28 days of treatment. The results suggest that the combination of compound I with ofatumumab provides a well-tolerated, non-cytotoxic treatment regimen in patients with previously treated CLL.
Example 39
Effect of Compound in Combination with BCL-2 Antagonists in CLL
This example shows the effect of compound I in combination with BCL-2 antagonists ABT-737 and ABT-263 on the stroma-exposed CLL cells.
CLL Cell Purification:
Peripheral blood, bone marrow, and lymph node were obtained from consent patients fulfilling diagnostic and immunophenotypic criteria for CLL. Peripheral blood mononuclear cells (PBMCs) were isolated from blood and tissue samples using the Ficoll-Paque (GE Healthcare, Waukesha, Wis.) density gradient centrifugation. Samples were either analyzed fresh or viably frozen in 10% dimethyl sulfoxide (DMSO; Sigma-Aldrich, St. Louis, Mo.) in fetal bovine serum (BD Biosciences, San Diego, Calif.) and stored in liquid nitrogen and later thawed for analysis. Single cell suspensions were prepared for analysis on a fluorescence activated cell sorting (FACS) machine, and CD19+ CLL cells generally accounted for >85% of analyzed cells.
Cell Lines:
Murine CD154+L cell line was maintained in RPMI 1640 medium supplemented with 10% FBS, 2.05 mM L-glutamine (HyClone, Logan, Utah), and penicillin-streptomycin (Cellgro, Manassas, Va.). The human stromal cell line StromaNKTert was purchased from the Riken cell bank (Tsukuba, Japan) and maintained in alpha-MEM supplemented with 1 μg/mL hydrocortisone, 10% FBS, 10% human serum (Invitrogen, Grand Island, N.Y.), 2.05-mM L-glutamine, and penicillin-streptomycin. Nurse-like cells (NLCs) were established by suspending PBMC from patients with CLL in complete RPMI 1640 medium with 10% FBS and penicillin-streptomycin-glutamine to a concentration of 107 cells/mL (2 mL total). Cells were grown for 14 days in 24-well plates (Corning Life Sciences).
CLL Cell and Stromal Cell Co-Cultures:
CLL cells were cultured under standardized conditions on stromal cell lines or primary NLC. Briefly, stromal cells were seeded one day prior to each experiment onto 24-well plates (Corning Life Sciences) at a concentration of 3×105 cells/mL/well and incubated at 37° C. in 5% CO2. Stromal cell confluence was confirmed by phase contrast microscopy, and CLL cells were then added onto the stromal cell layer at a concentration of 3×106 cells/mL. Cultures were then treated with compounds for the specified time periods. CLL cells were removed for analysis by gentle pipetting with media, and were then washed in PBS prior to analysis. A 24-hour co-culture time point was used unless otherwise indicated.
Cell Viability Testing and Reagents:
CLL cell viability was determined by analysis of Annexin V-FITC (BD Biosciences, San Diego, Calif.) and Propidium Iodine (PI) (Sigma) by FACS. ABT-737, ABT-263, and compound I were stored in DMSO at −20° C. until use.
BH3 Profiling:
CLL patient peripheral blood, bone marrow, and lymph node samples were analyzed by either the plate-based fluorimetry or FACS method. Briefly, PBMCs from CLL patients were made into single cell suspensions and gently permeabilized using digitonin (0.002%). For the fluorimetry-based method, 100 μM JC-1 (Invitrogen) was added at this time and cells were then loaded onto a 384-well plate, with individual wells containing individual BH3-only peptides. The JC1-BH3 assays were then conducted in triplicate on a Tecan Safire 2 with Ex 545+/−20 nM and Em 590+/−20 nm with a three-hour time course. For the FACS-based method, single cell suspensions from CLL patient PBMCs were stained using human Fc Block (BD Pharmingen) followed by anti-CD19-V450 (BD Pharmingen) and anti-CXCR4-APC (BD Pharmingen). Cells were washed in PBS and then added into individual FACS tubes, each of which contained an individual BH3-only peptide. Samples were incubated at room temperature for 30 minutes, 100 μM JC-1 was added to each tube, and the samples were incubated for an additional 30 minutes. FACS measurements were conducted on a BD FACS Canto II with lasers at 407, 488, and 633 nm. JC-1 was measured from the 488-nm laser using a 530/30-nm filter (FITC) and a 585/42-nm filter (PE), and the degree of mitochondrial depolarization was calculated using the surrogate of the change in the median of PE signal. The mitochondrial depolarization reported in response to each BH3 peptide is normalized relative to the median percentage change in PE fluorescence of the JC-1 dye with a negative control, dimethyl sulfoxide (DMSO) (0%) and a positive control, the mitochondrial uncoupling agent carbonyl cyanide 4-(trifluoromethoxy)-phenylhydrazone (FCCP) (100%).
Calcein-Based Adhesion Assay:
a confluent monolayer of CD154+ L or StromaNKTert cells was generated by plating 1×104 cells/well in 96-well plates for 24 hours. Single cell suspensions of CLL cells at 0.5×106 cells/ml were then labeled with 1 μg/mL Calcein-AM (Invitrogen) for 1 hour. Cells were then spun down and treated with compound or vehicle for 1 to 24 hours. Non-adherent cells were washed off by aspiration. CLL cell adhesion was quantified by fluorimetry (Ex/Em=485/520 nm), and visualized directly using the Nikon TE2000 inverted live-cell imaging system.
Data Analysis and Statistics:
Results are shown with standard error of mean and number of replicates as described in each figure. Student's paired or unpaired t-tests, Mann-Whitney U test, or linear regression analyses were used for statistical comparisons. Analyses were performed with GraphPad Prism 5 software for PC (GraphPad Software, San Diego, Calif.). Flow cytometry data were analyzed using FACS Diva version 6.1.1 (BD Pharmingen). Clinical response was assessed using 2008 IW-CLL criteria with responders defined as patients achieving a complete or partial response as best response, and non-responders as patients with stable disease, refractory disease, or progressive disease within 6 months of finishing first therapy. A two-tailed p-value ≤0.05 was considered statistically significant unless otherwise indicated.
Currently, many patients receiving the first-line traditional CLL therapy often relapse and develop resistant to their treatment. Because CLL cells exposed to various stroma are resistant to treatment with both cytotoxic chemotherapy (Kurtova A V et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009; 114(20):4441-4450) and BH3-mimetics such as ABT-737 or ABT-263 (Vogler M et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood. 2009; 113(18):4403-4413), CLL cells in the stromal microenvironment may receive proliferative or anti-apoptoic signals from stroma and become protected from cell apoptosis. Thus, agents that antagonize the interactions may reduce the stroma-mediated resistance in CLL.
The compound of formula I may modulate the stromal microenvironment. In clinical studies, most patients treated with compound I and other agents targeting the BCR pathway exhibited a rapid and transient lymphocytosis. Without being bound to any theory, compound I may modulate the stromal microenvironment by inhibiting CLL cell chemotaxis towards CXCL12/13, reducing CLL cell migration beneath stromal cells, down-regulating chemokine secretion, or inhibiting phosphorylation of other downstream targets such as AKT and ERK. To characterize whether compound I modulate the CLL-stroma interaction by increasing mitochondrial apoptosis or priming, the BH3 profiling was used to measure the permeabilization of mitochondria induced by peptides derived from the pro-death BH3 domains of pro-death BCL-2 family proteins.
First, CLL cells from the peripheral blood of 30 patients were examined. Most patients had not been treated previously, and none had recently received therapy. At a final concentration of 0.03 ptM in the BH3 profiling, BIM BH3 peptide induced a significant amount of depolarization in most patient samples, with 22/30 (73.3%) of samples having >50% depolarization by 1 hour. As shown in FIG. 41A, CLL cells were highly primed for apoptosis. Also, the results of BH3 profiling showed that most CLL patient samples showed relatively increased depolarization from BAD BH3 peptide, suggesting primary dependence on BCL-2 (n=23). As shown in FIG. 41B, some samples were observed to be more dependent on MCL-1 (n=5), or BCL-XL (n=2). As shown in FIG. 41C, pre-treatment samples from treatment-naïve patients achieving a partial response (PR) or complete response (CR) by 2008 IW-CLL criteria were observed to be more primed than samples from patients with progressive disease (PD) during or within 6 months of completing frontline CLL therapy (p=0.024). As shown in FIG. 41D, BH3 profiling shows that patients with unmutated IGHV status (n=7) were significantly more primed than patients with mutated IGHV status (n=18) (p=0.0026). As shown in FIG. 41E, percentage of VH homology to germline was observed to be positively correlated with level of priming (p=0.0043). Thus, it was observed that CLL cells were highly primed for apoptosis, that CLL cells were usually BCL-2 dependent, and that increased priming was associated with improved clinical response and unmutated IGHV.
Next, the effects of compound I on the adhesion, viability, and priming of the stroma-exposed CLL cells in vitro were evaluated. FIG. 42A-E generally show that compound I was observed to release CLL cells sequestered in stroma to overcome stroma-mediated resistance. Peripheral blood-derived CLL cells were labeled with calcein-AM and co-cultured on stromaNKTert for 24 hours with or without compound I (10 μM), rinsed by gentle pipetting, and visualized by wide-field microscopy. As shown in FIG. 42A, CLL cells co-cultured with stromaNKTert and treated with compound I exhibited less adherent at 24 hours. Also, FIG. 42B showed that the reduced adherence of CLL cells was detectable even after only one hour treatment of compound I, which was before CLL cell death would occur. Moreover, FIG. 42C showed that the de-adherence of CLL cells from stroma in response to compound I resulted in enhanced killing of CLL cells. In particular, mean percent viability for two patients was depicted along with SEM in FIG. 42C, and both of these patients demonstrated profound stroma-mediated resistance to either ABT-737 at 100 nM or compound I at 10 μM alone. This resistance was observed to be overcome by the combination of the two compounds.
To avoid examine the direct killing of CLL cells by compound I, two CLL patient samples that were resistant to both ABT-737 and compound I were treated in the presence of stroma. In both samples, compound I restored sensitivity of CLL cells to ABT-737 in the presence of stroma. In addition, stroma-exposed CLL cells treated with compound I (10 μM) in combination of various doses of ABT-737 and its oral analogue ABT-263 showed that stroma-exposed CLL cells exhibited a dose-dependent increase in killing with either BH3 mimetic. In particular, with reference to FIG. 42D, resistance to ABT-737 was observed in the presence of StromaNKTert, but may be overcome with concentrations of ABT-737 as low as 10 nM. With reference to FIG. 42E, ABT-263 had a similar dose-response curve.
To determine whether PI3K inhibition increased the sensitivity of stroma-exposed CLL cells by increasing priming, PB-derived CLL cells cultured with or without StromaNKTert cells for 24 hours and were examined using Annexin-PI and BH3 profiling. Untreated CLL cells generally exhibited apoptosis in ex vivo culture over 24 hours (Collins R J et al. Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culture in vitro. British journal of haematology. 1989; 71(3):343-350). Stromal co-culture of four CLL patient samples led to protection from apoptosis in untreated cells. In particular, with reference to FIG. 43A, a two-way ANOVA analysis showed that stroma provided protection from apoptosis in the absence of compound I. In the absence of stroma, compound I was observed to induce more apoptosis than the control. In the presence of stroma, compound I was observed to induce significantly more apoptosis than the control. Thus, no significant difference was observed between killing by compound I in the presence or absence of stroma.
However, the resistance or protection from apoptosis was reversed by compound I. More than 40% of apoptosis were detected in stroma-exposed CLL cells treated with compound I (10 μM) compared to less than 10% of apoptosis in untreated stroma-exposed CLL cells. Also, as shown in FIG. 43B, the BH3 profiling showed that stroma-exposed CLL cells treated with compound I exhibited an increased mitochondrial priming at 24 hours compared to untreated cells (p=0.075). As shown in FIG. 43C, both BAD BH3 peptide and ABT-737 used as a peptide induced significantly more mitochondrial depolarization in CLL cells treated with compound I (p=0.046 and p=0.047, respectively). This suggests that the treatment with compound I results in de-adherence of CLL from stroma, accompanied by increased mitochondrial priming and increased sensitivity to BCL-2 antagonism.
Overall, this example suggested that PI3K inhibition antagonized the protection of CLL cells by stroma, and that compound I was effective at reversing the effects of stroma on CLL cells: adhesion, decreased mitochondrial priming, and decreased sensitivity to therapies that inhibit BCL-2. Also, the efficicay of compound I may be associated with lymphocyte redistribution in patients. By releasing CLL cells from stroma, compound I likely allowed CLL cells to emerge from the anti-apoptotic stromal milieu, thereby increasing their mitochondrial priming and being susceptible to apoptosis. This example also suggested the combinations of PI3K inhibition with BCL-2 inhibition increase the responses to BCL-2 inhibition.
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15277857
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Oct 1st, 2013 12:00AM
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Apr 20th, 2010 12:00AM
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https://www.uspto.gov?id=US08546409-20131001
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Methods of treatment for solid tumors
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The invention provides methods that relate to a novel therapeutic strategy for the treatment of hematological malignancies and inflammatory diseases. In particular, the method comprises administration of a compound of formula I,
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound admixed with at least one pharmaceutically acceptable excipient.
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8546409
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1. A method of treating a solid tumor in a subject comprising administering to said subject an optically active compound of formula I
or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition comprising an optically active compound of formula I or a pharmaceutically acceptable salt thereof;
wherein the amount of the optically active compound of formula I or a pharmaceutically acceptable salt thereof is an amount effective to treat the solid tumor.
2. The method of claim 1, wherein the solid tumor is selected from the group consisting of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors, bone cancer, and soft tissue sarcoma.
3. The method of claim 1, wherein the solid tumor is selected from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.
4. The method of claim 1, wherein the pharmaceutical composition comprises the optically active compound of formula I and the corresponding R-enantiomer of the optically active compound of formula I, or pharmaceutically acceptable salts thereof, and wherein the optically active compound of formula I or pharmaceutically acceptable salt thereof predominates over the corresponding R-enantiomer of the optically active compound of formula I or pharmaceutically acceptable salt thereof by a ratio of at least about 9:1.
5. The method of claim 1, wherein the pharmaceutical composition comprises the optically active compound of formula I and the corresponding R-enantiomer of the optically active compound of formula I, or pharmaceutically acceptable salts thereof, and wherein the optically active compound of formula I or pharmaceutically acceptable salt thereof predominates over the corresponding R-enantiomer of the optically active compound of formula I or pharmaceutically acceptable salt thereof by a ratio of at least about 19:1.
6. The method of claim 1, wherein the optically active compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered orally.
7. The method of claim 1, wherein the optically active compound of formula I, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered in solid form.
8. The method of claim 7, wherein the solid form comprises the optically active compound of formula I or pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient.
9. The method of claim 7, wherein the solid tumor is ovarian, renal, breast, lung, colon or prostate cancer.
10. The method of claim 1, wherein the subject is refractory to chemotherapy treatment, or in relapse after treatment with chemotherapy.
11. The method of claim 1, wherein the optically active compound of formula I or pharmaceutically acceptable salt thereof is administered at a dose of 20-500 mg/day.
12. The method of claim 1, wherein the optically active compound of formula I or pharmaceutically acceptable salt thereof is administered at a dose of 50-250 mg/day.
13. The method of claim 1, wherein the optically active compound of formula I or pharmaceutically acceptable salt thereof is administered at a dose of 50-150 mg twice per day.
14. The method of claim 1, wherein the optically active compound of formula I or pharmaceutically acceptable salt thereof is administered at least twice daily.
15. The method of claim 1, wherein the subject is a human subject.
16. The method of claim 15, wherein the concentration of the optically active compound of formula I or pharmaceutically acceptable salt thereof in the subject's blood is between 40-3000 ng/mL over a 12 hour period from the time of administration.
17. The method of claim 15, wherein the concentration of the optically active compound or pharmaceutically acceptable salt thereof in the subject's blood is between about 100 nM and 2000 nM.
18. The method of claim 1, wherein the optically active compound of formula I, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to the subject orally, intravenously or by inhalation.
19. The method of claim 1, further comprising administering in addition to the optically active compound of formula I or pharmaceutically acceptable salt thereof to said subject, a therapeutically effective amount of at least one therapeutic agent and/or therapeutic procedure to treat said solid tumor in said subject.
20. The method of claim 19, wherein said therapeutic agent is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, a platin, and a taxane.
21. The method of claim 19, wherein said therapeutic procedure is selected from the group consisting of peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, immunohistochemistry staining method, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, high-dose chemotherapy and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
22. The method of claim 1 further comprising obtaining a biological sample from said subject; and analyzing said biological sample with an analytical procedure selected from the group consisting of blood chemistry analysis, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, laboratory biomarker analysis, immunohistochemistry staining method, flow cytometry or a combination thereof.
23. The method of claim 22, wherein the optically active compound of formula I, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered twice daily for about 28 days, and is then discontinued for at least 7 days.
24. The method of claim 19, wherein said therapeutic agent is selected from the following group consisting of docetaxel, mitoxantrone, prednisone, estramustine, anthracyclines, taxanes, cyclophosphamide, capecitabine, 5-fluorouracil, gemcitabine, methotrexate, vinorelbine, an EGFR inhibitor, trastuzumab, bevacizumab, platins, temazolamide, interferon alpha, and IL-2.
25. The method of claim 19, wherein said therapeutic agent is selected from the following group consisting of docetaxel, mitoxantrone, prednisone, estramustine, doxorubicin, epirubicin, liposomal doxorubicin, paclitaxel, and protein-bound paclitaxel, cyclophosphamide, capecitabine, 5-fluorouracil, gemcitabine, methotrexate, vinorelbine, erlotinib, trastuzumab, bevacizumab, cisplatin, carboplatin, temazolamide, interferon alpha, and IL-2.
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25
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. provisional application No. 61/171,047 filed Apr. 20, 2009, the contents of which are incorporated herein by reference in its entirety.
TECHNICAL FIELD
The invention is in the field of therapeutics and medicinal chemistry. In particular, the invention concerns methods of treatment for certain solid tumors that include administration of certain quinazolinone derivatives.
BACKGROUND ART
Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring.
PI 3-kinase activation, is believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis. FIG. 1 shows some cellular pathways by which PI3K (represented by p110 and p85) participates in solid tumor activation.
The initial purification and molecular cloning of PI3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits. Four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct p110 catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., p110α, p110β and p110δ, each interact with the same regulatory subunit, p85; whereas p110γ interacts with a distinct regulatory subunit, p101. The patterns of expression of each of these PI3Ks in human cells and tissues are also distinct.
Identification of the p110δ isoform of PI 3-kinase is described in Chantry et al., J. Biol. Chem., 272:19236-41 (1997). It was observed that the human p110δ isoform is expressed in a tissue-restricted fashion. It is expressed at high levels in lymphocytes and lymphoid tissues, suggesting that the protein might play a role in PI3-kinase-mediated signaling in the immune system. The p110β isoform of PI3K may also play a role in PI3K-mediated signaling in certain cancers. FIG. 2 illustrates the relative amounts of these isoforms of p110 in a number of different cancer cell lines. Some solid tumors exhibit little or no p110α, and many have low levels of p110δ, but all of the ones tested showed significant levels of p110β.
There is a need for a treatment of PI3K-mediated disorders relating to cancers, inflammatory diseases, and autoimmune diseases. Quinazolinone compounds have been described as generally useful for treating mainly hematologic cancers that express relatively high levels of p110δ, because the quinazolinones are more active as inhibitors of p110δ. Other PI3K inhibitors are under development for treatment of solid tumors, but they appear to be non-selective inhibitors of several isoforms of p110, or inhibitors mainly of p110α. For example, XL-147 inhibits p110α and p110δ and p110γ with similar IC-50's according to Exelixis, and has 10× lower activity on p110β; BEZ235 is described as a pan-PI3K inhibitor that also acts on mTOR; and GDC-0941 is described as a p110α inhibitor. Inhibitors with lower selectivity, or with higher levels of p110α activity, could be expected to have off-target activities; p110α, for example, is involved in regulation of glucose and insulin levels. The present invention provides a specific isomer of one quinazolinone compound that is particularly useful for the treatment of solid tumors. While it is more active on p110δ than other isoforms of PI3K, this compound's ability to treat solid tumors is believed to be due to its relatively high activity as an inhibitor of p110β combined with a high level of oral bioavailability, and it exhibits relatively low levels of functional activity against p110α.
SUMMARY
The invention provides novel methods to treat certain solid tumors, using a compound of formula (I). In one aspect, the invention provides a method of treating cancer in a subject comprising administering to said subject an optically active compound of formula I:
or a pharmaceutically acceptable salt thereof. The optically active compound is predominantly the S-isomer shown here, though it may contain as a minor component some proportion of the R enantiomer. Preferably the compound used in the methods of the invention consists primarily of the S-isomer as further discussed herein.
The methods of the invention include delivery of this compound by various routes of administration, but preferably the compound is administered orally.
The subject can be any mammal; in preferred embodiments the subject is a human.
Without being bound by theory, the antitumor activity of this compound is believed to arise from its inhibition of p110β more than from inhibition of p110δ or p110α. It exhibited activity in a variety of cancer cell lines that expressed little p110δ, and some that did not express significant amounts of p110α; but all of the tested cell lines expressed p110β.
Moreover, compound I exhibited comparatively low functional activity on p110α in a cell-transformation system designed to measure functional activity of these kinases, but is a potent inhibitor of both p110β and p110δ in that assay. See Example 1. This chick embryo fibroblast (CEF) transformation system has been reported as a useful way to assess the functional activity of the PI3K signaling pathway. Denley, et al., “Oncogenic signaling of class I PI3K isoforms,” Oncogene, vol. 27(18), 2561-74 (2008). Transformation of CEF cells in the assay depends upon functional kinase activity. Kang, et al., Proc. Nat'l Acad. Sci. USA, vol. 103(5), 1289-94 (2006). Similarly in other functional cell-based assays, Compound I is most active on p110δ and p110β, with relatively lower activity against p110α.
As FIG. 4 illustrates, Compound I at 10 micromolar inhibits phosphorylation of Akt, which is a downstream mediator of PI3K activation (See FIG. 1), in two cancer cell lines, T47D (breast cancer) and OVCAR-3 (ovarian cancer). It is significant, too, that T47D has a mutation that activates p110α, yet that does not significantly reduce the effect of Compound I against this cell line, further suggesting that the antitumor activity of this compound must reside in its effect on other isoforms rather than on p110α. This distinguishes compound I from other known PI3K inhibitors in development for treatment of solid tumors, which are believed to act primarily at the p110α isoform or on p110α plus other isoforms, or even on all PI3Ks plus mTOR.
Compound I is useful to treat certain cancers. In some embodiments the cancer is a non-hematopoietic cancer. In some embodiments, the cancer is a solid tumor selected from pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancers; CNS cancers; brain tumors; bone cancer; and soft tissue sarcoma. In some embodiments it is lung cancer (non-small cell lung cancer, small-cell lung cancer), colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast cancer.
In some embodiments, the method comprises administering an effective amount of compound I or a pharmaceutically acceptable salt of compound I, to a subject afflicted with one of these cancers. In preferred embodiments, the compound is administered orally. The compound may be administered alone or in the form of a pharmaceutical composition that comprises compound I admixed with at least one pharmaceutically acceptable excipient.
In particular embodiments, the cancer is breast cancer, lung cancer, prostate cancer, renal cancer, or ovarian cancer. In a particular embodiment, the method comprises administering to the subject to be treated, in addition to a compound of formula I, a therapeutically effective amount of at least one additional therapeutic agent and/or an additional therapeutic procedure selected to treat the cancer.
The invention thus provides a method of treating a solid tumor in a subject comprising administering to said subject an optically active compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an optically active compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of Formula I or its salt is an amount effective to treat the solid tumor.
In certain embodiments, the solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancers; CNS cancers; brain tumors; bone cancer; and soft tissue sarcoma. In some embodiments, the solid tumor is selected from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.
For methods of the invention, compound I is optically active. Preferably, the S-enantiomer predominates over the R enantiomer by a ratio of at least about 9:1. In specific embodiments, the S-enantiomer predominates over the R enantiomer by a ratio of at least about 19:1.
In preferred embodiments, Compound I is administered orally. Typically, it is administered in a solid form, and commonly it is admixed with a pharmaceutically acceptable diluent or excipient.
The method is applicable to the treatment of a variety of tumor types. In some embodiments, the cancer is ovarian, renal, breast, lung, colon or prostate cancer.
The subject is a mammal, and is typically a human. In some embodiments, the subject is refractory to chemotherapy treatment, or is in relapse after treatment with chemotherapy. The methods of the invention are also useful to reduce the level of activity of p110β in the subject.
The compound of Formula I can be administered at a dose of 20-500 mg/day. In some embodiments, the compound of formula I is administered at least twice daily. In specific embodiments, it is administered at a dose of 50-250 mg/day. In some embodiments, it is administered at a dose of 50-150 mg twice per day.
In some embodiments, the dose of Compound I is selected to provide a concentration of compound I in the blood that reaches a point between 40 and 10,000 ng/mL over a 12 hour period from the time of administration. In some embodiments, the dosing provides a concentration of compound I in the blood that is between about 100 ng/mL and 6000 ng/mL in the treated subject. In some embodiments, dosing is selected to produce a Cmax (peak plasma level) of Compound I between 1000 ng/mL and 8,000 ng/mL.
Compound I can be administered orally, transdermally, or by injection or inhalation. In some embodiments, it is administered orally.
In another aspect, the invention provides a combination therapy for treating cancer, comprising administering Compound I to a subject who is concurrently receiving treatment with an additional therapeutic agent, or an additional cancer therapy.
In some embodiments, the additional therapeutic agent to be used along with Compound I is selected from the following group consisting of Docetaxel, Mitoxantrone, Prednisone, Estramustine, Anthracyclines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)) , Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda) and 5 fluorouracil (5 FU), Gemcitabine (Gemzar), methotrexate, Vinorelbine (Navelbine), an EGFR inhibitor such as erlotinib, Trastuzumab, Herceptin, Avastin, Platins (cisplatin, carboplatin), Temazolamide, Interferon alpha, and IL-2. In some embodiments, it is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, a platin, and a taxane.
In some embodiments, the therapeutic procedure to be used along with Compound I is selected from the group consisting of peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, immunohistochemistry staining method, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, high-dose chemotherapy and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
In some embodiments, the methods of the invention further comprise obtaining a biological sample from said subject; and analyzing the biological sample with an analytical procedure selected from the group consisting of blood chemistry analysis, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, laboratory biomarker analysis, immunohistochemistry staining method, flow'cytometry or a combination thereof. Analysis provides information that can be used to determine whether to adjust the dose of Compound I up or down, or to terminate treatment with Compound I, or to add an additional therapeutic agent or therapeutic procedure to the treatment methods using Compound I.
In some embodiments, Compound I is administered twice daily for about 28 days, and is then discontinued for at least 7 days.
The following detailed description is to aid in understanding and employing the methods of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows part of the PI3K signaling pathway associated with solid tumor activation.
FIG. 2 shows the relative levels of the alpha, beta, delta and gamma isoforms of p110 in six different cancer cell lines, along with levels of Akt and pAkt.
FIG. 3 shows the readout of a functional CEF transformation assay for the relative activity of various isoforms of p110.
FIG. 4a-b shows how Compound I, at concentrations from 0.01 uM to 10 uM, affects phosphorylation of Akt, GSKβ, and S6 in two cancer cell lines, compared to how GDC-0941, which is described as a p110alpha inhibitor affects the same phosphorylations.
FIG. 5 illustrates a reaction scheme for synthesis of Compound I.
FIG. 6 shows plasma levels of Compound I in mice that received a single oral dose of the compound, compared to plasma levels of another quinazolinone compound (Compound B) with a similar structure, to illustrate the high oral bioavailability provided by Compound I.
FIG. 7a-b shows dose-dependent inhibition of growth of tumor cell cultures for two different tumor lines.
FIG. 8 shows that Compound I at 30 mg/kg BID completely inhibited growth of a tumor xenograft over a five week period, while the corresponding xenografts in untreated control animals more than doubled in volume over the same time period.
FIG. 9 shows that Compound I at 30 mg/kg BID significantly inhibited growth of a tumor xenograft over a three week period, while the corresponding xenografts in untreated control animals expanded much more rapidly during the same time period.
FIG. 10 shows the plasma concentration profile for Compound I in the xenograft-bearing mice of FIGS. 8 and 9, when administered as a single dose of 30 mg/kg.
FIG. 11 shows the plasma concentration profiles on the first and last days of multi-day testing of compound I in healthy mice receiving 60 mg/kg, 120 mg/kg, or 240 mg/kg per day. The 60 mg/kg dose was well tolerated, demonstrating that the treatment dose (30 mg/kg BID) is both tolerated and effective in mice.
MODES OF CARRYING OUT THE INVENTION
Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted.
The discussion of the general methods given herein is intended for illustrative purposes only. Other alternative methods and embodiments will be apparent to those of skill in the art upon review of this disclosure.
A group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should also be read as “and/or” unless expressly stated otherwise. Although items, elements, or components of the invention may be described or claimed in the singular, the plural is contemplated to be within the scope thereof unless limitation to the singular is explicitly stated.
The invention provides methods that relate to a novel therapeutic method for the treatment of cancer and particularly solid tumors. The invention comprises administering to said subject a compound of formula I:
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally admixed with at least one pharmaceutically acceptable excipient.
Compound I for use in the methods described herein is optically active, meaning it consists of predominantly one of two enantiomers. The compound has a single chiral center, in the noncyclic linking group between the quinazolinone moiety and the purine moiety. The chiral center of the preferred enantiomer of the compound of Formula (I) is the S-isomer depicted above. The compound is used in optically active form, which contains predominantly the S-enantiomer. This compound may be synthesized in optically active form, or it may be prepared in racemic form (containing equal amounts of R and S isomers), and then the isomers may be separated. A chiral synthesis of Compound I that provides the S enantiomer in very high optical purity is depicted herein. See FIG. 5. While it is preferable to substantially exclude the enantiomeric R isomer from the compound of Formula (I) for purposes of the invention, the methods can be practiced with mixtures of R and S isomers, provided the S isomer is the major component of the mixture. Typically such mixture will contain no more than about 10% of the R isomer, meaning the ratio of S to R isomers is at least about 9:1, and preferably less than 5% of the R-isomer, meaning the ratio of S to R enantiomers is at least about 19:1. In some embodiments the compound used has less than 2% R enantiomer, meaning it has an enantiomeric excess of at least about 96%.
The methods of the invention utilize an optically active form of Compound I (the compound of Formula I), meaning in each instance, the compound is optically active and contains predominantly the S-enantiomer, although it may contain the R-enantiomer of Compound I as a minor component. For clarity, where a dosage of a compound of Formula I, or a dosage of Compound I is described herein, the dosage refers to the weight of the compound of Formula I, including each enantiomer that is present. Thus a dosage of 100 mg of Compound I as used herein, for example, refers to the weight of the mixture of enantiomers rather than the weight of the S-enantiomer specifically. It could, for example, refer to 100 mg of a 9:1 mixture of S and R enantiomers, which would contain about 90 mg of the S enantiomer, or to 100 mg of a 19:1 mixture of S and R enantiomers, which would contain about 95 mg of the S enantiomer.
The methods of the invention are useful to treat cancers, particularly solid tumors. In some embodiments, the cancer is a solid tumor selected from pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancers; CNS cancers; brain tumors; bone cancer; and soft tissue sarcoma. In some embodiments it is lung cancer (non-small cell lung cancer, small-cell lung cancer), colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast cancer.
The efficacy of compound I is believed to arise from its in vivo inhibition of p110β activity primarily, though it also inhibits p110δ activity. Compound I is selective for inhibition of p110β and p110δ over p110α, and is selective for these two kinases over other kinases against which it has been tested. Its selectivity is illustrated by its activity in a cellular assay of functional activity, where it inhibited p110β with an EC-50 of about 150 nM, and p110δ with an EC-50 of about 15 nM, while showing much less activity on p110α (EC-50 was above 2000 nM). Even though its activity against p110β is lower than its activity on p110δ, because p110β is the dominant isoform of p110 that is observed in solid tumors, it is believed that the activity on the delta isoform is less important to its solid tumor activity than its activity on p110β. This is also consistent with the observation that Compound I exhibits activity against tumors that express little or no p110δ (suggesting they do not rely on it), and against tumor cell lines where p110α is activated (see T47D discussion above), suggesting that high levels of the alpha isoform do not reduce sensitivity to Compound I.
Selectivity with respect to p110α is important to the safety profile of Compound I: p110α plays an essential role in insulin signaling and glucose metabolism. Nonselective PI3K inhibitors that also inhibit p110α activity are expected to cause side effects or off-target adverse effects by affecting insulin signaling and/or glucose metabolism, which do not seem to occur with Compound I. This is believed to contribute to reduction of off-target effects for Compound I.
Compound I is also selective for these PI3K isoforms over other lipid kinases, including other PI3K kinases, DNA-PK (another serine-threonine kinase), and mTOR. This table provides IC-50's for inhibition of kinase activity of these other lipid kinases:
PIKC3
2500 nM
DNA-PK
13,000 nM
mTOR
100,000 nM
Moreover, compound I has comparatively low activity on p110α in a cell-transformation system designed to measure functional activity of these kinases, but is a potent inhibitor of both p110β and p110δ in that assay. See Example 1. This chick embryo fibroblast (CEF) transformation system has been reported as a useful way to assess the functional activity of the PI3K signaling pathway. Denley, et al., “Oncogenic signaling of class I PI3K isoforms,” Oncogene, vol. 27(18), 2561-74 (2008). Transformation of CEF cells in the assay depends upon functional kinase activity. Kang, et al., Proc. Nat'l Acad. Sci. USA, vol. 103(5), 1289-94 (2006). The readout of this assay is based on the frequency of transformation of CEF cells exposed to viral vectors carrying a specific p110 isoform of interest. See FIG. 3.
In this system, an EC-50 for functional activity of p110α was not reached at the highest concentration of Compound I tested (2000 nM); the EC-50 for inhibition of functional activity of p110β by Compound I was about 150 nM; and the EC-50 for inhibition of functional activity of p110δ by Compound I was about 15 nM.
Similarly, other functional assays of inhibition of specific isoforms in cell-based tests showed compound Ito have higher activity on the delta and beta isoforms of p110 than on p110α. The p110α assay used SW3T3 cells stimulated by PDGF, and p110 kinase activity was measured by Akt phosphorylation. The p110β activity was measured by lysophosphatidic acid stimulation of Akt phosphorylation in mouse embryonic fibroblasts. The activity of p110δ was measured by anti-FcεR1 antibody cross linking stimulation of CD63 movement to the surface of basophils. Finally, the activity of p110γ was measured by fMLP stimulation of CD63 antigen movement to the cell surface of basophils. Again, compound I showed little inhibition of the alpha isoform, and was most active on the delta and beta isoforms.
Cell-based
p110α
>20,000
assay
p110β
1,200
EC50 (nM)
p110δ
FB/WB
8.4/19
p110γ
3,000/5,400
As FIG. 4 illustrates, Compound I at 10 micromolar inhibits phosphorylation of Akt, which is a downstream mediator of PI3K activation (See FIG. 1), in two cancer cell lines, T47D (breast cancer) and OVCAR-3 (ovarian cancer). It is significant to note that T47D has a mutation that activates p110α, yet compound I provides good activity against this cell line, further demonstrating that the antitumor activity of this compound most likely resides in its effect on other isoforms rather than on p110α.
Bioavailability of Compound I upon oral administration is especially good; even compared to other quinazolinones of similar structures. For example, FIG. 6 illustrates that Compound I produces higher plasma concentrations of drug than another quinazolinone compound having a similar structure (Compound B). Note that Compound I was administered orally to mice at half the dosage of Compounds B, but produced a higher peak plasma level. The degree of difference in oral bioavailability between Compound I and Compound B observed in this test is surprising.
Treatments of the invention typically involve administration of compound Ito a subject in need of treatment on a daily basis for at least one week or more than one week, often for 2-4 weeks, and sometimes for 1-3 months or more. The half-life of Compound I in vivo in mice and rats is several hours—see FIG. 6. It is thus sometimes desirable to administer compound I in multiple doses each day, in order to maintain efficacious plasma levels over a prolonged period of time. Administration may be done in two doses per day, or three doses per day, or in some embodiments, four doses per day or more, particularly when Compound I is administered orally. Alternatively, Compound I can be administered intravenously at a rate that maintains an efficacious plasma level for a prolonged period of time. Suitably, it would be administered at a rate to achieve a plasma level of at least about 1 micromolar, or at least 3 micromolar, or at least 5 micromolar. FIG. 6 shows that plasma levels of about 500 ng/mL (over 1 micromolar) can be maintained for several hours following a single oral dose of 20 mg/kg of Compound I; this demonstrates that high plasma levels of Compound I, e.g., concentrations consistent with the levels shown to be effective in functional assays, can be achieved with tolerated doses of compound I.
Compound I has been shown to induce apoptosis of a variety of solid tumor cells. FIG. 7 shows its dose-dependent inhibition of tumor cell culture growth, measured by optical density at 459 nm, for a breast cancer cell line (T47D) and an ovarian cancer cell line (OVCAR-3). It demonstrates that exposure to 5-10 micromolar levels of Compound I provides strong inhibition of growth in cell cultures.
FIG. 8 shows a dose-dependent inhibition of growth of an ovarian cancer xenograft tumor, as judged by measuring tumor volume, upon treatment with Compound I. Tumor volume actually decreased during a treatment lasting over 30 days in treated animals receiving 30 mg/kg Compound I, BID, while tumor volume more than doubled in the untreated control animals during the same time period. This demonstrates that Compound I is effective to treat a solid tumor in vivo.
Similarly, FIG. 9 shows efficacy of Compound I for treating another solid tumor xenograft (A498, a human renal cancer cell line). As the Figure shows, treatment of mice bearing A498 tumors with Compound I at 30 mg/kg BID for 20 days produced effective antitumor activity in vivo. While tumor volume approximately doubled over this time in the treated animals, it increased more than 5-fold in the untreated animals. Again, this shows compound I is effective to treat a solid tumor in vivo.
FIG. 10 shows plasma concentrations of Compound I in the mice bearing each of the tumor xenografts used for FIGS. 8 and 9, following a single oral dose of Compound I at 30 mg/kg. At this range, which was the effective dosage used in the tests shown in FIGS. 8 and 9, plasma concentration of compound I reaches about 5000-7000 ng/mL.
FIG. 11 shows the plasma concentration profiles on the first and last days of multi-day testing of compound I in healthy mice receiving 60 mg/kg, 120 mg/kg, or 240 mg/kg per day. The 60 mg/kg dose was well tolerated, demonstrating that the treatment dose (30 mg/kg BID) is both tolerated and effective in mice.
Compound I has also been tested in a battery of tumor cell assays known as the NCI panel. It demonstrated substantial growth inhibition of most of the cancer cell lines in the panel, and was generally more active on these cancer cell lines than Compound B, which was included for comparison. The following Table shows the GI-50 (concentration providing 50% growth inhibition, in μM) for each compound in these cell culture assays.
Tumor
Compound B
Compound I
Type
Cell Line
GI-50 (μM)
GI-50 (μM)
Non-
A549
50.4
20.7
Small Cell
EKVX
28.2
16.7
Lung
HOP-62
39.7
14.8
Cancer
HOP-92
34.8
0.3
NCI-H226
100
100
NCI-H23
100
100
NCI-H322M
32.2
10.5
NCI-H460
34.7
25.7
NCI-H522
52.7
51.8
Colon
COLO 205
30.1
33.8
Cancer
HCC-2998
53.3
32.4
HCT-116
54.3
37.9
HCT-15
48.4
30.3
HT29
39.1
16.5
KM12
54.1
2
SW-620
86.4
69.3
CNS
SF-268
29.8
1.89
Cancer
SF-295
8.18
1.81
SF-539
28.6
15.9
SNB-19
54.8
19.3
SNB-75
2.96
0.0594
U251
70.4
59.6
Melanoma
LOX IMVI
31.1
36.1
MALME-3M
31.6
4.58
M14
58.4
88.9
SK-MEL-2
100
100
SK-MEL-28
38.6
12.8
SK-MEL-5
32.9
31.3
UACC-257
33.5
17.4
UACC-62
4.2
1.43
Ovarian
IGROV1
3.54
2.7
OVCAR-3
15.5
0.316
OVCAR-4
100
100
OVCAR-5
40.1
27.7
OVCAR-8
96
44.6
SK-OV-3
13.8
4.02
Renal
786-0
5.48
1.99
A498
2.38
0.615
ACHN
24.4
10.7
CAKI-1
13.4
1.01
RXF 393
74.2
1.14
SN12C
11
22.5
TK-10
31.7
1.24
UO-31
5.32
2.01
Prostate
PC-3
12
0.647
DU-145
43.8
1.35
Breast
MCF7
7.08
2.54
Cancer
ADR-RES
77.9
58.6
MDA-MB-231
100
100
HS 578T
6.91
2.24
MDA-MB-435
16.4
43.1
BT-549
14.3
0.538
T-47D
3.18
0.571
MDA-MB-468
13.6
As a means of comparing the overall activity of these two compounds on diverse solid tumor cell types, the numbers of cell lines that have GI50 values of 2 micromolar or less were determined for each compound; these cell lines were considered particularly sensitive ones. Using this measure, 1.8% of cell lines were particularly sensitive to Compound B at this level, while 39% were particularly sensitive to Compound I at the same concentration. Despite structural similarity to Compound B, it is apparent that Compound I is much more active on solid tumors than compound B.
Below is a table of the number of cell lines for each type of tumor that were found to have GI50 values less than 2 micromolar for Compound I.
Tumor Type
Cell line number
% EC50 < 2 μM
NSCLC
1/9
11%
Colon
1/7
14%
CNS
3/6
50%
Melanoma
1/8
12%
Ovarian
2/6
33%
Prostrate
2/2
100%
Renal
6/8
75%
Breast
5/8
62%
In a particular embodiment, the cancer is a solid tumor such as lung cancer (non-small cell lung cancer, small-cell lung cancer), colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast cancer. As the above table indicates, breast, renal, prostate and CNS cancers are particularly sensitive to compound I, so in some embodiments, the method is used to treat a subject having any one of these cancers.
In a particular embodiment, the cancer is not a hematological cancer, e.g., it is not a lymphoma or leukemia or multiple myeloma. Exemplary solid tumors treatable by the methods disclosed herein include breast, lung, colon, ovarian, renal, and prostate cancer.
In a particular embodiment, a compound of formula I is administered in a therapeutically effective amount, to a subject diagnosed with at least one cancer disclosed as treatable by the methods herein.
The therapeutically effective amount can be determined by one of ordinary skill based on the subject's health, age, body weight, and condition. In some embodiments, the amount is normalized to the subject's body weight. For example, a dosage may be expressed as a number of milligrams of Compound I per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 100 mg/kg are often appropriate, and in some embodiments a dosage of between 0.5 and 60 mg/kg is used. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as when converting an effective dosage in a dog to a dosage suitable for a human subject.
In other embodiments, the daily dosage may be described as a total amount of Compound I administered per dose or per day. Daily dosage of Compound I is typically between about 10 mg and 1000 mg. When administered orally, the total daily dosage for a human subject is typically between about 50 mg and 750 mg.
In a particular embodiment, a compound of formula I is administered at a dose of 20-500 mg/day.
In a particular embodiment, a compound of formula I is administered at a dose of 50-250 mg/day.
In a particular embodiment, a compound of formula I is administered at a dose of 25 to 150 mg per dose, and two to four doses are administered per day (e.g., BID dosing with 25 to 150 mg doses, or TID dosing with doses between 25 and 150 mg, or QID dosing with doses between 25 and 150 mg). In a preferred embodiment, a subject is treated with 50 mg to 100 mg doses of Compound I twice per day, or 50-100 mg doses three times per day, or 50-100 mg doses four times per day.
Treatment with the compounds of the invention are frequently continued for a number of days; for example, commonly treatment would continue for at least 7 days, about 14 days, or about 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of 1-28 days, commonly 7 days or 14 days, between cycles.
In a particular embodiment, the method comprises administering to said subject an initial daily dose of 20-500 mg of a compound of formula I and increasing said dose by increments until clinical efficacy is achieved. Increments of about 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
In a particular embodiment, this method comprises continuing to treat said subject by administering the compound of formula I at a dosage where clinical efficacy is achieved for a week or more, or reducing said dose by increments to a level at which efficacy can be maintained. Efficacy can be monitored by conventional methods such as assessing tumor size or spreading (metastasis).
In a particular embodiment, the method comprises administering to said subject an initial daily dose of 20-500 mg of a compound of formula I and increasing said dose to a total dosage of 50-400 mg per day over at least 6 days. Optionally, the dosage can be further increased to about 750 mg/day.
In a particular embodiment, a compound of formula I is administered at least twice daily. In some embodiments the compound is administered three times per day. In some embodiments the compound is administered four times per day, or more than four times per day.
In a particular embodiment, the method comprises reducing the level of PI3Kβ activity in the subject.
In a particular embodiment, the subject is a human subject. Typically the subject is a human diagnosed as having a cancer disclosed herein as treatable by compound I.
In a particular embodiment, the compound is administered at a rate selected to produce a concentration of compound in the blood between about 40 ng/mL and 3,000 ng/mL, and maintaining such concentration during a 4-12 hour period following administration. In another particular embodiment, the dose size and frequency are selected to achieve a concentration of compound in the blood that is between 75-2,000 ng/mL and maintain that concentration during a 4-12 hour period from the time of administration. In some embodiments, the dose size and frequency are selected to achieve a concentration of compound in the blood that is between 100-1,000 ng/mL following administration. In some embodiments, the dose size and frequency are selected to achieve a concentration of compound in the blood that is between 100-500 ng/mL over a 12 hour period from the time of administration. Desirably, the dose size and frequency are selected to achieve a Cmax, plasma level of Compound I that is at least about 500 ng/mL and does not exceed about 10,000 ng/mL.
In certain embodiments, Compound I is administered orally, intravenously, transdermally, or by inhalation. Preferably, the compound is administered orally. In some embodiments, it is administered orally in a dose of about 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, or 100 mg, 125 mg, 150 mg, or 200 mg per dose, and the dose may be administered at a frequency of once per day, twice per day, three times per day, or four times per day.
In a particular embodiment, the method comprises administering in addition to a compound of formula Ito said subject a therapeutically effective amount of at least one additional therapeutic agent and/or a therapeutic procedure selected to treat said cancer or autoimmune disease in said subject.
In a particular embodiment, said therapeutic agent is selected from the following group consisting of Docetaxel, Mitoxantrone, Prednisone, Estramustine, Anthracyclines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda) and 5 fluorouracil (5 FU), Gemcitabine (Gemzar), methotrexate, Vinorelbine (Navelbine), an EGFR inhibitor such as erlotinib, Trastuzumab (Herceptin, this drug is only of use in women whose breast cancers have the HER-2 gene), Avastin, Platins (cisplatin, carboplatin), Temazolamide, Interferon alpha, and IL-2.
In a particular embodiment, said therapeutic agent is selected from the group consisting of an EGFR inhibitor, an mTOR inhibitor, and a taxane.
In a particular embodiment, the therapeutic procedure is selected from the group consisting of peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, immunohistochemistry staining method, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, high-dose chemotherapy and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
In a particular embodiment, the method further comprises obtaining a biological sample from said subject; and analyzing said biological sample with an analytical procedure selected from the group consisting of blood chemistry analysis, chromosomal translocation analysis, needle biopsy, fluorescence in situ hybridization, laboratory biomarker analysis, immunohistochemistry staining method, flow cytometry or a combination thereof. Analysis provides information about progression of the tumor or of the treatment, and is useful for determining dosages to administer, for adjusting dosages during a treatment cycle, and for deciding whether to continue or discontinue the treatments of the invention.
In certain embodiments, the optically active compound used in the methods described herein is enriched with the S-enantiomer shown here, and preferably it is at least 90% S-enantiomer, containing no more than about 10% of the enantiomeric R isomer:
In some embodiments, the compound of Formula I used in the methods described herein is at least 80% the S-enantiomer, containing less than 20% of its enantiomeric R-isomer In some embodiments the compound has an enantiomeric excess (e.e.) of at least 90% or at least 95% favoring the S-isomer.
In certain embodiments, the compound is primarily composed of the S-enantiomer, wherein this isomer comprises at least 66-95%, or about 85-99% of the S-isomer, in excess over any R-enantiomer present. In certain embodiments, the compound comprises at least 95% of the S-enantiomer. In the cellular and patient experiments provided in the Example section, the sample of compound I used was over 99% the S enantiomer, with less than 1% of the R enantiomer.
The term “selective PI3Kδ inhibitor” or “selective PI3Kβ inhibitor”, etc., as used herein, refers to a compound that inhibits the PI3Kδ or PI3Kβ isozyme, respectively, more effectively than at least one other isozyme of the PI3K family. The selective inhibitor may also inhibit other isozymes of PI3K, but requires higher concentrations to achieve the same degree of inhibition of the other isozymes. “Selective” can also be used to describe a compound that inhibits a particular PI3-kinase more so than a comparable compound. A “selective PI3Kδ inhibitor” compound is understood to be more selective for PI3Kδ than compounds conventionally and generically designated PI3K inhibitors, e.g., wortmannin or LY294002, which are considered non-selective PI3K inhibitors.
“Treating” as used herein refers to inhibiting a disorder, i.e., arresting its development; relieving the disorder, i.e., causing its regression; or ameliorating the disorder, i.e., reducing the severity of at least one of the symptoms associated with the disorder. In some embodiments, “treating” refers to preventing a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it. “Disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
In certain embodiments, the invention provides methods to treat a solid tumor, typically a non-hematopoietic carcinoma. In some embodiments, the cancer is a solid tumor selected from pancreatic cancer; bladder cancer; colorectal cancer; breast cancer; prostate cancer; renal cancer; hepatocellular cancer; lung cancer; ovarian cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer; melanoma; neuroendocrine cancers; CNS cancers; brain tumors; bone cancer; and soft tissue sarcoma. In some embodiments it is lung cancer (non-small cell lung cancer, small-cell lung cancer), colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast cancer. In some embodiments, the cancer is breast, lung, colon, renal, ovarian, or prostate cancer.
In certain embodiments, the invention provides methods to treat a solid tumor that is associated with abnormal or undesirable cellular signaling activity mediated by PI3Kβ. In certain embodiments, the solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma.
In one embodiment, the cancer to be treated with the methods described herein is a solid tumor that exhibits a functional loss of PTEN (phosphatase and tensin homolog, a phosphatase that acts as a tumor suppressor) activity. Loss of PTEN activity often occurs in cancers, and enhances the sensitivity of a tumor to PI3K inhibitors. The NCI panel contains a number of cell lines known to have mutations in PTEN, and 70% of those cell lines were inhibited by Compound I, and two of the ones that were not sensitive to Compound I proved to have no functional loss of PTEN activity. The following Table summarizes the cell lines found to be sensitive to Compound I and the known mutations in those cell lines. Of these mutations, only PTEN was found to be significantly correlated with efficacy of Compound I (p<0.036).
Tumor Type
CDKN2
TP53
PTEN
PI3KCA
BRAF
HRAS
SMAD4
BRCA1
Hop-92
X
X
KM12
X
X
X
SF-268
X
X
SF-295
X
X
SNB-75
X
UACC-62
X
X
X
IGROV-1
X
X
X
X
OVCAR-3
X
786-0
X
X
X
A498
X
CAKI-1
X
RXF-393
X
X
X
TK-10
X
UO-31
X
PC-3
X
X
DU-145(RB1)
X
X
MCF7
X
E545K
HS-578T
X
X
BT-549(RB1)
X
T47D
X
H1047R
50%
75%
35%
10%
5%
5%
5%
10%
Accordingly, solid tumors with significantly reduced PTEN phosphatase activity are particularly suitable for treatment with compound I. The Wellcome Trust Sanger Institute recently published information on the incidence of PTEN mutations in primary tumor tissues, indicating that breast, CNS, cervix, endometrial, kidney, ovary, prostate, skin, testis, and urinary tract tumors frequently include PTEN mutations. Accordingly, in some embodiments, the methods of the invention are used to treat a subject afflicted with one or more of these particular cancers, or a PTEN-deficient cancer selected from breast, CNS, cervix, endometrial, kidney, ovary, prostate, skin, testis, and urinary tract tumors.
In certain embodiments, the method described herein is useful in targeting cells mediating Akt phosphorylation, because compound I inhibits Akt phosphorylation as illustrated in FIG. 4.
For the treatment of a solid tumor, it is advantageous that the compound of Formula I exhibits good activity against p110β, since solid tumors often utilize this isozyme rather than or more than p110δ. Thus in some embodiments, the solid tumor is one that expresses p110β at a higher level than its level of expression of p110δ. In some embodiments, the solid tumor is one with a low level of p110δ activity, such as one expressing less than about 20% as much p110δ as p110β.
In some embodiments, the subject for treatments described herein is one who has been diagnosed with at least one of the cancers described herein as treatable by the use of a compound of Formula I. In some embodiments, the subject has been diagnosed with a cancer named herein, and has proven refractory to treatment with at least one conventional chemotherapeutic agent. Thus in one embodiment, the treatments of the invention are directed to patients who have received one or more than one such treatment and remain in need of more effective treatment.
In one embodiment, the method described herein comprises administering to a subject a compound of formula I described herein, in combination with a therapy used to treat cancer. The “therapy” used to treat cancer, as used herein, is any well-known or experimental form of treatment used to treat cancer that does not include the use of a compound of formula I. In certain embodiments, the combination of a compound of formula I with a conventional or experimental therapy used to treat cancer provides beneficial and/or desirable treatment results superior to results obtained by treatment without the combination. In certain embodiments, said therapies used to treat cancer are well-known to a person having ordinary skill in the art and are described in the literature. Therapies include, but are not limited to, chemotherapy, combinations of chemotherapy, biological therapies, immunotherapy, radioimmunotherapy, and the use of monoclonal antibodies, and vaccines. In certain embodiments, the combination method provides for a compound of formula I administered simultaneously or during the period of administration of the therapy. In certain embodiments, the combination method provides for a compound of formula I administered prior to or after the administration of the therapy. The exact details regarding the administration of the combination may be determined experimentally. The refinement of sequence and timing of administering a compound of formula I with a selected therapy will be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.
Additional therapeutic agents for combinations with Compound I include those routinely used in the treatment of solid tumors, particularly Docetaxel, Mitoxantrone, Prednisone, Estramustine, Anthracyclines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda) and 5 fluorouracil (5 FU), Gemcitabine (Gemzar), methotrexate, Vinorelbine (Navelbine), an EGFR inhibitor such as erlotinib, Trastuzumab (Herceptin, this drug is only of use in women whose breast cancers have the HER-2 gene), Avastin, Platins (cisplatin, carboplatin), Temazolamide, Interferon alpha, and IL-2.
In certain embodiments, the method comprises administering to said subject, in addition to an effective amount of compound I, at least one therapeutic agent and/or therapeutic procedure selected to treat said cancer in said subject. In certain embodiments, the method comprises administering in addition to a compound of Ito said subject, a therapeutically effective amount of an additional therapeutic agent selected from Docetaxel, Mitoxantrone, Prednisone, Estramustine, Anthracyclines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda) and 5 fluorouracil (5 FU), Gemcitabine (Gemzar), methotrexate, Vinorelbine (Navelbine), an EGFR inhibitor such as erlotinib, Trastuzumab (Herceptin, this drug is only of use in women whose breast cancers have the HER-2 gene), Avastin, Platins (cisplatin, carboplatin), Temazolamide, Interferon alpha, and IL-2.
The compounds of the invention may be formulated for administration to animal subject using commonly understood formulation techniques well known in the art. Formulations which are suitable for particular modes of administration and for the compounds of formula I may be found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, Pa.
A compound of the present invention can be administered as the neat chemical, but it is typically preferable to administer the compound in the form of a pharmaceutical composition or formulation. Accordingly, the present invention also provides pharmaceutical compositions that comprise a compound of formula I and a biocompatible pharmaceutical carrier, adjuvant, or vehicle. The composition can include the agent as the only active moiety or in combination with other agents, such as oligo- or polynucleotides, oligo- or polypeptides, drugs, or hormones mixed with excipient(s) or other pharmaceutically acceptable carriers. Carriers and other ingredients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions are formulated to contain suitable pharmaceutically acceptable carriers, and can optionally comprise excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The administration modality will generally determine the nature of the carrier. For example, formulations for parenteral administration can comprise aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration are physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For preparations comprising proteins, the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
Alternatively, formulations for parenteral use can comprise dispersions or suspensions of the active compounds prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxy-methylcellulose, sorbitol, or dextran. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT™ series available from Rohm America Inc. (Piscataway, N.J.). Emulsions, e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants). Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
Liposomes containing the active agent also can be employed for parenteral administration. Liposomes generally are derived from phospholipids or other lipid substances. The compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See,. e.g., Prescott (Ed.), METHODS IN CELL BIOLOGY, Vol. XIV, p. 33, Academic Press, New York (1976).
The pharmaceutical compositions comprising the agent in dosages suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art. The preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders. To illustrate, pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragée cores. Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or excipients, which include, without limitation:
a) diluents, such as sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
b) binders, such as magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.;
c) cellulose materials, such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof, such as sodium alginate, or effervescent compositions;
e) lubricants, such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol;
f) flavorants and sweeteners;
g) colorants or pigments, e.g., to identify the product or to characterize the quantity (dosage) of active compound; and
h) other ingredients, such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
In some preferred oral formulations, the pharmaceutical composition comprises at least one of the materials from group (a) above, or at least one material from group (b) above, or at least one material from group (c) above, or at least one material from group (d) above, or at least one material from group (e) above. Preferably, the composition comprises at least one material from each of two groups selected from groups (a)-(e) above.
Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
Dragée cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
The pharmaceutical composition can be provided as a salt of the active agent. Salts tend to be more soluble in aqueous or other protonic solvents than the corresponding free acid or base forms. Pharmaceutically acceptable salts are well known in the art. Compounds that contain acidic moieties can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include, for example, alkali metal (e.g., sodium or potassium) and alkaline earth (e.g., calcium or magnesium) cations.
Compounds of structural formula (I) that contain basic moieties can form pharmaceutically acceptable acid addition salts with suitable acids. For example, Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharm. Sci., 66:1 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorolsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate or sulfate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate or hydrogen phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include, without limitation, such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid.
Basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain alkyl halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides; and others. Products having modified solubility or dispersibility are thereby obtained.
Compositions comprising a compound of the invention formulated in a pharmaceutical acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of a compound of the invention and a label containing instructions for use of the compound. Kits are also contemplated under the invention. For example, the kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. In either case, conditions indicated on the label can include treatment of inflammatory disorders, cancer, etc.
Methods of Administration
Pharmaceutical compositions comprising a compound of formula I can be administered to the subject by any conventional method, including parenteral and enteral techniques. Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullarly, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enteral administration modalities include, for example, oral (including buccal and sublingual) and rectal administration. Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and rectal administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Parenteral administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT™.
Surgical techniques include implantation of depot (reservoir) compositions, osmotic pumps, and the like. A preferred route of administration for treatment of inflammation can be local or topical delivery for localized disorders such as arthritis, or systemic delivery for distributed disorders, e.g., intravenous delivery for reperfusion injury or for systemic conditions such as septicemia. For other diseases, including those involving the respiratory tract, e.g., chronic obstructive pulmonary disease, asthma, and emphysema, administration can be accomplished by inhalation or deep lung administration of sprays, aerosols, powders, and the like.
The compound of formula I can be administered before, during, or after administration of chemotherapy, radiotherapy, and/or surgery. The formulation and route of administration chosen will be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.
The therapeutic index of the compound of formula I can be enhanced by modifying or derivatizing the compounds for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compounds can be linked to an antibody that recognizes a marker that is selective or specific for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described (see for example, Pietersz, et al., Immunol. Rev., 129:57 (1992); Trail et al., Science, 261:212 (1993); and Rowlinson-Busza, et al., Curr. Opin. Oncol., 4:1142 (1992)). Tumor-directed delivery of these compounds enhances the therapeutic benefit by, inter alia, minimizing potential nonspecific toxicities that can result from radiation treatment or chemotherapy. In another aspect, the compound of formula I and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibody.
The characteristics of the agent itself and the formulation of the agent can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Such pharmacokinetic and pharmacodynamic information can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for any compound used in the method of the invention, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the “therapeutic index,” which typically is expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantially higher than the effective dose, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
For the methods of the invention, any effective administration regimen regulating the timing and sequence of doses can be used. Doses of the agent preferably include pharmaceutical dosage units comprising an effective amount of the agent. As used herein, “effective amount” refers to an amount sufficient to modulate PI3 Kbeta expression or activity and/or derive a measurable change in a physiological parameter of the subject through administration of one or more of the pharmaceutical dosage units. “Effective amount” can also refer to the amount required to ameliorate a disease or disorder in a subject.
Suitable dosage ranges for the compounds of formula I vary according to these considerations, but in general, the compounds are administered in the range of 10.0 μg/kg-15 mg/kg of body weight; 1.0 μg/kg-10 mg/kg of body weight, or 0.5 mg/kg-5 mg/kg of body weight. For a typical 70-kg human subject, thus, the dosage range is from 700 μg-1050 mg; 70 μg-700 mg; or 35 mg-350 mg per dose, and two or more doses may be administered per day. Dosages may be higher when the compounds are administered orally or transdermally as compared to, for example, i.v. administration. In certain embodiments, the treatment of cancers comprises oral administration of up to 750 mg/day of Compound I. The reduced toxicity of this compound permits the therapeutic administration of relatively high doses. For treatment of many solid tumors, a dosage of about 50-100 mg per dose, administered orally once or preferably at least twice per day, is often suitable. In some embodiments, compound I is administered orally, in three to five doses per day, using 20-150 mg per dose for a total daily dose between about 60 and 750 mg. In some embodiments, the total daily dose is between 100 and 500 mg, and in some embodiments the normalized daily dosage (adjusted for subject's body weight) is up to about 60 mg per kg of the treated subject's body weight.
The compounds may be administered as a single bolus dose, a dose over time, as in i.v. or transdermal administration, or in multiple dosages. For IV or transdermal delivery, a dosage may be delivered over a prolonged period of time, and may be selected or adjusted to produce a desired plasma level of the active compound. In some embodiments, the desired level will be at least about 1 micromolar, or at least about 10 micromolar.
When the compound is administered orally, it is preferably administered in two or more doses per day. In some embodiments, three doses per day are administered. In some embodiments four doses per day are administered.
Dosing may be continued for one day or for multiple days, such as about 7 days. In some embodiments, daily dosing is continued for about 14 days or about 28 days. In some embodiments, dosing is continued for about 28 days and is then discontinued for about 7 days; the efficacy of the treatment can be assessed during the break, when treatment with compound I has been stopped, and if the assessment shows that the treatment is achieving a desired effect, another 7-28 day cycle of treatment with Compound I can be initiated.
Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosage regimen will be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the agent's specific activity, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
The frequency of dosing will depend on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent. Short-acting pharmaceutical compositions (i.e., short half-life) can be administered once a day or more than once a day (e.g., two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks. Pumps, such as subcutaneous, intraperitoneal, or subdural pumps, can be preferred for continuous infusion.
Subjects that will respond favorably to the method of the invention include medical and veterinary subjects generally, including human patients. Among other subjects for whom the methods of the invention is useful are cats, dogs, large animals, avians such as chickens, and the like. In general, any subject who would benefit from a compound of formula I is appropriate for administration of the invention method.
The biological data disclosed herein was produced using a sample of Compound I that contains less than 1% of the R isomer and >99% s enantiomer, as determined by chiral HPLC using a 4.6×250 mm Chiralcel OD-H column operated at 40oC, using a flow rate of 1 mL/min of 90:10 hexanes/ethanol. This material was prepared as summarized in FIG. 9. The material was characterized by HPLC to be over 99% pure (according to both 214 nm and 254 nm UV detection), and was also characterized by nmr and electrospray mass spectroscopy. It was a white powder.
The material used in the Examples had the following characteristics:
Test
Test Result
Appearance
White powder
1H-NMR
Consistent with structure
HPLC Assay
99+%
Chiral Purity
99.2% ee (99.6:0.4 ratio of
(HPLC)
S:R isomers)
EXAMPLE 1
Chick Embryo Fibroblast Transformation Assay
Chick embryo fibroblasts (CEF) are transduced with viral stocks with versions of the human genes for the individual PI3K isoforms p110α, p110β, p110δ and p110γ. These transduced CEF lines are then plated in a growth medium where oncogenically transformed cells form foci that can then be stained and counted. Compound 1 inhibited the formation of transformed foci in CEF cells that had been transduced with p110β with an EC50 of 150 nM. In contrast Compound 1 did not inhibit CEF cells transduced with p110α significantly at the highest concentration tested (2000 nM). Denley A, Kang S, Karst U and Vogt PK, “Oncogenic signaling of class 1 PI3K isoforms.” Oncogene (2008) 27: 2561-2574. FIG. 3 illustrates the readout of this assay.
EXAMPLE 2
Preparation of Compound I
Compound I was synthesized by the route depicted in FIG. 5, using methods known in the art including adaptations of methods described in Zhichkin, et al., Organic Letters, vol. 9(7), 1415-18 (2007), and U.S. Pat. No. 6,800,620.
EXAMPLE 3
Effect of Compound I on Ovarian Cancer Cell Xenografts
Female nu/nu mice bearing OVCAR-3 xenografts (human ovarian cancer cells) were maintained until tumor volume measured about 100 mm3. At that point, treatment began with compound I at a rate of 30 mg/kg administered twice per day. Results of tumor volume measurements over a 36 day period are shown in FIG. 8, and demonstrate that not only was tumor growth inhibited, but the size of the existing tumor was actually reduced by treatment with Compound I.
EXAMPLE 4
Effect of Compound I on Renal Cancer Xenografts
Female nu/nu mice bearing A498 xenografts (human renal cancer cells) were maintained until tumor volume measured about 100 mm3. At that point, treatment began with compound I at a rate of 30 mg/kg administered twice per day. Results of tumor volume measurements over a 20 day period are shown in FIG. 9, which demonstrates that this dosing level provides a significant reduction in tumor growth in vivo.
EXAMPLE 5
Plasma Levels of Compound I in Mice Carrying Tumor Xenografts
Plasma levels of Compound I were observed in female nu/nu mice carrying one of the cancer cell xenografts used in the preceding two examples. Compound I was administered in a single dose at a rate of 30 mg/kg to each test subject, and plasma levels were monitored for 12 hours thereafter. Plasma levels of Compound I peaked around 2-4 hours after administration in each case, and had essentially returned to zero 8 hours after the single dose at this rate, as shown in FIG. 10. The peak plasma concentration for these subjects, after a single injection at the dose shown to be effective for inhibiting tumor growth of each xenograft (see the preceding examples, and FIGS. 8-9) were generally below about 7000 ng/mL.
EXAMPLE 6
Pharmacokinetics and Toxicokinetics of Compound I in Rats
Compound I was dosed at 60, 120, or 240 mg/kg/day administered as a single dose for up to 14 days in healthy rats. FIG. 11 shows the measured blood levels of Compound I over a 24-hour period for each test subject during the first day of treatment (dashed lines) and the last day of treatment (solid lines) for the tolerated doses. The peak concentration of compound I (Cmax) and area under the curve (AUC) for tolerated doses were higher than those observed with effective doses of Compound I in the xenograft model tumors in mice. For example, the 60 mg/kg per day dosing produced a Cmax of 7300 ng/mL, while the C max for effective antitumor doses in the xenograft test were 2800 and 5600 ng/mL. Similarly, the AUC for the 60 mg/kg/day dosing in this study was 58,000 ng-h/mL, while the corresponding AUC in the xenograft bearing mice receiving effective treatment doses were 15,000 and 18,000 ng-h/mL.
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12763991
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gilead calistoga llc
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/266.1
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Mar 31st, 2022 02:23PM
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Mar 31st, 2022 02:23PM
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Gilead
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Health Care
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Pharmaceuticals & Biotechnology
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nasdaq:gild
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Gilead
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Feb 23rd, 2016 12:00AM
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Apr 14th, 2015 12:00AM
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https://www.uspto.gov?id=US09266878-20160223
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Phosphatidylinositol 3-kinase inhibitors
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The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I),
or pharmaceutically acceptable salts thereof, in which R1, R2, n, R3, R4, R5 and R6 are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.
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9266878
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1. A compound having the structure of formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is unsubstituted C6-12 aryl; C6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1b, —C(O)R1b and C1-6 alkyl substituted with OH, wherein R1b is C1-6 alkyl or C1-6 haloalky; unsubstituted C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1c, —C(O)OR1c, —C(O)R1c, NH2, C1-6 haloalkyl, C1-6 alkyl, and C1-6 alkyl substituted with OH or NH2, wherein R1c is H, C1-6 alkyl, C1-6 haloalkyl, NH2, or —O(C1-6 alkyl); unsubstituted C3-12 cycloalkyl; unsubstituted C1-6 alkyl; or C1-6 alkyl substituted with OH;
n is 0, 1, 2, or 3;
each R2 is independently selected from the group, consisting of OH CN, C1-6 alkyl, C1-6 haloalkyl, and SO2R2a, wherein R2a is C1-6 alkyl;
R3 is unsubstituted C6-12 aryl; C6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, aryl, cyano, —OR3a, —C(O)NR3aR3b, —SO2R3a, —SO2NR3aR3b, alkyl substituted with NR3aR3b, wherein R3a and R3b are independently hydrogen, C1-6 alkyl, or —SO2R3c, wherein R3c is C1-6 alkyl; unsubstituted C3-12 heteroaryl 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; unsubstituted C3-12 heterocycloalkyl with 1 or 2 heteroatom independently selected from the group consisting of nitrogen, oxygen and sulfur; or C3-12 heterocycloalkyl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and substituted with 1 or 2 C1-6 alkyl substituents;
R4 is hydrogen, C1-6 alkyl, or NH2;
R5 is C1-6 alkyl substituted with OH or OR5a, wherein R5a is C1-6 alkyl; and
R6 is hydrogen, or R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a, four-, five- or six-membered heterocycle.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted cyclopentyl; unsubstituted cycloheryl; unsubstituted phenyl; phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, —OR1b, —C(O)R1b, and CH2OH, wherein R1b is methyl or trifluoromethyl; unsubstituted pyridyl; pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro —OR1c, —C(O)OR1c, —C(O)R1c, NH2, methyl, ethyl, trifluoromethyl, CHF2, CH2OH, CH(CH3)OH, and CH2NH2, wherein R1c is H, methyl, trifluoromethyl, NH2, or —OCH(CH3)2; unsubstituted pyridazinyl; unsubstituted pyrazinyl; unsubstituted pyrimidinyl; pyrimidinyl substituted with NH2; unsubstituted pyrazolyl; unsubstituted benzothiazolyl; or benzothiazolyl substituted with NH2.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently OH, CN, methyl, CF3, CHF2, or SO2CH3.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted C3-12 heterocycloalkyl with 1 or 2 heteroatom independently selected from the group consisting of nitrogen, oxygen and sulfur; or 3-12 heterocycloalkyl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and substituted with 1 or 2 C1-6 alkyl substituents; wherein the C3-12 heterocycloalkyl moiety is bicycle.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted phenyl; or phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl, phenyl, cyano, halomethyl, —OR3a, —C(O)NR3aR3b, —SO2R3a, —S(O)2NR3aR3b, methyl substituted with NR3aR3b, wherein R3a and R3b are independently hydrogen, methyl, ethyl, propyl, butyl, or —SO2R3c, wherein R3c is methyl, ethyl, propyl, or butyl.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, methyl, or NH2.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is methyl, ethyl, methyl substituted with OH or —OCH3, or ethyl substituted with OH or —OCH3.
10. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a five- or six-membered heterocycloalkyl.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is unsubstituted cyclopentyl; unsubstituted cyclohexyl; unsubstituted phenyl; phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, —OR1b, —C(O)R1b, and CH2OH, wherein R1b is methyl or trifluoromethyl; unsubstituted pyridyl; pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, —OR1c, —C(O)OR1c, —C(O)R1c, NH2, methyl, ethyl, trifluoromethyl, CHF2, CH2OH, CH(CH3)OH, and CH2NH2, wherein R1c is H, methyl, trifluomethyl, NH2, or —OCH(CH3)2; unsubstituted pyridazinyl; unsubstituted pyrazinyl; unsubstituted pyrimidinyl; pyrimidinyl substituted with NH2; unsubstituted pyrazolyl; unsubstituted benzothiazolyl; or benzothiazolyl substituted with NH2;
R2 is independently OH, CN, methyl, CF3, CHF2, or SO2CH3;
R3 is unsubstituted phenyl; or phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl, phenyl, cyano, halomethyl, —OR3a, —C(O)NR3aR3b, —SO2R3a, —S(O)2NR3aR3b, or methyl substituted with NR3aR3b; wherein R3a and R3b are independently hydrogen, methyl, ethyl, propyl, butyl, or —SO2R3c, wherein R3c is methyl, ethyl, propyl, or butyl;
R4 is hydrogen, methyl, or NH2;
R5 is methyl, ethyl, methyl substituted with OH or —OCH3, or ethyl substituted with OH or —OCH3; and
R6 is hydrogen.
13. The compound of claim 1, wherein the compound is the (R)-enantiomer.
14. The compound of claim 1, wherein the compound is the (S)-enantiomer.
15. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable vehicle.
17. A pharmaceutical composition comprising a compound of claim 15, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable vehicle.
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17
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Non-provisional patent application Ser. No. 14/137978, filed Dec. 12, 2013, now U.S. Pat. No. 9,018,221, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/745,429, filed Dec, 21, 2012, the disclosure of which are hereby incorporated by reference in their entirety.
FIELD
The present disclosure relates generally to inhibitors of phosphatidylinositol 3-kinase (PI3K) activity and, more specifically, to novel compounds that are selective inhibitors of PI3K delta activity.
BACKGROUND
Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. See generally Rameh et al., J. Biol. Chem., 274:8347-8350 (1999). The enzyme responsible for generating these phosphorylated signaling products is phosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally was identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring. See Panayotou et al., Trends Cell Biol 2:358-60 (1992).
Presently, three classes of the PI 3-kinase (PI3K) enzymes are distinguished, based on their substrate specificities. Class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, whereas Class III PI3Ks can only phosphorylate PI.
The initial purification and molecular cloning of PI 3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits. See Otsu et al., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992). Since then, four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., p110α, p110β, and p110δ, each interact with the same regulatory subunit, i.e., p85, whereas p110γ interacts with a distinct p101 regulatory subunit. As described below, the patterns of expression of each of these PI3Ks in human cells and tissues also are distinct.
Identification of the p110δ isoform of PI 3-kinase is described in Chantry et al., J. Biol. Chem., 272:19236-41 (1997). It was observed that the human p110δ isoform is expressed in a tissue-restricted fashion. It is expressed at high levels in lymphocytes and lymphoid tissues, suggesting that the protein might play a role in PI 3-kinase-mediated signaling in the immune system. Details concerning the p110δ isoform also can be found in U.S. Pat. Nos. 5,858,753; 5,822,910; and 5,985,589, each of which is incorporated herein by reference. See also Vanhaesebroeck et al., Proc. Natl. Acad. Sci. USA, 94:4330-5 (1997); and WO 97/46688.
A need remains, however, for additional therapeutic agents useful to treat proliferative disorders or diseases that are mediated by PI3K. The present invention provides novel compounds that are inhibitors of PI3K isoforms.
SUMMARY
Compounds and pharmaceutically acceptable salts thereof useful for inhibiting PI3K isoforms, such as PI3Kδ, are described herein. Compositions, including pharmaceutical compositions, and kits that include the compounds are also provided, as are methods of using and making the compounds. The compounds provided herein may find use in treating diseases, disorders, or conditions that are mediated by PI3K isoforms, such as PI3Kδ.
In one aspect, provided is a compound of Formula (I):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo or unsubstituted or substituted alkyl;
R3 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl;
R4 is hydrogen, alkyl, or NH2;
R5 is alkyl; and
R6 is hydrogen, or R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a four-, five- or six-membered heterocycle.
In another aspect, provided herein is also a compound of formula (IA):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo or unsubstituted or substituted alkyl;
R3 is unsubstituted or substituted aryl; and
R4 is hydrogen or NH2.
In yet another aspect, provided herein is also a compound of formula (TB):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo or unsubstituted or substituted alkyl;
R4 is hydrogen or NH2;
m is 0, 1 or 2; and
each R7 is independently halo, —C(O)NR3aR3b and —S(O)2NR3aR3b,
wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
In yet another aspect, provided herein is also a compound of formula (IC):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
R2a and R2b are independently hydrogen, halo or unsubstituted or substituted alkyl;
R4 is hydrogen or NH2; and
R7a and R7b are independently hydrogen, halo, —C(O)NR3aR3b and —S(O)2NR3aR3b,
wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
Provided is also a compound of formula (II):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo, OH, CN, unsubstituted or substituted alkyl, haloalkyl, or SO2R2a, wherein R2a is alkyl;
R3 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl;
R4 is hydrogen, alkyl, or NH2;
R5 is alkyl or alkyl substituted with OH or OR5a, wherein R5a is alkyl; and
R6 is hydrogen, or R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a four-, five- or six-membered heterocycle.
In yet another aspect, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof. In yet another aspect, provided is a compound selected from Table 1a, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.
Also provided is a pharmaceutical composition that includes a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, together with at least one pharmaceutically acceptable vehicle. Examples of pharmaceutically acceptable vehicle may be selected from carriers, adjuvants, and excipients.
Also provided is a method of treating a subject, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of PI3Kδ activity by administering to the subject a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof. In some embodiments, the subject is a human.
Also provided is a kit that includes a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof; and a label and/or instructions for use of the compound in the treatment of a disease or condition mediated by PI3Kδ activity.
Also provided are articles of manufacture that include a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof; and a container. In one embodiment, the container may be a vial, jar, ampoule, preloaded syringe, or an intravenous bag.
DETAILED DESCRIPTION
The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH2 is attached through the carbon atom.
Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
“Alkyl” refers to a monoradical unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl as used herein, such as in compounds of formula (I), (IA), (IB), (IC), or (II), has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed; thus, for example, “butyl” can include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” can include n-propyl and isopropyl. In some embodiments, “lower alkyl” refers to alkyl groups having 1 to 6 carbons (i.e., C1-6 alkyl).
“Cycloalkyl” refers to a cyclic alkyl group. In some embodiments, cycloalkyl as used herein, such as in compounds of formula (I), (IA), (IB), (IC), or (II), has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), or 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), or 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
“Heterocycloalkyl” refers to a cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl as used herein, such as in compounds of formula (I), (IA), (IB), (IC), or (II), has 2 to 20 ring carbon atoms (i.e., C2-20 heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocycloalkyl), or 2 to 8 ring carbon atoms (i.e., C2-8 heterocycloalkyl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. In one example, a heterocycloalkyl has 2 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyl groups may include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. The heterocycloalkyl may have one or more rings. For example, the heterocycloalkyl may be monocyclic or bicyclic.
“Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings (e.g., naphthyl, fluorenyl, and anthryl). In certain embodiments, aryl as used herein, such as in compounds of formula (I), (IA), (IB), (IC), or (II), has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), or 6 to 12 carbon ring atoms (i.e., C6-12 aryl). Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. In certain embodiments, if one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
“Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, in some embodiments, heteroaryl is an aromatic, monocyclic or bicyclic ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur with the remaining ring atoms being carbon. In certain embodiments, heteroaryl as used herein, such as in compounds of formula (I), (IA), (IB), (IC), or (II), has 3 to 20 ring carbon atoms (i.e., C3-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl) and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In one example, a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl. In one embodiment, heteroaryl is selected from 2-pyridyl, 3-pyridyl, 3-pyridazinyl, 2-pyrazinyl, benzo[d]thiazol-6-yl, and 4-pyrazolyl Heteroaryl does not encompass or overlap with aryl as defined above.
The term “substituted”, as used herein, means that any one or more hydrogen atoms on the designated atom or group is replaced with a moiety other than hydrogen, provided that the designated atom's normal valence is not exceeded.
“Substituted alkyl” refers to an alkyl group having one or more substituents including, for example, hydroxyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, cyano, halo, and carboxyl. In some embodiments, a substituted alkyl may have 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent.
“Substituted cycloalkyl” refers to a cycloalkyl group having one or more substituents including, for example, alkyl, haloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amino, cyano, halo, carboxyl, and hydroxyl. In some embodiments, a substituted cycloalkyl may have 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent.
“Substituted heterocycloalkyl” refers to a heterocycloalkyl group having one or more substituents including, for example, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, alkoxy, amino, cyano, halo, carboxyl, and hydroxyl. In some embodiments, a substituted heterocycloalkyl may have 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent. In certain embodiments, a substituted heterocycloalkyl may contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
“Substituted aryl” refers to an aryl group having one or more substituents including, for example, halo, OR, —C(O)NR2, —SO2NR2, alkyl, haloalkyl, heterocycloalkyl, heteroaryl, alkoxy, amino, cyano, and carboxyl, where each R is independently selected from hydrogen, alkyl, and haloalkyl. In some embodiments, a substituted aryl may have 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent.
“Substituted heteroaryl” refers to a heteroaryl group having one or more substituents including, for example, alkyl, haloalkyl, halo, NH2, OR, —C(O)OR, heterocycloalkyl, aryl, and cyano, where each R is independently selected from hydrogen, alkyl, and haloalkyl. In some embodiments, a substituted heteroaryl may have 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent. In certain embodiments, a substituted heteroaryl may contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
The term “halogen” or “halo” includes fluoro, chloro, bromo, and iodo, and the term “halogen” includes fluorine, chlorine, bromine, and iodine. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, and trihaloaryl refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen; thus, for example, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 4-chloro-3-fluorophenyl, and 3,5-difluoro-4-chlorophenyl is within the scope of dihaloaryl. Other examples of a haloalkyl group include difluoromethyl (—CHF2) and trifluoromethyl (—CF3). It should be understood that trifluoromethyl (—CF3) may also be referred to as perfluoromethyl.
PI3K Inhibitor Compounds
Provided herein are compounds that function as PI3Kδ inhibitors. In one aspect, provided is a compound of formula (I):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo or unsubstituted or substituted alkyl;
R3 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl;
R4 is hydrogen, alkyl, or —NH2;
R5 is alkyl; and
R6 is hydrogen, or R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a four-, five- or six-membered heterocycle.
In some embodiments of formula (I), R1 is:
unsubstituted aryl;
unsubstituted heteroaryl;
unsubstituted cycloalkyl;
aryl, heteroaryl, or cycloalkyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1a, —C(O)OR1a, —C(O)R1a, NH2, alkyl, and haloalkyl, wherein R1a is alkyl or haloalkyl;
unsubstituted alkyl; or
alkyl substituted with OH.
In certain embodiments of formula (I), R1 is:
unsubstituted C6-12 aryl;
C6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo and —OR1b, wherein R1b is C1-6 alkyl or C1-6 haloalkyl;
unsubstituted C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and sulfur;
C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and sulfur, and substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1c, C(O)OR1c, —C(O)R1c, NH2, and C1-6 haloalkyl, wherein R1c is C1-6 alkyl or C1-6 haloalkyl;
unsubstituted C3-12 cycloalkyl;
unsubstituted C1-6 alkyl; or
C1-6 alkyl substituted with OH.
In one embodiment of formula (I), R1 is substituted C1-6 alkyl. For example, the substituted C1-6 alkyl is -hydroxyethyl or hydroxy-isopropyl.
In certain embodiments of formula, R1 is:
unsubstituted phenyl;
phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro and —OR1b, wherein R1b is methyl or perfluoromethyl;
unsubstituted pyridyl;
pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, —C(O)OR1c, —C(O)R1c, NH2, perfluoromethyl, wherein R1c is methyl or perfluoromethyl;
unsubstituted pyridazinyl;
unsubstituted pyrazinyl;
unsubstituted pyrimidinyl;
pyrimidinyl substituted with NH2;
unsubstituted pyrazolyl;
unsubstituted benzothiazolyl; or
benzothiazolyl substituted with NH2.
In certain embodiments of formula (I), R1 is:
In one embodiment of formula (I), R1 is:
It is intended and understood that each and every variation of R1 may be combined with each and every variation of n and R2, R3, R4, R5 and R6 as described for formula (I), as if each and every combination is individually described.
In one embodiment of formula (I), n is 0. In other embodiments, n is 1, 2 or 3. In certain embodiments, n is 1 or 2. In one embodiment, n is 1. The R2 moiety may be located on any position of the quinazolinone ring, as depicted below.
In another embodiment, n is 2. In embodiments where n is 2, both R2 may be the same or different. Two R2 moieties may be located of any two positions of the quinazolinone ring as depicted below. For example, two R2 moieties may be in para-, meta- or ortho-positions to each other.
In yet another embodiment, n is 3. In embodiments where n is 3, all R2 may be the same or different, or two R2 may be the same and different from the third R2. Three R2 moieties may be located on any three positions of the quinazolinone ring as depicted below. For example, the first R2 may be ortho to the second R2, and the first R2 may be para to the third R2.
In some embodiments, each R2 is independently halo or unsubstituted alkyl, alkyl substituted with cyano or haloalkyl. In certain embodiments, R2 is independently fluoro, chloro, methyl, or halomethyl. In one embodiment, n is 0. In another embodiment, n is 1, wherein R2 is fluoro or chloro. In yet another embodiment, n is 2, wherein each R2 is independently fluoro or chloro.
It is intended and understood that each and every variation of n and R2 may be combined with each and every variation of R1, R3, R4, R5 and R6 as described for formula (I), as if each and every combination is individually described.
In some embodiments, R3 is:
unsubstituted C6-12 aryl; or
C6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, —C(O)NR3aR3b and —SO2NR3aR3b, wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
In certain embodiments, R3 is:
unsubstituted phenyl; or
phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, halomethyl, —C(O)NR3aR3b and —S(O)2NR3aR3b, wherein R3a and R3b are independently hydrogen, methyl or ethyl.
In certain embodiments, R3 is:
In one embodiment, R3 is:
It is intended and understood that each and every variation of R3 may be combined with each and every variation of R1, n, R2, R4, R5 and R6 as described for formula (I), as if each and every combination is individually described.
In some embodiments, R4 is R4 is hydrogen, C1-6 alkyl, or NH2. In one embodiment, R is hydrogen. In another embodiment, R4 is methyl. In yet another embodiment, R4 is NH2.
It is intended and understood that each and every variation of R4 may be combined with each and every variation of R1, n, R2, R3, R5 and R6 as described for formula (I), as if each and every combination is individually described.
In some embodiments, R5 is C1-6 alkyl. In one embodiment, R5 is methyl. In one embodiment, R6 is hydrogen. In other embodiments, R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a five- or six-membered heterocycloalkyl.
It is intended and understood that each and every variation of R5 may be combined with each and every variation of R1, n, R2, R3, R4 and R6 as described for formula (I), as if each and every combination is individually described.
In some embodiments, the compound of formula (I) is the (S)-enantiomer. In other embodiments of formula (II), the compound of formula (II) is the (R)-enantiomer. In certain embodiments, the compound has the structure of formula (I′):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R1, R2, n, R3, R4, R5 and R6 are as defined above for compounds of formula (I).
In some embodiments, the compound of formula (I) is a compound of formula (IA):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R1, R2, n, R3, and R4 are as defined above for compounds of formula (I). In some embodiments, the compound of formula (IA) is the (S)-enantiomer.
In certain embodiments of formula (IA),
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo or alkyl;
R3 is unsubstituted or substituted aryl; and
R4 is hydrogen or NH2.
In other embodiments, the compound of formula (I) is a compound of formula (IB):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1, R2, n, and R4 are as defined above for compounds of formula (I);
m is 0, 1 or 2; and
each R7 is independently halo, —C(O)NR3aR3b and —S(O)2NR3aR3b,
wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
In certain embodiments of formula (IB),
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo or unsubstituted or substituted alkyl;
R4 is hydrogen or NH2;
m is 0, 1 or 2; and
each R7 is independently halo, —C(O)NR3aR3b and —S(O)2NR3aR3b,
wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
In some embodiments, the compound of formula (IB) is the (S)-enantiomer. In some embodiments, each R7 is independently fluoro, —C(O)NH2, —S(O)2NR3aR3b, wherein R3a and R3b are independently hydrogen, methyl, or ethyl. In one embodiment, m is 0. In another embodiment, m is 1, and R7 is —C(O)NH2, —S(O)2NR3aR3b, wherein R3a and R3b are independently hydrogen, methyl, or ethyl. In yet another embodiment, m is 2, and each R7 is fluoro.
In yet other embodiments, the compound of formula (I) is a compound of formula (IC):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 and R4 are as defined above for compounds of formula (I);
R2a and R2b are independently hydrogen, halo or unsubstituted or substituted alkyl; and
R7a and R7b are independently hydrogen, halo, —C(O)NR3aR3b and —S(O)2NR3aR3b,
wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
In certain embodiments of formula (IC),
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
R2a and R2b are independently hydrogen, halo or unsubstituted or substituted alkyl;
R4 is hydrogen, alkyl, or NH2; and
R7a and R7b are independently hydrogen, halo, —C(O)NR3aR3b and —S(O)2NR3aR3b,
wherein R3a and R3b are independently hydrogen or C1-6 alkyl.
In some embodiments, the compound of formula (IC) is the (S)-enantiomer. In some embodiments, R2a and R2b are independently halo or unsubstituted alkyl, alkyl substituted with cyano or haloalkyl. In certain embodiments, R2a and R2b are independently hydrogen, fluoro, chloro, or C1-6-alkyl. In one embodiment, R2a and R2b are both fluoro or are both chloro. In another embodiment, one of R2a and R2b is hydrogen, and the other is fluoro or chloro. In yet another embodiment, one of R2a and R2b is fluoro, and the other is chloro. In yet another embodiment, one of R2a and R2b is hydrogen, and the other is methyl.
In some embodiments, R7a and R7b are independently hydrogen, fluoro, chloro, —C(O)NR3aR3b and —S(O)2NR3aR3b, and R3a and R3b are independently hydrogen, methyl or ethyl. In one embodiment, R7a and R7b are both hydrogen or are both fluoro. In another embodiment, one of R7a and R7b is hydrogen, and the other is —C(O)NH2, —S(O)2NR3aR3b, wherein R3a and R3b are independently hydrogen, methyl, or ethyl.
It should be understood that the embodiments and structures as described herein with respect to formula (I) are suitable for compounds of any formulae detailed herein, including (IA), (IB), and (IC) where applicable.
In another aspect, provided is a compound having the structure of formula (II):
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R1 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted alkyl;
n is 0, 1, 2, or 3;
each R2 is independently halo, OH, CN, unsubstituted or substituted alkyl, haloalkyl, or SO2R2a, wherein R2a is alkyl;
R3 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl;
R4 is hydrogen, alkyl, or NH2;
R5 is alkyl or alkyl substituted with OH or OR5a, wherein R5a is alkyl; and
R6 is hydrogen, or R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a four-, five- or six-membered heterocycle.
In some embodiments of formula (II), R1 is:
unsubstituted aryl;
unsubstituted heteroaryl;
unsubstituted cycloalkyl;
aryl, heteroaryl, or cycloalkyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1a, —C(O)OR1a, —C(O)R1a, NH2, alkyl, haloalkyl, and C1-6 alkyl substituted with OH or NH2, wherein R1a is H, alkyl, haloalkyl, NH2, or —O(C1-6 alkyl);
unsubstituted alkyl; or
alkyl substituted with OH.
In some embodiments of formula (II), R1 is aryl, heteroaryl, or cycloalkyl substituted with C1-6 alkyl substituted with OH or NH2, wherein R1a is H, alkyl, haloalkyl, NH2, or —O(C1-6 alkyl).
In other embodiments of formula (II), R1 is:
unsubstituted C6-12 aryl;
C6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1b, —C(O)R1b and C1-6 alkyl substituted with OH, wherein R1b is C1-6 alkyl or C1-6 haloalkyl;
unsubstituted C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and substituted with 1 or 2 substituents independently selected from the group consisting of halo, —OR1c, —C(O)OR1c, —C(O)R1c, NH2, C1-6 haloalkyl, C1-6 alkyl, and C1-6 alkyl substituted with OH or NH2, wherein R1c is H, C1-6 alkyl, C1-6 haloalkyl, NH2, or —O(C1-6 alkyl);
unsubstituted C3-12 cycloalkyl;
unsubstituted C1-6 alkyl; or
C1-6 alkyl substituted with OH.
In certain embodiments of formula (II), R is:
unsubstituted cyclopentyl;
unsubstituted cyclohexyl;
unsubstituted phenyl;
phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, —OR1b, —C(O)R1b, and CH2OH, wherein R1b is methyl or perfluoromethyl;
unsubstituted pyridyl;
pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, —OR1c, —C(O)OR1c, —C(O)R1c, NH2, methyl, ethyl, perfluoromethyl, CHF2, CH2OH, CH(CH3)OH, and CH2NH2, wherein R1c is H, methyl, perfluoromethyl, NH2, or —OCH(CH3)2;
unsubstituted pyridazinyl;
unsubstituted pyrazinyl;
unsubstituted pyrimidinyl;
pyrimidinyl substituted with NH2;
unsubstituted pyrazolyl;
unsubstituted benzothiazolyl; or
benzothiazolyl substituted with NH2.
In one embodiment of formula (II), R1 is:
It is intended and understood that each and every variation of R1 may be combined with each and every variation of n, R2, R3, R4, R5 and R6 as described for formula (II), as if each and every combination is individually described.
In one embodiment of formula (iiII), n is 0. In other embodiments, n is 1, 2 or 3. In certain embodiments, n is 1 or 2. In one embodiment, n is 1. The R2 moiety in formula (II) may be located on any position of the quinazolinone ring, as depicted above for formula (I).
In some embodiments of formula (II), each R2 is independently selected from the group consisting of halo, OH, CN, unsubstituted alkyl, alkyl substituted with cyano or haloalkyl, haloalkyl, and SO2R2a, wherein R2a is alkyl. In certain embodiments, each R2 is independently fluoro, chloro, OH, CN, methyl, CF3, CHF2, or SO2CH3. In one embodiment, each R2 is independently OH, CN, haloalkyl, or SO2R2a, wherein R2a is alkyl.
It is intended and understood that each and every variation of R2 may be combined with each and every variation of n, R1, R3, R4, R5 and R6 as described for formula (II), as if each and every combination is individually described.
In some embodiments of formula (II), R3 is:
unsubstituted C6-12 aryl;
C6-12 aryl substituted with 1 or 2 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, aryl, cyano, —OR3a, —C(O)NR3aR3b, —SO2R3a, —SO2NR3aR3b, alkyl substituted with NR3aR3b, wherein R3a and R3b are independently hydrogen, C1-6 alkyl, or —SO2R3c, wherein R3c is alkyl;
unsubstituted C3-12 heteroaryl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
unsubstituted C3-12 heterocycloalkyl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; or
C3-12 heterocycloalkyl with 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and substituted with 1 or 2 alkyl substituents.
In certain embodiments of formula (II), R3 is:
unsubstituted phenyl; or
phenyl substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl, phenyl, cyano, halomethyl, —OR3a, —C(O)NR3aR3b, —SO2R3a, —S(O)2NR3aR3b, methyl substituted with NR3aR3b, wherein R3a and R3b are independently hydrogen, methyl, ethyl, propyl, butyl, or —SO2R3c, wherein R3c is methyl, ethyl, propyl, butyl.
In one embodiment of formula (II), R3 is:
It is intended and understood that each and every variation of R3 may be combined with each and every variation of R1, n, R2, R4, R5 and R6 as described for formula (II), as if each and every combination is individually described.
In some embodiments of formula (II), R4 is hydrogen, C1-6 alkyl, or NH2. In one embodiment, R4 is hydrogen. In another embodiment, R4 is methyl. In yet another embodiment, R4 is NH2.
It is intended and understood that each and every variation of R4 may be combined with each and every variation of R1, n, R2, R3, R5 and R6 as described for formula (II), as if each and every combination is individually described.
In some embodiments of formula (II), R5 is C1-6 alkyl. In one embodiment, R5 is methyl. In one embodiment, R6 is hydrogen. In other embodiments, R5 together with the carbon to which it is attached and R6 together with the nitrogen to which it is attached are taken together to form a five- or six-membered heterocycloalkyl. In some embodiments of formula (II), R5 is alkyl substituted with OH or OR5a, wherein R5a is alkyl.
It is intended and understood that each and every variation of R5 may be combined with each and every variation of R1, n, R2, R3, R4 and R6 as described for formula (II), as if each and every combination is individually described.
In some embodiments of formula (II), the compound of formula (II) is the (S)-enantiomer. In other embodiments of formula (II), the compound of formula (II) is the (R)-enantiomer.
For compounds of the invention, including the compounds of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, bearing one or more chiral centers, each unique stereoisomer has a compound number bearing a suffix “a”, “b”, etc. As an example, Compound 1 bearing one chiral center can be resolved into its individual enantiomers 1a and 1b.
In any one of the foregoing embodiments, the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, is the (S)-enantiomer. In other embodiments. In some embodiments of formula (II), the compound of formula (II) is the (R)-enantiomer.
A composition containing a mixture of enantiomers of the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, is also provided herein. In some embodiments, the composition contains the (S)-enantiomer of the compound and is substantially free of its corresponding (R)-enantiomer. In certain embodiments, a composition substantially free of the (R)-enantiomer has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, the composition containing the (S)-enantiomer of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, predominates over its corresponding (R)-enantiomer by a molar ratio of at least or about 9:1, at least or about 19:1, at least or about 40:1, at least or about 80:1, at least or about 160:1, or at least or about 320:1.
The composition containing a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, may also contain the compound in enantiomeric excess (e.e.). For instance, a compound with 95% (S)-isomer and 5% (R)-isomer will have an e.e. of 90%. In some embodiments, the compound has an e.e. of at least or about 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%. In some of the foregoing embodiments, the compound is enantiomerically-enriched in the (S)-isomer of compound of formula (I), (IA), (IB), (IC), or (II).
Provided is also a composition comprising a mixture of the (S)-enantiomer and the (R)-enantiomer of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof. In one embodiment, the mixture is a racemic mixture. In other embodiments, the composition comprises the (S)-enantiomer of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of the compound is present in excess of over the corresponding the (R)-enantiomer of the compound, or a pharmaceutically acceptable salt thereof.
In any one of the foregoing embodiments, the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, is an atropisomer. A composition containing a mixture of atropisomers of the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt thereof, is also provided herein. “Atropisomers” refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical, i.e., they do not require a stereocenter. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted. Atropisomers are enantiomers without a single asymmetric atom. As an example, Compound 81 can be resolved into its individual atropisomers as depicted below.
Representative compounds of the invention are listed in Table 1 and Table 1a below in its non-isomeric form. The compounds in Table 1 and Table 1a are named using ChemBioDraw Ultra 12.0 and it should be understood that other names may be used to identify compounds of the same structure. Other compounds or radicals may be named with common names, or systematic or non-systematic names. The compounds may also be named using other nomenclature systems and symbols that are commonly recognized in the art of chemistry including, for example, Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC), The naming and numbering of the compounds of the present disclosure is illustrated with representative compounds of formula (I), (IA), (IB), (IC), or (II) shown in Table 1 and Table 1a below. The compounds provided in Table 1 and Table 1a may be a single enantiomer (e.g., (S)-enantiomer, (R)-enantiomer), or the compounds may be present in a composition having an enantiomeric mixture.
TABLE 1
Representative Compounds
#
Structure
Name
1
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3,5-difluorophenyl)- 5,8-difluoroquinazolin- 4(3H)-one 1a: (S)-enantiomer 1b: (R)-enantiomer
2
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-3-(3,5- difluorophenyl)-8- fluoroquinazolin-4(3H)- one 2a: (S)-enantiomer 2b: (R)-enantiomer
3
methyl 6-((4-amino- 6-((1-(5-chloro-4- oxo-3-phenyl-3,4- dihydroquinazolin- 2-yl)ethyl)amino) pyrimidin-5- yl)ethynyl)nicotinate 3a: (S)-enantiomer 3b: (R)-enantiomer
4
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5,8- difluoro-3- phenylquinazolin- 4(3H)-one 4a: (S)-enantiomer 4b: (R)-enantiomer
5
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-8- chloro-3- phenylquinazolin- 4(3H)-one 5a: (S)-enantiomer 5b: (R)-enantiomer
6
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-8-fluoro-3- phenylquinazolin- 4(3H)-one 6a: (S)-enantiomer 6b: (R)-enantiomer
7
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3,5-difluorophenyl)- 5-fluoroquinazolin- 4(3H)-one 7a: (S)-enantiomer 7b: (R)-enantiomer
8
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- fluoro-3- phenylquinazolin- 4(3H)-one 8a: (S)-enantiomer 8b: (R)-enantiomer
9
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 9a: (S)-enantiomer 9b: (R)-enantiomer
10
2-(1-((6-amino-5-((5- methoxypyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5,8- dichloro-3- phenylquinazolin- 4(3H)-one 10a: (S)-enantiomer 10b: (R)-enantiomer
11
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)- 5,8-dichloro-3- phenylquinazolin- 4(3H)-one 11a: (S)-enantiomer 11b: (R)-enantiomer
12
2-(1-((6-amino-5-((5- methoxypyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-8- fluoro-3- phenylquinazolin- 4(3H)-one 12a: (S)-enantiomer 12b: (R)-enantiomer
13
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-8- fluoro-3- phenylquinazolin- 4(3H)-one 13a: (S)-enantiomer 13b: (R)-enantiomer
14
2-(1-((6-amino-5- (pyridazin-3- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 14a: (S)-enantiomer 14b: (R)-enantiomer
15
2-(1-((6-amino-5-((6- aminopyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 15a: (S)-enantiomer 15b: (R)-enantiomer
16
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 16a: (S)-enantiomer 16b: (R)-enantiomer
17
2-(1-((6-amino-5-((6- amino-4-(trifluoro- methyl)pyridin-3- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 17a: (S)-enantiomer 17b: (R)-enantiomer
18
2-(1-((6-amino-5-((6- amino-4- (trifluoromethyl)pyridin- 3-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 18a: (S)-enantiomer 18b: (R)-enantiomer
19
2-1-((6-amino-5-(3- hydroxybut-1-yn-1- yl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 19a: (S),(R)-diastereomer 19b: (S),(S)-diastereomer
20
2-(1-((6-amino-5-(3- hydroxybut-1-yn-1- yl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 20a: (S),(R)-diastereomer 20b: (S),(S)-diastereomer
23
2-(1-((6-amino-5- (cyclopropylethynyl) pyrimidin-4- yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 23a: (S)-enantiomer 23b: (R)-enantiomer
24
2-(1-((6-amino-5-(cyclo- propylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 24a: (S)-enantiomer 24b: (R)-enantiomer
25
5-chloro-2-(1-((2,6- diamino-5-(phenyl- ethynyl)pyrimidin-4- yl)amino)ethyl)-3- phenylquinazolin- 4(3H)-one 25a: (S)-enantiomer 25b: (R)-enantiomer
26
2-(1-((6-amino-5-((4- (trifluoromethoxy) phenyl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 26a: (S)-enantiomer 26b: (R)-enantiomer
27
2-(1-((6-amino-5-((4- (trifluoromethoxy) phenyl)ethynyl)pyrimidin- 4-yl)amino)ethyl)- 5-chloro-3- phenylquinazolin- 4(3H)-one 27a: (S)-enantiomer 27b: (R)-enantiomer
28
2-(1-((6-amino-5-(3- hydroxy-3-methylbut-1- yn-1-yl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 28a: (S)-enantiomer 28b: (R)-enantiomer
29
2-(1-((6-amino-5-(3- hydroxy-3- methylbut-1-yn-1- yl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 29a: (S)-enantiomer 29b: (R)-enantiomer
30
2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- methyl-3- phenylquinazolin- 4(3H)-one 30a: (S)-enantiomer 30b: (R)-enantiomer
31
2-(1-((6-amino-5-((6- aminopyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 31a: (S)-enantiomer 31b: (R)-enantiomer
32
2-(1-((6-amino-5-((2- aminopyrimidin-5- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 32a: (S)-enantiomer 32b: (R)-enantiomer
33
2-(1-((6-amino-5-((2- aminopyrimidin-5- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 33a: (S)-enantiomer 33b: (R)-enantiomer
34
2-(1-((6-amino-5-((5- aminopyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 34a: (S)-enantiomer 34b: (R)-enantiomer
35
2-(1-((6-amino-5-((5- aminopyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 35a: (S)-enantiomer 35b: (R)-enantiomer
36
2-(1-(6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)piperidin-2-yl)-5- chloro-3- phenylquinazolin- 4(3H)-one 36a: (S)-enantiomer 36b: (R)-enantiomer
37
2-(1-(6-amino-5- (pyridin-2- ylethynyl)pyrimidin- 4-yl)pyrrolidin-2-yl)- 5-chloro-3- phenylquinazolin- 4(3H)-one 37a: (S)-enantiomer 37b: (R)-enantiomer
38
3-(2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-4-oxoquinazolin- 3(4H)-yl)benzamide 38a: (S)-enantiomer 38b: (R)-enantiomer
39
3-(2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-4- oxoquinazolin-3(4H)- yl)-N-ethyl- benzenesulfonamide 39a: (S)-enantiomer 39b: (R)-enantiomer
40
3-(2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-4-oxoquinazolin- 3(4H)- yl)benzenesulfonamide 40a: (S)-enantiomer 40b: (R)-enantiomer
41
2-(1-((6-amino-5- (pyrimidin-5- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 41a: (S)-enantiomer 41b: (R)-enantiomer
42
2-(1-((6-amino-5- (pyrimidin-5- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 42a: (S)-enantiomer 42b: (R)-enantiomer
43
2-(1-((6-amino-5- (pyridin-3- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 43a: (S)-enantiomer 43b: (R)-enantiomer
44
2-(1-((6-amino-5- (pyridin-3- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 44a: (S)-enantiomer 44b: (R)-enantiomer
45
2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 45a: (S)-enantiomer 45b: (R)-enantiomer
46
2-(1-((6-amino-5-((2- aminobenzo[d]thiazol- 6-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 46a: (S)-enantiomer 46b: (R)-enantiomer
47
2-(1-((6-amino-5-((3- fluoro-5-methoxy- phenyl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 47a: (S)-enantiomer 47b: (R)-enantiomer
48
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 48a: (S)-enantiomer 48b: (R)-enantiomer
49
2-(1-((5-((1H- pyrazol-4- yl)ethynyl)-6- aminopyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 49a: (S)-enantiomer 49b: (R)-enantiomer
50
2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 50a: (S)-enantiomer 50b: (R)-enantiomer
51
2-(1-((6-amino-5-(phenyl- ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 51a: (S)-enantiomer 51b: (R)-enantiomer
TABLE 1a
Representative Compounds
#
Structure
Name
52
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- hydroxy-3- phenylquinazolin- 4(3H)-one 52a: (S)-enantiomer 52b: (R)-enantiomer
53
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-8-methyl-3- phenylquinazolin-4(3H)- one 53a: (S)-enantiomer 53b: (R)-enantiomer
54
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- methyl-3- phenylquinazolin- 4(3H)-one 54a: (S)-enantiomer 54b: (R)-enantiomer
55
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-4-oxo-3- phenyl-3,4- dihydroquinazoline-5- carbonitrile 55a: (S)-enantiomer 55b: (R)-enantiomer
56
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-8- methyl-3- phenylquinazolin- 4(3H)-one 56a: (S)-enantiomer 56b: (R)-enantiomer
57
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-3-(3- butylphenyl)-5- chloroquinazolin-4(3H)- one 57a: (S)-enantiomer 57b: (R)-enantiomer
58
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3- (methylsulfonyl)phenyl) quinazolin-4(3H)-one 58a: (S)-enantiomer 58b: (R)-enantiomer
59
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-3-(3- (tert-butyl)phenyl)-5- chloroquinazolin-4(3H)- one 59a: (S)-enantiomer 59b: (R)-enantiomer
60
3-([1,1′-biphenyl]-3- yl)-2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloroquinazolin- 4(3H)-one 60a: (S)-enantiomer 60b: (R)-enantiomer
61
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- chloro-3-(3- ethylphenyl)quinazolin- 4(3H)-one 61a: (S)-enantiomer 61b: (R)-enantiomer
62
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-8- fluoro-5-methyl-3- phenylquinazolin- 4(3H)-one 62a: (S)-enantiomer 62b: (R)-enantiomer
63
2-(1-((6-amino-5-((3- fluoro-5- methoxyphenyl)ethynyl) pyrimidin-4- yl)amino)ethyl)-5,8- difluoro-3-phenyl- quinazolin-4(3H)-one 63a: (S)-enantiomer 63b: (R)-enantiomer
64
2-(1-((6-amino-5-((3- fluoro-5-methoxy- phenyl)ethynyl) pyrimidin-4- yl)amino)ethyl)-8- fluoro-3- phenylquinazolin- 4(3H)-one 64a: (S)-enantiomer 64b: (R)-enantiomer
65
2-(1-((6-amino-5-((3- fluoro-5- methoxyphenyl)ethynyl) pyrimidin-4- yl)amino)ethyl)-5-fluoro- 3-phenylquinazolin- 4(3H)-one 65a: (S)-enantiomer 65b: (R)-enantiomer
66
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- (difluoromethyl)-3- (3,5-difluoro- phenyl)quinazolin- 4(3H)-one 66a: (S)-enantiomer 66b: (R)-enantiomer
67
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- (difluoromethyl)-3- phenylquinazolin-4(3H)- one 67a: (S)-enantiomer 67b: (R)-enantiomer
68
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- phenyl-5-(trifluoro- methyl)quinazolin- 4(3H)-one 68a: (S)-enantiomer 68b: (R)-enantiomer
69
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-fluoro- 8-methyl-3- phenylquinazolin-4(3H)- one 69a: (S)-enantiomer 69b: (R)-enantiomer
70
3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- (difluoromethyl)-4- oxoquinazolin-3(4H)- yl)benzonitrile 70a: (S)-enantiomer 70b: (R)-enantiomer
71
3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- (difluoromethyl)-4- oxoquinazolin-3(4H)- yl)benzonitrile 71a: (S)-enantiomer 71b: (R)-enantiomer
72
3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-8- fluoro-5-methyl-4- oxoquinazolin-3(4H)- yl)benzonitrile 72a: (S)-enantiomer 72b: (R)-enantiomer
73
3-(2-(1-((6-amino-5- (pyrazin-2- ylethyny)pyrimidin-4- yl)amino)ethyl)-8-fluoro- 5-methyl-4- oxoquinazolin-3(4H)- yl)benzonitrile 73a: (S)-enantiomer 73b: (R)-enantiomer
74
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)propyl)- 5-(difluoromethyl)-3- (3,5-difluoro- phenyl)quinazolin- 4(3H)-one 74a: (S)-enantiomer 74b: (R)-enantiomer
75
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-8-fluoro- 5-methyl-3- phenylquinazolin-4(3H)- one 75a: (S)-enantiomer 75b: (R)-enantiomer
76
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- (difluoromethyl)-3- phenylquinazolin- 4(3H)-one 76a: (S)-enantiomer 76b: (R)-enantiomer
77
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5- (difluoromethyl)-3- (3,5-difluoro- phenyl)quinazolin- 4(3H)-one 77a: (S)-enantiomer 77b: (R)-enantiomer
78
5-chloro-2-(1-((2,6- diamino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3,5-difluoro- phenyl)quinazolin- 4(3H)-one 78a: (S)-enantiomer 78b: (R)-enantiomer
79
2-(1-((6-amino-5-((3- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 79a: (S)-enantiomer 79b: (R)-enantiomer
80
2-(1-((6-amino-5-((3- methoxypyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 80a: (S)-enantiomer 80b: (R)-enantiomer
81
2-(1-((6-amino-5-((3- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(3-methoxy-2- methylphenyl)quinazolin- 4(3H)-one 81a: (S)-enantiomer 81a-1 and a-2: atropisomers 81b: (R)-enantiomer 81b-1 and b-2: atropisomers
82
2-(1-((6-amino-5- ((3,5-difluoropyridin- 2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 82a: (S)-enantiomer 82b: (R)-enantiomer
83
5-chloro-2-(1-((2,6- diamino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-3- phenylquinazolin-4(3H)- one 83a: (S)-enantiomer 83b: (R)-enantiomer
84
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5- difluorophenyl)-8- fluoroquinazolin- 4(3H)-one 84a: (S)-enantiomer 84b: (R)-enantiomer
85
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 85a: (S)-enantiomer 85b: (R)-enantiomer
86
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- fluoro-3- phenylquinazolin- 4(3H)-one 86a: (S)-enantiomer 86b: (R)-enantiomer
87
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-3-(3,5- difluorophenyl)-5- fluoroquinazolin-4(3H)- one 87a: (S)-enantiomer 87b: (R)-enantiomer
89
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(3- chlorophenyl)quinazolin- 4(3H)-one 89a: (S)-enantiomer 89b: (R)-enantiomer
90
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-6- fluoro-3- phenylquinazolin- 4(3H)-one 90a: (S)-enantiomer 90b: (R)-enantiomer
91
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-6-fluoro- 3-phenylquinazolin- 4(3H)-one 91a: (S)-enantiomer 91b: (R)-enantiomer
92
3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-4- oxoquinazolin-3(4H)- yl)benzonitrile 92a: (S)-enantiomer 92b: (R)-enantiomer
93
3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 4-oxoquinazolin-3(4H)- yl)benzonitrile 93a: (S)-enantiomer 93b: (R)-enantiomer
94
3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-6- fluoro-4- oxoquinazolin-3(4H)- yl)benzonitrile 94a: (S)-enantiomer 94b: (R)-enantiomer
95
3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-6-fluoro- 4-oxoquinazolin-3(4H)- yl)benzonitrile 95a: (S)-enantiomer 95b: (R)-enantiomer
96
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3-chlorophenyl)-6- fluoroquinazolin- 4(3H)-one 96a: (S)-enantiomer 96b: (R)-enantiomer
97
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-3-(3- chlorophenyl)-6- fluoroquinazolin-4(3H)- one 97a: (S)-enantiomer 97b: (R)-enantiomer
98
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- methyl-3- phenylquinazolin- 4(3H)-one 98a: (S)-enantiomer 98b: (R)-enantiomer
99
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-fluoro- 3-(3- fluorophenyl)quinazolin- 4(3H)-one 99a: (S)-enantiomer 99b: (R)-enantiomer
100
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3,5-difluorophenyl)- 8-fluoroquinazolin- 4(3H)-one 100a: (S)-enantiomer 100b: (R)-enantiomer
101
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-fluoro- 3-(3- fluorophenyl)quinazolin- 4(3H)-one 101a: (S)-enantiomer 101b: (R)-enantiomer
102
2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 102a: (S)-enantiomer 102b: (R)-enantiomer
103
2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 103a: (S)-enantiomer 103b: (R)-enantiomer
104
2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- methyl-3- phenylquinazolin- 4(3H)-one 104a: (S)-enantiomer 104b: (R)-enantiomer
105
2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-3-(3,5- difluorophenyl)-5- methylquinazolin-4(3H)- one 105a: (S)-enantiomer 105b: (R)-enantiomer
106
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3-fluorophenyl)-5- methylquinazolin- 4(3H)-one 106a: (S)-enantiomer 106b: (R)-enantiomer
107
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)propyl)-3-(3,5- difluorophenyl)-5- fluoroquinazolin-4(3H)- one 107a: (S)-enantiomer 107b: (R)-enantiomer
108
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)propyl)- 3-(3,5- difluorophenyl)-5- methylquinazolin- 4(3H)-one 108a: (S)-enantiomer 108b: (R)-enantiomer
109
2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-fluoro- 3-phenylquinazolin- 4(3H)-one 109a: (S)-enantiomer 109b: (R)-enantiomer
110
3-(2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- fluoro-4- oxoquinazolin-3(4H)- yl)benzonitrile 110a: (S)-enantiomer 110b: (R)-enantiomer
111
2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- fluoro-3-(3- fluorophenyl)quinazolin- 4(3H)-one 111a: (S)-enantiomer 111b: (R)-enantiomer
112
2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- (methylsulfonyl)-3- phenylquinazolin- 4(3H)-one 112a: (S)-enantiomer 112b: (R)-enantiomer
113
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- (methylsulfonyl)-3- phenylquinazolin-4(3H)- one 113a: (S)-enantiomer 113b: (R)-enantiomer
114
2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-4- oxo-3-phenyl-3,4- dihydroquinazoline- 5-carbonitrile 114a: (S)-enantiomer 114b: (R)-enantiomer
115
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-fluoro- 3-(pyridin-3- yl)quinazolin-4(3H)-one 115a: (S)-enantiomer 115b: (R)-enantiomer
116
2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- fluoro-3-(pyridin-3- yl)quinazolin-4(3H)- one 116a: (S)-enantiomer 116b: (R)-enantiomer
117
2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(pyridin-3- yl)quinazolin-4(3H)-one 117a: (S)-enantiomer 117b: (R)-enantiomer
118
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(pyridin-3- yl)quinazolin-4(3H)- one 118a: (S)-enantiomer 118b: (R)-enantiomer
119
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5- methyl-3-(pyridin-3- yl)quinazolin-4(3H)-one 119a: (S)-enantiomer 119b: (R)-enantiomer
120
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (5-fluoropyridin-3- yl)-5- methylquinazolin- 4(3H)-one 120a: (S)-enantiomer 120b: (R)-enantiomer
121
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-morpholinoquinazolin- 4(3H)-one 121a: (S)-enantiomer 121b: (R)-enantiomer
122
2-(1-((6-amino-5-((3- fluoro-5-methoxy- phenyl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- morpholinoquinazolin- 4(3H)-one 122a: (S)-enantiomer 122b: (R)-enantiomer
123
N-(3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 4-oxoquinazolin-3(4H)- yl)benzyl)methane- sulfonamide 123a: (S)-enantiomer 123b: (R)-enantiomer
124
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-((1R,5S)-8- methyl-8- azabicyclo[3.2.1]octan- 3-yl)quinazolin- 4(3H)-one 124a: (S)-enantiomer 124b: (R)-enantiomer
125
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-((1R,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3- yl)quinazolin-4(3H)-one 125a: (S)-enantiomer 125b: (R)-enantiomer
126
2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (azepan-1-yl)-5- chloroquinazolin- 4(3H)-one 126a: (S)-enantiomer 126b: (R)-enantiomer
127
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(piperazin-1- yl)quinazolin-4(3H)-one 127a: (S)-enantiomer 127b: (R)-enantiomer
128
N-(3-(2-(1-((6- amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- methyl-4- oxoquinazolin-3(4H)- yl)benzyl)-N-methyl- methanesulfonamide 128a: (S)-enantiomer 128b: (R)-enantiomer
129
(S)-N-(3-(2-(1-((6- amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)(methyl)amino)ethyl)- 5-chloro-4- oxoquinazolin-3(4H)- yl)benzyl)-N-methyl- methanesulfonamide 129a: (S)-enantiomer 129b: (R)-enantiomer
130
N-(3-(2-(1-((6- amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-4-oxoquinazolin- 3(4H)-yl)benzyl) methanesulfonamide 130a: (S)-enantiomer 130b: (R)-enantiomer
131
N-(3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 4-oxoquinazolin-3(4H)- yl)benzyl)-2- methylpropane-1- sulfonamide 131a: (S)-enantiomer 131b: (R)-enantiomer
132
2-(1-((6-amino-5-((5- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 132a: (S)-enantiomer 132b: (R)-enantiomer
133
2-(1-((6-amino-5-((5- methylpyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 133a: (S)-enantiomer 133b: (R)-enantiomer
134
2-(1-((6-amino-5-((5- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 134a: (S)-enantiomer 134b: (R)-enantiomer
135
6-((4-amino-6-((1-(5- chloro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)nicotinamide 135a: (S)-enantiomer 135b: (R)-enantiomer
136
6-((4-amino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4- oxo-3,4-dihydro- quinazolin-2-yl)ethyl) amino)pyrimidin-5- yl)ethynyl)nicotinamide 136a: (S)-enantiomer 136b: (R)-enantiomer
137
isopropyl 6-((4-amino-6- ((1-(5-chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)nicotinate 137a: (S)-enantiomer 137b: (R)-enantiomer
138
6-((4-amino-6-((1-(5- chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)nicotinic acid 138a: (S)-enantiomer 138b: (R)-enantiomer
139
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)-2- hydroxyethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 139a: (S)-enantiomer 139b: (R)-enantiomer
140
2-(1-((6-amino-5-((5- fluoro-6- methylpyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 140a: (S)-enantiomer 140b: (R)-enantiomer
141
2-(1-((6-amino-5-((6- methylpyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 141a: (S)-enantiomer 141b: (R)-enantiomer
142
2-(1-((6-amino-5-((3- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 142a: (S)-enantiomer 142b: (R)-enantiomer
143
2-(1-((6-amino-5-((3- methylpyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 143a: (S)-enantiomer 143b: (R)-enantiomer
144
2-(1-((6-amino-5- (cyclopentylethynyl) pyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 144a: (S)-enantiomer 144b: (R)-enantiomer
145
2-(1-((6-amino-5- (cyclohexylethynyl) pyrimidin-4-yl)amino) ethyl)-5-chloro-3- phenylquinazolin-4(3H)- one 145a: (S)-enantiomer 145b: (R)-enantiomer
146
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)-2- methoxyethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 146a: (S)-enantiomer 146b: (R)-enantiomer
147
2-(1-((6-amino-5-((4- methylpyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 147a: (S)-enantiomer 147b: (R)-enantiomer
148
2-(1-((6-amino-5-((4- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 148a: (S)-enantiomer 148b: (R)-enantiomer
149
2-(1-((6-amino-5-((4- (difluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 149a: (S)-enantiomer 149b: (R)-enantiomer
150
2-(1-((6-amino-5-((4- ethylpyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 150a: (S)-enantiomer 150b: (R)-enantiomer
151
2-(1-((6-amino-5-((6- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 151a: (S)-enantiomer 151b: (R)-enantiomer
152
2-(1-((5-((3- acetylpyridin-2- yl)ethynyl)-6- aminopyrimidin-4- yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 152a: (S)-enantiomer 152b: (R)-enantiomer
153
2-(1-((5-((6- acetylpyridin-2- yl)ethynyl)-6- aminopyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 153a: (S)-enantiomer 153b: (R)-enantiomer
154
2-(1-((6-amino-5-((4- (hydroxymethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 154a: (S)-enantiomer 154b: (R)-enantiomer
155
2-(1-((6-amino-5-((6- (hydroxymethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 155a: (S)-enantiomer 155b: (R)-enantiomer
156
2-((4-amino-6-((1-(5- chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2- yl)ethyl)amino) pyrimidin-5-yl) ethynyl)isonicotinamide 156a: (S)-enantiomer 156b: (R)-enantiomer
157
2-(1-((6-amino-5-((6-(1- hydroxyethyl)pyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 157a: (S)-enantiomer 157b: (R)-enantiomer
158
methyl 2-((4-amino- 6-((1-(5-chloro-4- oxo-3-phenyl-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)isonicotinate 158a: (S)-enantiomer 158b: (R)-enantiomer
159
2-(1-((6-amino-5-((6- (aminomethyl)pyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 159a: (S)-enantiomer 159b: (R)-enantiomer
160
2-((4-amino-6-((1-(5- chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)isonicotinic acid 160a: (S)-enantiomer 160b: (R)-enantiomer
161
2-(1-((5-((3- acetylphenyl)ethynyl)-6- aminopyrimidin-4- yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 161a: (S)-enantiomer 161b: (R)-enantiomer
162
2-(1-((6-amino-5-((3- (hydroxymethyl)phenyl) ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 162a: (S)-enantiomer 162b: (R)-enantiomer
163
2-(1-((6-amino-5-((3- (hydroxymethyl)pyridin- 2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 163a: (S)-enantiomer 163b: (R)-enantiomer
164
2-(1-((6-amino-5-((5- methylpyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 164a: (S)-enantiomer 164b: (R)-enantiomer
165
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(3- ((methylamino)methyl) phenyl)quinazolin- 4(3H)-one 165a: (S)-enantiomer 165b: (R)-enantiomer
166
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (azetidin-3-yl)-5- chloroquinazolin- 4(3H)-one 166a: (S)-enantiomer 166b: (R)-enantiomer
167
2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro- 3-(tetrahydro-2H-pyran- 4-yl)quinazolin-4(3H)- one 167a: (S)-enantiomer 167b: (R)-enantiomer
Provided are also compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof, when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds of formula (I), (IA), (IB), (IC), or (II).
“Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.
A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds of formula (I), (IA), (IB), (IC), or (II) are also provided. Hydrates of the compounds of formula (I), (IA), (IB), (IC), or (II) are also provided.
A “prodrug” includes any compound that becomes a compound of formula (I), (IA), (IB), (IC), or (II) when administered to a subject, e.g., upon metabolic processing of the prodrug.
In certain embodiments, provided are optical isomers, racemates, or other mixtures thereof, of the compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof. In those situations, the single enantiomer or diastereomer, i.e., optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column. In addition, provided are also Z- and E-forms (or cis- and trans-forms) of the compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof with carbon-carbon double bonds. Provided are also all tautomeric forms of the compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof.
Compositions provided herein that include a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.
In certain embodiments, provided herein are also crystalline and amorphous forms of the compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof.
In certain embodiments, provided are also chelates, non-covalent complexes, and mixtures thereof, of the compounds of formula (I), (IA), (IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, or solvates thereof. A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
Therapeutic Uses of the Compounds
The compounds of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof may be used for the treatment of diseases and/or conditions mediated by PI3K isomers, such as PI3Kδ. Thus, provided herein are methods for inhibiting one or more PI3K isomers. In one embodiment, provided are methods for inhibiting PI3Kδ activity using a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof. The PI3K isomers may be selectively or specifically inhibited. Additionally, the compounds may be used to inhibit MK activity therapeutically or prophylactically.
In some embodiments, the methods include administering a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, in a therapeutically effective amount to a subject (including a human) in need thereof. The method can be employed to treat a subject who has or is believed to have a disease or condition whose symptoms or pathology is mediated by PI3Kδ expression or activity.
“Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following:
a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition);
b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or
c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
“Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
“Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
The term “therapeutically effective amount” of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of PI3Kδ activity. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
The term “inhibition” indicates a decrease in the baseline activity of a biological activity or process. “Inhibition of activity of PI3K isomers” or variants thereof refer to a decrease in activity in any PI3K isomer (e.g., alpha, beta, gamma, or delta) as a direct or indirect response to the presence of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvent thereof, relative to the activity of PI3K isomer in the absence of the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvent thereof. “Inhibition of PI3Kδ activity” or variants thereof refer to a decrease in PI3Kδ activity as a direct or indirect response to the presence of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, relative to the activity of PI3Kδ in the absence of the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof. In some embodiments, the inhibition of PI3Kδ activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
Without wishing to be bound to any theory, the decrease in PI3Kδ activity may be due to the direct interaction of the compound with PI3Kδ, or due to the interaction of the compounds described herein with one or more other factors that in turn affect PI3Kδ activity. For example, the presence of the compounds of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, may decrease PI3Kδ activity by directly binding to the PI3Kδ, by causing (directly or indirectly) another factor to decrease PI3Kδ activity, or by (directly or indirectly) decreasing the amount of PI3Kδ present in the cell or organism.
The terms “PI3K isoform selective inhibitor” generally refers to a compound that inhibits the activity of one or more PI3K isoforms more effectively than the other remaining PI3K isoforms. By way of example, the term “PI3Kδ selective inhibitor” generally refers to a compound that inhibits the activity of the PI3Kδ isoform more effectively than other isoforms of the PI3K family (e.g., PI3K α, β, or γ).
The relative efficacies of compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. In one embodiment, the efficacy of a compound as an inhibitor of one or more PI3K isoforms can be measured by the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or “IC50”. IC50 determinations can be accomplished using conventional techniques known in the art, including the techniques describes in the Examples below. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the compound under study. The experimentally obtained values of enzyme activity may then be plotted against the compound concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC50 value. Analogously, other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it may be desirable to establish a 90% inhibitory concentration, i.e., IC90.
In one embodiment, a PI3Kδ selective inhibitor is a compound that exhibits a 50% inhibitory concentration (IC50) with respect to PI3Kδ that is at least 10-fold, in another aspect at least 20-fold, and in another aspect at least 30-fold, lower than the IC50 value with respect to any or all of the other Class I PI3K family members. In another embodiment, a PI3Kδ selective inhibitor is a compound that exhibits an IC50 with respect to PI3Kδ that is at least 50-fold, in another aspect at least 100-fold, in an additional aspect at least 200-fold, and in yet another aspect at least 500-fold, lower than the IC50 with respect to any or all of the other PI3K Class I family members. A PI3Kδ selective inhibitor is typically administered in an amount such that it selectively inhibits PI3Kδ activity, as described above.
The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention may be used ex vivo to determine the optimal schedule and/or dosing of administration of a PI3Kδ selective inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art. The selected compounds of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
Compared to other PI3K isoforms, PI3Kδ is generally expressed in hematopoietic cells. Consequently, the direct effects of selective inhibitors of PI3Kδ can be observed in hematopoietic cells. Hematopoietic cells typically differentiate into either lymphoid progenitor cells or myeloid progenitor cells, both of which ultimately differentiate into various mature cell types including leukocytes. Aberrant proliferation of hematopoietic cells of one type often interferes with the production or survival of other hematopoietic cell types, which can result in compromised immunity, anemia, and/or thrombocytopenia. The methods described herein may treat aberrant proliferation of hematopoietic cells by inhibiting aberrant proliferation of hematopoietic cells. As a result, these methods may also ameliorate the symptoms and secondary conditions that result from a primary effect such as excessive system or localized levels of leukocytes or lymphocytes.
In some embodiments, the compounds described herein may be used to treat subjects having various disease states, disorders, and conditions (also collectively referred to as “indications”) involving aberrant proliferation of hematopoietic cells (including excessive production of lymphoid progenitor cell-derived cells and/or myeloid progenitor cell-derived cells). Such indications may include, for example, leukemias, lymphomas, myeloproliferative disorders, myelodysplastic syndromes, and plasma cell neoplasms. In certain embodiments, the compounds described herein may be used to treat hematologic malignancies, inflammation, autoimmune disorders, allergic conditions, cardiovascular disease, and autoimmune diseases. In certain embodiments, allergic conditions may include all forms of hypersensitivity.
In other embodiments, the compounds described herein may be used to treat cancers that are mediated by, dependent on or associated with PI3K activity, such as PI3Kδ activity. In certain embodiments, the disease is a hematologic malignancy. In certain embodiments, the disease is lymphoma, multiple myeloma, or leukemia. In particular embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the disease is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), Hodgkin lymphoma, indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic lymphoma, marginal zone lymphoma, or Burkitt lymphoma. In one embodiment, the disease is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). It should be understood that the non-Hodgkin lymphoma may, in certain embodiments, encompass the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
In other embodiments, the disease is a solid tumor. In particular embodiments, the solid tumor is from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.
In some embodiments, the disease is an autoimmune disease. In particular embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD). In other embodiments, the disease is inflammation. In yet other embodiments, the disease is excessive or destructive immune reactions, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.
Provided is a method for treating a subject, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of PI3Kδ activity by administering to the subject a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.
Provided is also a method of inhibiting kinase activity of a phosphatidylinositol 3-kinase delta polypeptide by contacting the polypeptide with a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof. Also provided is a method for increasing sensitivity of cancer cells to chemotherapy, comprising administering to a patient undergoing chemotherapy with a chemotherapeutic agent an amount a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, sufficient to increase the sensitivity of cancer cells to the chemotherapeutic agent. In some embodiments, the cancers cells are of hematopoietic origin.
Combination Therapies
In one embodiment, the compounds of the present application (e.g., a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof) may be used in combination with one or more additional therapeutic agent that are being used and/or developed to treat cancers or inflammatory disorders. The one or more additional therapeutic agent may be an inhibitor to PI3K such as PI3Kγ, PI3Kβ, and/or PI3Kα, Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3, spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1, serine/threonine kinase TPL2, discoidin domain receptor (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), or any combination thereof.
One, two, three, or more of the therapeutic agents (e.g. a PI3K inhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4 inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDH inhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBK inhibitor, a HDAC inhibitor, a PKC inhibitor) may be further used or combined with a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.
As used herein the term “chemotherapeutic agent” or “chemotherapeutic” (or “chemotherapy,” in the case of treatment with a chemotherapeutic agent) may encompass any non-proteinaceous (e.g., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin phiI1, see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL®, Bristol Meyers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent are used or included in the present application. For example, gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAK inhibitor and/or PI3Kδ inhibitor for treating hyperproliferative disorders.
Chemotherapeutic agents may also include, for example, anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston®); inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole (Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®.); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor-1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide; angiostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors” (1999) Nature Medicine 5:1359-1364.
The anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct. 23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled “Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate,” relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled “Inhibitors of lysyl oxidase,” relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g., U.S. Pat. Nos. 5,021,456; 5,5059,714; 5,120,764; 5,182,297; 5,252,608 (relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent Application No. 2004/0248871, which are herein incorporated by reference. Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate.
The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine 1-131.
The application also provides a method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.
In certain embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).
In certain embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.
Examples of immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient's tumor, such as lymphoma vaccine example is GTOP-99 (MyVax®).
Examples of chemotherapy agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin, Temsirolimus (CC1-779), Thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (R-MCP).
The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine 1-131. Examples of combination therapies include, but are not limited to, Iodine-131 tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.
Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
Kits
Provided herein are also kits that include a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
Provided herein are also articles of manufacture that include a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
Pharmaceutical Compositions and Administration
Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provides herein are also pharmaceutical compositions that contain one or more of the compounds of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).
The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. In certain embodiments, the compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, is administered intraveneously, intramuscularly, parenterally, nasally or orally.
One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions that include at least one compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
Exemplary unit dosage levels of a compound of formula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, for a human subject may, in certain variations, be between about 0.01 mg to about 1000 mg, between about 1 mg to about 15 mg, or between about 50 mg to about 200 mg, or about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg, or about 175 mg, about 200 mg, or about 250 mg.
The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
Dosing
The specific dose level of a compound of formula (I), (IA), (IB), (IC), or (II), for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound of formula (I), (IA), (IB), (IC), or (II) per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
The daily dosage may also be described as a total amount of a compound of formula (I), (IA), (IB), (IC), or (II) administered per dose or per day. Daily dosage of a compound of formula (I), (IA), (IB), (IC), or (II) may be between about 1 mg/day and 4,000 mg/day, between about 2,000 mg/day to 4,000 mg/day, between about 1 mg/day to 2,000 mg/day, between about 1 mg/day to 1,000 mg/day, between about 10 mg/day to 500 mg/day, between about 20 mg/day to 500 mg/day, between about 50 mg/day to 300 mg/day, between about 75 mg/day to 200 mg/day, between about 15 mg/day to 150 mg/day, or between 1 mg/day and 15 mg/day.
When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
The compounds of formula (I), (IA), (IB), (IC), or (II) or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds formula (I), (IA), (IB), (IC), or (II) may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 500 mg of a compound of formula (I), (IA), (IB), (IC), or (II) and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
Synthesis of the Compounds of Formula (I), (IA), (IB), (IC) or (II)
The compounds of formula (I), (IA), (IB), (IC) or (II) may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
General Synthesis
Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.
Synthetic Reaction Parameters
The terms “solvent”, “inert organic solvent”, or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
The term “q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
Compounds of Formula I or II
One method of preparing compounds of formula (I) is shown in Reaction Scheme I.
It should be understood that Reaction Scheme I depicted above and described in further detail below may also be used to synthesize compounds of formula (II).
Step 1—Preparation of a Compound of Formula (1)
The compound of formula (1) can be made by combining compounds (A), (B) and (C) in the presence of a dehydrating agent in a solvent. Compounds (A), (B) and (C) are commercially available. With respect to compound (A), R2 is as defined herein. With respect to compound (B), R5 is as defined herein. With respect to compound (C), R3 is as defined herein. Compound (A) can be mixed with Compound (B) in the presence of a coupling agent such as diphenyl phosphite in a solvent such as pyridine. After stirring at a temperature between ambient and 100° C. for between 1 and 5 hours, compound (C) is added. After further stirring at a temperature between ambient and 100° C. for between 5 and 24 hours, the reaction mixture is allowed to cool to room temperature. To extract the compound of formula (1), an organic solvent such as ethyl acetate (EtOAc) may be added, followed by washing with, mild acid, water, and brine. The organic phase can be concentrated to obtain the compound of formula (1). The compound of formula (1) may be purified by any suitable methods known in the art, such as chromatography on silica gel. Alternatively, the compound of formula (1) may be used in the next step without purification.
Step 2—Preparation of a Compound of Formula (2)
The compound of formula (2) can be made by removing the protecting group from the compound of formula (1). The compound of formula (1) is dissolved in a suitable solvent and treated with a suitable acid. Suitable solvents may include, for example, dichloromethane, dioxane, or mixtures thereof. Suitable acids may include, for example, trifluoroacetic acid or hydrochloric acid. The reaction can be carried out temperatures between −20° C. to ambient temperature. On reaction completion, solvent is removed to obtain the compound of formula (2).
Step 3—Preparation of Compound (3)
Compound (3) can be made by performing a Sonogashira coupling of commercially available trimethylsilylalkyne (TMS-alkyne; compound (C)) and 4-amino-6-chloro-5-iodopyrimidine (compound (D)). This type of reaction generally uses a palladium catalyst, a copper catalyst and a base to form a carbon-carbon bond between the terminal alkyne of compound (C) and the heteroaryl halide (i.e., compound (D)). An example of a suitable palladium catalyst is Pd(PPh3)4. An example of a suitable copper catalyst is CuI. An example of a suitable base is triethylamine (TEA). The coupling reaction may also be performed in the presence of a solvent. An example of a suitable solvent is N-methylpyrrolidone (NMP). The coupling reaction may be performed at elevated temperatures, for example, between 80° C. and 100° C. for about 30 minutes to 24 hours. The reaction can be quenched by addition of water, and the reaction mixture can be extracted with a suitable solvent such as ethyl acetate (EtOAc). The organic layer can be isolated, dried (e.g., using Na2SO4), and concentrated. The residue can then be purified using any suitable methods known in the art, for example, on a silica column, to yield compound (3). The residue may also be used crude, without purification, in the next step.
Step 4—Preparation of a Compound of Formula (4)
The compound of formula (4) can be made by a second Sonogashira coupling between compound (3) and compound (E) having the formula R1—X, where R1 is as defined herein, and X is halo. The conditions for this second Sonogashira coupling is similar to the first coupling discussed above; however, this reaction further involves the use of a reagent to remove the TMS protecting group. Such a suitable reagent is tetra-n-butylammonium fluoride (TBAF). Similar to the first Sonogashira coupling, this reaction generally uses a palladium catalyst, a copper catalyst and a base. An example of a suitable palladium catalyst is Pd(PPh3)4. An example of a suitable copper catalyst is CuI. An example of a suitable base is triethylamine (TEA). The coupling reaction may also be performed in the presence of a solvent. An example of a suitable solvent is N-methylpyrrolidone (NMP). This coupling reaction may be performed at elevated temperatures, for example, between 80° C. to 100° C. for about 1 to 24 hours. The reaction is quenched by addition of water, and the reaction mixture can be extracted with a suitable solvent such as ethyl acetate (EtOAc). The organic layer can be isolated, dried (e.g., using Na2SO4), and concentrated. The residue can then be purified using any suitable methods known in the art, for example, on a silica column, to yield a compound of formula (4). The residue may also be used crude, without purification, in the next step.
Step 5—Preparation of a Compound of Formula (I)
The compound of formula (I) can generally be prepared by coupling compound of formula (2) and compound of formula (4) in the presence of a suitable base in a suitable solvent. An example of a suitable base is diisopropylethylamine. An example of a suitable solvent is N-methylpyrrolidone (NMP). The reaction is typically performed at a temperature between 50° C. to 150° C. for about 30 minutes to 24 hours. Alternatively the reaction can be performed in a microwave at a temperature between 100° C. to 150° C. for about 30 minutes to 24 hours. Water can be added to quench the reaction upon completion, and the precipitate may be filtered and then dissolved in an organic solvent such as dichloromethane (DCM). The product can be isolated by methods known in the art, for example by removal of solvent under reduced pressure. The product can be purified using any suitable methods known in the art, for example, chromatography of the residue on a silica column.
Alternative Preparation
Another method of preparing compounds of formula (I) or (II) is shown in Reaction Scheme II.
It should be understood that Reaction Scheme II depicted above and described in further detail below may also be used to synthesize compounds of formula (II).
The compound of formula (I) may also be prepared by coupling a compound of formula (6) with commercially available compound of formula (G). The compound of formula (6) may be prepared in a manner similar to that described above for a compound of formula (1), by reacting a compound of formula (2) with an appropriately-substituted 4-chloro-6-aminopyrimidine. Compound (G) has a structure of formula R1—C≡C, where R1 is as defined herein.
The coupling reaction is performed in the presence of a palladium catalyst, a copper catalyst and a base to form a carbon-carbon bond between the terminal alkyne of Compound (G) and the compound of formula (6). An example of a suitable palladium catalyst is Pd(PPh3)2Cl2. An example of a suitable copper catalyst is CuI. An example of a suitable base is triethylamine (TEA). The coupling reaction may also be performed in the presence of a solvent. An example of a suitable solvent is tetrahydrofuran (THF). The coupling reaction may be performed at elevated temperatures, for example, between 50° C. and 120° C. for about 1 to 12 hours. Upon completion, the reaction is concentrated by removal of the solvent. The residue can be purified using any suitable methods known in the art, for example, chromatography of the residue on a silica column.
EXAMPLE 1a
Preparation of a Compound of Formula (1)
A. Preparation of a Compound of Formula (1) in which n is 1, R2 is Chloro, and R3 is Phenyl
Diphenyl phosphonate (1.9 mL, 10 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol) in pyridine (3 mL). The reaction mixture was stirred at 40° C. for 2 hours. Aniline (274 mg, 3.48 mmol) was then added to the reaction mixture, which was then stirred at 55° C. for 12 hours. The reaction mixture was cooled to room temperature. This mixture was then diluted with EtOAc (50 mL), washed with 1N aqueous HCl (2×50 mL), brine (50 mL), and dried over sodium sulfate. The organics layer was filtered and concentrated in vacuuo to afford material which was purified by column chromatography on SiO2 eluting with EtOAc in hexanes (0-50%) to afford (S)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate as a solid. ES/MS m/z=400.1 (M+H)+.
B. Preparation of a Compound of Formula (1), Varying R2 and R3
Following the procedure described in Example 1a.A and Reaction Scheme I, but varying the R2 and R3 substituents, other compounds of formula (1) were prepared including:
(S)-tert-butyl 2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate, ES/MS m/z=426.1 (M+H)+;
(S)-tert-butyl 2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate, ES/MS m/z=440.1 (M+H)+;
(S)-tert-butyl 1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate, ES/MS m/z=384.1 (M+H)+;
(S)-tert-butyl 1-(5,8-dichloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate, ES/MS m/z=434.2 (M+H)+;
(S)-tert-butyl 1-(5-chloro-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate, ES/MS m/z=418.1 (M+H)+;
(S)-tert-butyl 1-(8-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate, ES/MS m/z=400.1 (M+H)+;
(S)-tert-butyl 1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate, ES/MS m/z=402.1 (M+H)+;
(S)-tert-butyl(1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-butylphenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-t-butylphenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-(methylsulfonyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-([1,1′-biphenyl]-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-ethylphenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(8-fluoro-5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-(trifluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-fluoro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-cyanophenyl)-5-(difluoromethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-cyanophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(R)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-cyanophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;
(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;
(S)-tert-butyl(1-(3-(3-cyanophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-(methylsulfonyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(5-fluoropyridin-3-yl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-morpholino-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-(methyl sulfonamidomethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
tert-butyl((1S)-1-(5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(3-(azepan-1-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-methyl-3-(3-((N-methylmethylsulfonamido)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-((N-methylmethylsulfonamido)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(S)-tert-butyl(1-(5-chloro-3-(3-((N-isobutylmethylsulfonamido)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
(R)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate; and
(R)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyethyl)carbamate.
EXAMPLE 1b
Preparation of a Compound of Formula (1)
A. Preparation of a Compound of Formula (1) in which n is 1, R2 is Cyano, and R3 is Phenyl
(S)-tert-butyl(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (500 mg, 1.13 mmol), zinc cyanide (166 mg, 1.41 mmol), and tetrakis(triphenylphosphine)Pd(0) (124 mg, 0.11 mmol) were combined in NMP (5 mL). The mixture was degassed under Ar and heated to 90° C. overnight. The reaction was poured into EtOAc, washed with water (3×), and purified by flash chromatography (40 g silica, 0-50% EtOAc/hexanes) to give (S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate as a white solid. ES/MS 391.2 (M+H+).
EXAMPLE 2a
Preparation of a Compound of Formula (2)
A. Preparation of a Compound of Formula (2) in which n is 1, R2 is Chloro, and R3 is Phenyl
Trifluoroacetic acid (3 mL) was added to a solution of (S)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate (1 g, 2.5 mmol) in dichloromethane (3 mL). The resultant was stirred at room temperature for 3 hours. The solvent was removed in vacuuo to afford (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one 2,2,2-trifluoroacetic acid salt. ES/MS m/z=300.1 (M+H)+
B. Preparation of a Compound of Formula (2), Varying R2 and R3
Following the procedure described in Example 2a.A and Reaction Scheme I, but varying the R2 and R3 substituents, other compounds of formula (2) were prepared including:
(S)-5-chloro-3-phenyl-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one, ES/MS m/z=326.1 (M+H)+;
(S)-5-chloro-3-phenyl-2-(piperidin-2-yl)quinazolin-4(3H)-one, ES/MS m/z=340.1 (M+H)+;
(S)-2-(1-aminoethyl)-5-(3-morpholino-3-oxopropyl)-3-phenylquinazolin-4(3H)-one, ES/MS m/z=407.2 (M+H)+;
(S)-3-(2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)-N,N-dimethylpropanamide, ES/MS m/z=365.2 (M+H+);
(S)-2-(1-aminoethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one, ES/MS m/z=284.1 (M+H)+;
(S)-2-(1-aminoethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one, ES/MS m/z=334.1 (M+H)+;
(S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one, ES/MS m/z=318.1 (M+H)+;
(S)-2-(1-aminoethyl)-8-chloro-3-phenylquinazolin-4(3H)-one, ES/MS m/z=300.1 (M+H)+;
(S)-2-(1-aminoethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one, ES/MS m/z=302.1 (M+H)+;
(S)-2-(1-aminoethyl)-5-chloro-8-methyl-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2-(1-aminoethyl)-8-methyl-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(3-butylphenyl)-5-chloroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(3-ethylphenyl)-5-chloroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(3-t-butylphenyl)-5-chloroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(3-(methylsulfonyl)phenyl)quinazolin-4(3H)-one;
(S)-3-([1,1′-biphenyl]-3-yl)-2-(1-aminoethyl)-5-chloroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-(trifluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-fluoro-8-methyl-3-phenylquinazolin-4(3H)-one;
(S)-3-(2-(1-aminoethyl)-5-(difluoromethyl)-4-oxoquinazolin-3 (4H)-yl)benzonitrile;
(S)-3-(2-(1-aminoethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile;
(S)-2-(1-aminopropyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(3-methoxy-2-methylphenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;
(R)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(3-chlorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one;
(S)-3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile;
(S)-3-(2-(1-aminoethyl)-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;
(S)-2-(1-aminoethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-methylquinazolin-4(3H)-one;
(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;
(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one;
(S)-3-(2-(1-aminoethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;
(S)-2-(1-aminoethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2-(1-aminoethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-methyl-3-(pyridin-3-yl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(5-fluoropyridin-3-yl)-5-methylquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-morpholinoquinazolin-4(3H)-one;
(S)—N-(3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)methanesulfonamide;
(S)-1-aminoethyl)-5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-3-(azepan-1-yl)-5-chloroquinazolin-4(3H)-one;
(S)-2-(1-aminoethyl)-5-chloro-3-(piperazin-1-yl)quinazolin-4(3H)-one;
(S)—N-(3-(2-(1-aminoethyl)-5-methyl-4-oxoquinazolin-3 (4H)-yl)benzyl)-N-methylmethanesulfonamide;
(S)—N-(3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3 (4H)-yl)benzyl)-N-methylmethanesulfonamide;
(S)—N-(3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)-N-isobutylmethanesulfonamide;
(R)-2-(1-amino-2-hydroxyethyl)-5-chloro-3-phenylquinazolin-4(3H)-one; and
(R)-2-(1-amino-2-methoxyethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one.
EXAMPLE 2b
Preparation of a Compound of Formula (2)
A. Preparation of a Compound of Formula (2) in which n is 1, R2 is Hydroxy, and R3 is Phenyl
To a solution of (S)-tert-butyl(1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (100 mg, 0.25 mmol) in DCM (3 mL) at −78° C. was added BBr3 (1M/DCM, 0.63 mL, 0.63 mmol). The reaction was stirred at −78° C. for 20 min, then warmed to ambient temperature. After stirring 10 minutes at ambient temperature, MeOH (5 mL) was added. The reaction was concentrated in vacuo. Purification by flash chromatography (12 g silica, 0-100% EtOAc/DCM then 0-30% MeOH/DCM) provided (S)-2-(1-aminoethyl)-5-hydroxy-3-phenylquinazolin-4(3H)-on as an orange residue. ES/MS 282.1 (M+H+).
EXAMPLE 3
Preparation of a Compound of Formula (3)
To 4-amino-6-chloro-5-iodopyrimidine (2.0 g, 7.8 mmol) in NMP (20 mL) was added Pd(PPh3)4 (0.907 g, 0.785 mmol), CuI (0.149 g, 0.785 mmol), TEA (2.20 ml, 15.7 mmol), and TMS-alkyne (1.22 mL, 8.64 mmol). After stirring at 90° C. for 1 hour, water was added and the mixture was extracted with EtOAc (3×50 mL), dried (Na2SO4), and concentrated. The residue was purified on a silica column (0-75% ethyl acetate in hexanes) to give 6-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine. ES/MS m/z=226.1 (M+), 228.1(M+2).
EXAMPLE 4
Preparation of a Compound of Formula (4)
A. Preparation of a Compound of Formula (4) in which R1 is 5-Methoxycarbonylpyridin-2-yl
To 6-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (30.0 mg, 1.33 mmol) (prepared according to the procedure in Example 3 above) in NMP (5 mL) was added Pd(PPh3)4 (0.154 g, 0.133 mmol), CuI (25 mg, 0.78 mmol), TEA (0.371 mL, 2.66 mmol), tBAF (0.385 mL, 2.66 mmol), and methyl 6-bromonicotinate (0.345 g 1.60 mmol). After stirring at 90° C. overnight, water was added and the mixture was extracted with EtOAc (3×25 mL), dried (Na2SO4), and concentrated. Methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate was carried forward crude. ES/MS m/z=289.1 (M+), 291.0 (M+2).
B. Preparation of a Compound of Formula (4), Varying R1
Following the procedure described in Example 4A and Reaction Scheme I, but varying the R1 substituent, other compounds of formula (4) were prepared including:
6-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4-amine, ES/MS m/z=231.5 (M+H+);
5-((1H-pyrazol-4-yl)ethynyl)-6-chloropyrimidin-4-amine, ES/MS m/z=220 (M+H+);
6-chloro-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-amine, ES/MS m/z=249.5 (M+H+);
6-chloro-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-amine, ES/MS m/z=278.2 (M+H+);
6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)benzo[d]thiazol-2-amine, ES/MS m/z=302.5 (M+H+);
6-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4-amine, ES/MS m/z=231.2 (M+H+);
6-chloro-5-(pyridin-3-ylethynyl)pyrimidin-4-amine, ES/MS m/z=231.1 (M+H+);
6-chloro-5-(pyrimidin-5-ylethynyl)pyrimidin-4-amine, ES/MS m/z=232.6 (M+H+);
5-((5-aminopyridin-2-yl)ethynyl)-6-chloropyrimidin-4-amine, ES/MS m/z=246.7 (M+H+);
5-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyrimidin-2-amine, ES/MS m/z=247 (M+H+);
5-((6-aminopyridin-2-yl)ethynyl)-6-chloropyrimidin-4-amine, ES/MS m/z=246.1 (M+H+);
4-(4-amino-6-chloropyrimidin-5-yl)-2-methylbut-3-yn-2-ol, ES/MS m/z=212.3 (M+H+);
6-chloro-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-amine, ES/MS m/z=314.5 (M+H+);
6-chloro-5-(cyclopropylethynyl)pyrimidin-4-amine, ES/MS m/z=194 (M+H+);
(S)-4-(4-amino-6-chloropyrimidin-5-yl)but-3-yn-2-ol, ES/MS m/z=198.1 (M+H+);
(R)-4-(4-amino-6-chloropyrimidin-5-yl)but-3-yn-2-ol, ES/MS m/z=198.2 (M+H+);
5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)-6-chloropyrimidin-4 amine, ES/MS m/z=314.7 (M+H+);
6-chloro-5-(pyrazin-2-ylethynyl)pyrimidin-4-amine, ES/MS m/z=232.5 (M+H+);
6-chloro-5-(pyridazin-3-ylethynyl)pyrimidin-4-amine, ES/MS m/z=232.2 (M+H+);
6-chloro-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidine-2,4-diamine;
6-chloro-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((3-methoxypyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((3,5-difluoropyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-(pyrazin-2-ylethynyl)pyrimidin-4-amine;
6-chloro-5-(pyrimidin-2-ylethynyl)pyrimidin-4-amine;
6-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((5-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinamide;
isopropyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate;
6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinic acid;
6-chloro-5-((5-fluoro-6-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((6-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((3-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-(cyclopentylethynyl)pyrimidin-4-amine;
6-chloro-5-(cyclohexylethynyl)pyrimidin-4-amine;
6-chloro-5-((4-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((4-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((4-(difluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((4-ethylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
6-chloro-5-((6-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;
1-(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-3-yl)ethanone;
1-(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-6-yl)ethanone;
(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-4-yl)methanol;
(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-6-yl)methanol;
2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)isonicotinamide;
1-(6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-2-yl)ethanol;
methyl 2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)isonicotinate;
5-((6-(aminomethyl)pyridin-2-yl)ethynyl)-6-chloropyrimidin-4-amine;
2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)isonicotinic acid;
1-(3-((4-amino-6-chloropyrimidin-5-yl)ethynyl)phenyl)ethanone;
(3-((4-amino-6-chloropyrimidin-5-yl)ethynyl)phenyl)methanol; and
(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-3-yl)methanol.
EXAMPLE 5
Preparation of a Compound of Formula (6)
A. Preparation of a Compound of Formula (6) in which n is 1, R2 is Chloro, and R3 is Phenyl
To (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (400 mg, 1.33 mmol) (prepared according to the procedure in Example 2a.A above) and 4-amino-6-chloro-5-iodopyrimidine (338 mg, 1.32 mmol) in IPA (5 mL) was added Hunig's base (0.4 mL). After stirring at 90° C. for 2 hours in a microwave reactor, water was added and the mixture was extracted with EtOAc (3×50 mL), dried (MgSO4), and concentrated. The residue was purified on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) to give (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. ES/MS m/z=519.0 (M+), 521.0(M+2).
EXAMPLE 6
Preparation of a Compound of Formula (I) or (II)
A. Preparation of a Compound of Formula (I) in which n is 1, R1 is 5-Methoxycarbonylpyridin-2-yl, R2 is Chloro, and R3 is Phenyl (Compound 3a)
To methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate (50 mg, 0.17 mmol) (prepared according to the procedure in Example 3 above) in NMP (5 mL) was added (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (62 mg 0.21 mmol) (prepared according to the procedure in Example 2A above), KF (33 mg 0.35 mmol), and Hunig's base (0.15 ml, 0.21 mmol). After stirring overnight at 120° C. the reaction was cooled to rt. Water was added. The precipitate was filtered, and then dissolved in DCM. Purification on silica with 0 to 100% EtOAc in hexanes then 0 to 20% MeOH in EtOAc gave material that required further purification. Purification on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) gave (S)-methyl 6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate.
B. Preparation of a Compound of Formula (I) in which n is 1, R2 is Chloro, and R1 and R3 are Both Phenyl (Compound 51a)
To (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (58 mg, 0.11 mmol) (prepared according to the procedure in Example 5A) in THF (5 mL) was added Pd(PPh3)2Cl2 (2 mg, 2.5%), CuI (1 mg, 5%), TEA (0.1 mL, 0.16 mmol), and phenylacetylene (20 mg 0.16 mmol). After stirring at 70° C. for 2 hours, the solvent was stripped. The residue was purified on silica with 0 to 10% MeOH in DCM to give material that required further purification. Purification on silica with 0 to 100% EtOAc in hexanes gave (S)-2-(1-(6-amino-5-(phenylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. 1H NMR (400 MHz, DMSO-D6) δ 7.88 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.88 (dt, J=6.8, 1.6 Hz, 2H), 7.59-7.41 (m, 10H), 6.92 (d, J=7.0 Hz, 1H), 6.75 (bs, 2H), 4.73 (p, J=6.8 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS m/z=493.1 (M+H+).
C. Preparation of a Compound of Formula (I) or (II), Varying R1, R2 and R3
Following the procedure described in Examples 6A and 6B, and Reaction Scheme I, but varying the R1 substituent, other compounds of formula (I) or (II) were prepared including:
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one (Compound 4a); 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, 1H, J=2.3 Hz), 8.02 (s, 1H), 7.91-7.82 (m, 2H), 7.80-7.74 (m, 1H), 7.60-7.45 (m, 5H), 7.39-7.31 (m, 3H), 4.91-4.82 (m, 2H), 1.40 (d, 3H, J=6.6 Hz); ES/MS m/z=514.1 (M+H)+;
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5,8-difluoroquinazolin-4(3H)-one (Compound 1a); 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.39 (m, 1H), 8.06 (s, 1H), 7.95-7.71 (m, 2H), 7.64-7.37 (m, 3H), 7.42-7.08 (m, 3H), 5.01 (t, J=6.9 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS 550.3(M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one (Compound 2a); 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.44 (m, 1H), 8.05 (s, 1H), 7.98-7.64 (m, 3H), 7.64-7.39 (m, 3H), 7.39-7.13 (m, 2H), 5.19-4.89 (m, 1H), 1.70-1.32 (m, 3H). ES/MS 532.2(M+H+);
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-8-chloro-3-phenylquinazolin-4(3H)-one (Compound 5a); 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H, J=2.8 Hz), 8.09 (s, 1H), 8.07 (s, 1H), 7.99 (d, 1H, J=7.8 Hz), 7.92-7.84 (m, 2H), 7.68-7.47 (m, 8H), 5.09-5.01 (m, 2H), 1.38 (d, 3H, J=6.7 Hz); ES/MS m/z=512.1 (M+H)+;
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one (Compound 6a); 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H, J=2.7 Hz), 8.06 (s, 1H), 7.91-7.83 (m, 2H), 7.73 (dt, 1H, J=9.0 and 0.8 Hz), 7.65-7.44 (m, 8H), 4.91-4.84 (m, 2H), 1.40 (d, 3H, J=6.7 Hz); ES/MS m/z=530.1 (M+H)+;
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one (Compound 7a); 1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J=14.3 Hz, 1H), 8.05 (s, 1H), 7.88 (dtd, J=10.9, 8.5, 4.5 Hz, 2H), 7.65 (d, J=8.2 Hz, 1H), 7.57-6.98 (m, 8H), 5.00-4.69 (m, 1H), 1.33 (d, J=6.6 Hz, 3H). ES/MS m/z=532.2 (M+H+);
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound 8a); 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=2.9 Hz, 1H), 8.01-7.79 (m, 4H), 7.73-7.39 (m, 8H), 7.38-7.17 (m, 2H), 4.85-4.74 (m, 1H), 1.35 (dd, J=13.1, 6.6 Hz, 3H). ES/MS m/z=496.1 (M+H+);
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 9a); 1H NMR (400 MHz, dmso) δ 8.68 (d, J=2.4 Hz, 1H), 8.01 (s, 1H), 7.97-7.73 (m, 4H), 7.60 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.38 (m, 8.9 Hz, 4H), 4.97-4.80 (m, 1H), 1.38 (d, J=6.5 Hz, 3H). ES/MS m/z=548.3 (M+H+);
(S)-2-(1-(6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one (Compound 10a); 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, 1H, J=3.1 Hz), 8.04 (s, 1H), 7.93 (d, 1H, J=8.6 Hz), 7.76 (d, 1H, J=8.6 Hz), 7.60-7.48 (m, 8H), 7.45-7.32 (br s, 2H), 5.04-4.97 (m, 2H), 1.35 (d, 3H, J=6.6 Hz); ES/MS m/z=558.2 (M+H)+;
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one (Compound 11a); 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H, J=3.1 Hz), 8.04 (s, 1H), 7.94 (d, 1H, J=8.6 Hz), 7.91-7.84 (m, 2H), 7.60-7.49 (m, 8H), 5.04-4.97 (m, 2H), 1.36 (d, 3H, J=6.7 Hz); ES/MS m/z=546.1 (M+H)+;
(S)-2-(1-(6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one (Compound 12a); 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, 1H, J=3.5 Hz), 8.08 (s, 1H), 7.95 (dm, 1H, J=7.8 Hz), 7.77 (d, 1H, J=8.6 Hz), 7.76-7.67 (m, 2H), 7.60-7.47 (m, 8H), 4.96-4.89 (m, 2H), 1.43 (d, 3H, J=7.1 Hz); ES/MS m/z=508.2 (M+H)+;
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one (Compound 13a); 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, 1H, J=2.8 Hz), 7.99 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.84-7.76 (m, 2H), 7.70-7.50 (m, 2H), 7.54-7.35 (m, 6H), 4.89-4.82 (m, 2H), 1.35 (d, 3H, J=6.6 Hz); ES/MS found m/z=496.2 (M+H)+;
(S)-2-(1-(6-amino-5-(pyridazin-3-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 14a); 1H NMR (400 MHz, dmso) δ 13.07-12.79 (m, 1H), 9.15 (s, 1H), 8.93-8.52 (m, 1H), 8.37-7.97 (m, 2H), 8.01-7.47 (m, 8H), 7.40 (s, 2H), 4.81 (s, 1H), 1.49 (d, J=6.8 Hz, 3H). ES/MS m/z=495.2 (M+H+);
(S)-2-(1-(6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 15a); 1H NMR (400 MHz, dmso) δ 7.97 (s, 2H), 7.87 (s, 1H), 7.81-7.69 (m, 1H), 7.67-7.55 (m, 2H), 7.51 (d, J=9.7 Hz, 1H), 7.39 (m, 2H), 7.27 (d, J=10.2 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.85 (s, 1H), 1.46 (d, J=6.4 Hz, 3H). ES/MS m/z=545.9 (M+H+);
(S)-2-(1-(6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 16a); 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.6 Hz, 1H), 8.78 (dd, J=2.5, 1.6 Hz, 1H), 8.60 (d, J=24.1 Hz, 1H), 8.07 (s, 1H), 7.92-7.68 (m, 2H), 7.64-7.23 (m, 9H), 4.89-4.61 (m, 1H), 1.34 (d, J=6.7 Hz, 3H). ES/MS m/z=495.4 (M+H+);
(S)-2-(1-(6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 17a); 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=47.4 Hz, 1H), 8.11 (s, 1H), 7.76 (t, J=8.0 Hz, 1H), 7.68-7.34 (m, 6H), 7.32-7.13 (m, 2H), 7.10 (s, 3H), 6.81 (s, 1H), 4.96 (d, J=6.2 Hz, 1H), 1.41 (d, J=6.5 Hz, 3H). ES/MS m/z=613.7 (M+H+);
(S)-2-(1-(6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 18a); 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.09 (s, 1H), 7.86-7.60 (m, 1H), 7.63-7.37 (m, 8H), 7.04 (s, 4H), 6.83 (d, J=12.2 Hz, 1H), 5.02-4.52 (m, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS m/z=577.5 (M+H+);
2-((S)-1-(6-amino-5-((R)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 19a); 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.83-7.71 (m, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.55 (dd, J=16.0, 14.0 Hz, 10H), 4.84-4.48 (m, 2H), 1.52-1.38 (m, 3H), 1.33 (d, J=6.6 Hz, 3H). ES/MS m/z=461(M+H+);
2-((S)-1-(6-amino-5-((S)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 19b); 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.83-7.69 (m, 1H), 7.67 (dd, J=8.2, 1.1 Hz, 1H), 7.57-7.43 (m, 8H), 7.38-7.07 (m, 2H), 4.89-4.55 (m, 2H), 1.45 (d, J=6.6 Hz, 3H), 1.32 (d, J=6.7 Hz, 3H). ES/MS m/z=461.9(M+H+);
2-((S)-1-(6-amino-5-((R)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 20a); 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.79 (t, J=8.1 Hz, 5H), 7.67 (d, J=8.3 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.44-7.17 (m, 6H), 4.85 (s, 1H), 4.67 (d, J=6.6 Hz, 1H), 1.41 (dd, J=6.6, 6.6 Hz, 6H). ES/MS m/z=497.1(M+H+);
2-((S)-1-(6-amino-5-((S)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 20b); 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.46-7.10 (m, 6H), 4.85 (s, 1H), 4.66 (d, J=6.6 Hz, 1H), 1.51-1.34 (m, 6H). ES/MS m/z=497.3(M+H+);
(S)-2-(1-(6-amino-5-(cyclopropylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 23a); 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.81 (t, J=8.2 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.62 (dd, J=7.7, 7.9 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.37 (d, J=9.4 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.21-7.06 (m, 1H), 4.84 (s, 1H), 1.64 (s, 1H), 1.38 (d, J=6.6 Hz, 3H), 1.01-0.73 (m, 4H). ES/MS m/z=494.5(M+H+);
(S)-2-(1-(6-amino-5-(cyclopropylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 24a); 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.63 (dd, J=8.2, 1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.1 Hz, 1H), 7.56-7.54 (m, 2H), 7.49 (dd, J=4.5, 3.1 Hz, 4H), 7.34 (s, 2H), 4.83-4.66 (m, 1H), 1.69 (ddd, J=13.1, 8.2, 5.1 Hz, 1H), 1.33 (d, J=6.7 Hz, 3H), 1.05-0.73 (m, 4H). ES/MS m/z=457.2(M+H+);
(S)-2-(1-(6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 26a); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.87-7.81 (m, 2H), 7.78 (t, J=8.0 Hz, 1H), 7.60 (dd, J=12.2, 4.5 Hz, 3H), 7.52 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.36 (t, J=9.3 Hz, 2H), 7.29 (d, J=9.2 Hz, 1H), 5.00-4.81 (m, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MS m/z=613.9(M+H+);
(S)-2-(1-(6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 27a); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.89-7.80 (m, 1H), 7.80-7.64 (m, 1H), 7.64-7.26 (m, 13H), 4.88-4.64 (m, 1H), 1.38 (d, J=6.7 Hz, 3H). ES/MS m/z=577.2(M+H+);
(S)-2-(1-(6-amino-5-(3-hydroxy-3-methylbut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 28a); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.84-7.75 (m, 2H), 7.67 (dd, J=8.2, 1.2 Hz, 1H), 7.60 (dd, J=7.8, 1.2 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.35 (d, J=9.1 Hz, 1H), 7.10 (s, 2H), 4.85 (s, 1H), 1.52 (d, J=3.8 Hz, 6H), 1.38 (d, J=6.7 Hz, 3H). ES/MS m/z=511.9(M+H+);
(S)-2-(1-(6-amino-5-(3-hydroxy-3-methylbut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 29a); 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.71-7.63 (m, 1H), 7.60-7.46 (m, 8H), 7.30 (s, 2H), 4.89-4.61 (m, 1H), 1.54 (d, J=4.0 Hz, 6H), 1.32 (d, J=6.6 Hz, 3H). ES/MS m/z=475.9(M+H+);
(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 30a); 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.33-8.20 (m, 1H), 8.04 (s, 1H), 7.94-7.83 (m, 1H), 7.80-7.64 (m, 2H), 7.46 (dd, J=64.5, 30.9 Hz, 10H), 4.79 (s, 1H), 2.79-2.53 (m, 3H), 1.29 (dd, J=24.6, 6.7 Hz, 5H). ES/MS m/z=474.5(M+H+);
(S)-2-(1-(6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 31a); 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.88 (s, 1H), 7.76 (t, J=8.0 Hz, 1H), 7.55 (m, 9H), 7.23 (d, J=7.7 Hz, 2H), 6.88 (d, J=8.9 Hz, 1H), 4.84-4.53 (m, 1H), 1.42 (d, J=6.8 Hz, 3H). ES/MS m/z=509.3(M+H+);
(S)-2-(1-(6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 32a); 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 8.16 (s, 1H), 7.81 (dd, J=22.0, 13.9 Hz, 1H), 7.72-7.47 (m, 7H), 7.39 (s, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.21 (s, 1H), 4.95 (s, 1H), 1.48 (d, J=6.7 Hz, 3H). ES/MS m/z=546.5(M+H+);
(S)-2-(1-(6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 33a); 1H NMR (400 MHz, DMSO-d6) δ 8.68-8.47 (m, 2H), 8.16 (s, 1H), 7.91 (d, J=26.6 Hz, 1H), 7.77 (t, J=8.0 Hz, 2H), 7.62-7.39 (m, 8H), 7.24 (s, 2H), 4.92-4.73 (m, 1H), 1.43 (d, J=6.8 Hz, 3H). ES/MS m/z=510.1(M+H+);
(S)-2-(1-(6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 34a); 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.06 (s, 1H), 8.03 (d, J=2.6 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.83-7.77 (m, 1H), 7.71 (dd, J=14.0, 9.7 Hz, 3H), 7.62 (d, J=7.7 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.46-7.37 (m, 2H), 7.33 (d, J=9.0 Hz, 2H), 7.27 (m, 1H), 4.95-4.89 (m, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS m/z=545.9(M+H+);
(S)-2-(1-(6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 35a); 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=12.3 Hz, 2H), 7.84-7.67 (m, 4H), 7.67-7.47 (m, 6H), 7.25 (s, 1H), 4.93-4.62 (m, 1H), 1.35 (dd, J=42.9, 6.8 Hz, 3H). ES/MS m/z=508.3(M+H+);
(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)piperidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 36a); 1H NMR (400 MHz, DMSO-D6) δ 8.61 (d, J=5.5 Hz, 1H), 8.08 (s, 1H), 7.88 (t, J=9.5 Hz, 1H), 7.78-7.38 (m, 10H), 5.15 (m, 1H), 4.72 (m, 1H), 4.09 (m, 1H), 2.16-1.41 (m, 8H); ES/MS m/z=534.1 (M+H)+;
(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)pyrrolidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 37a); 1H NMR (400 MHz, DMSO-D6) δ 8.63 (m, 1H), 8.23 (d, J=14.2 Hz, 1H), 7.97-7.39 (m, 11H), 4.64 (m, 1H), 4.41 (m, 1H), 4.25 (m, 1H), 2.37-2.09 (m, 4H), 1.94 (m, 2H); ES/MS m/z=520.1 (M+H)+;
(S)-3-(2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzamide (Compound 38a); 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.9 Hz, 1H), 8.13 (d, J=11.7 Hz, 1H), 8.11-7.82 (m, 5H), 7.82-7.44 (m, 5H), 4.89-4.69 (m, 1H), 1.39 (dd, J=6.1, 3.7 Hz, 3H). ES/MS m/z=537.5(M+H+);
(S)-3-(2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)-N-ethylbenzenesulfonamide (Compound 39a); 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=4.9 Hz, 1H), 8.44-7.72 (m, 9H), 7.69-7.55 (m, 1H), 7.55-7.42 (m, 1H), 4.80 (d, J=32.4 Hz, 2H), 3.26-3.02 (m, 1H), 3.00-2.68 (m, 2H), 1.40 (dd, J=6.6, 4.3 Hz, 3H), 1.00 (dt, J=23.1, 7.2 Hz, 3H). ES/MS m/z=601.1(M+H+);
(S)-3-(2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide (Compound 40a); 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.68 (m, 1H), 8.21-8.02 (m, 2H), 8.04-7.72 (m, 7H), 7.65-7.42 (m, 4H), 4.84 (d, J=6.7 Hz, 1H), 4.71 (s, 1H), 1.40 (dd, J=17.0, 6.6 Hz, 3H). ES/MS m/z=573(M+H+);
(S)-2-(1-(6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 41a); 1H NMR (400 MHz, DMSO-d6) δ 9.14 (m, 2H), 8.10 (s, 1H), 7.80 (t, J=8.1 Hz, 2H), 7.70-7.48 (m, 3H), 7.46-7.20 (m, 2H), 5.07-4.82 (m, 1H), 1.44 (t, J=34.5 Hz, 3H). ES/MS m/z=531.4(M+H+);
(S)-2-(1-(6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 42a); 1H NMR (400 MHz, DMSO-d6) δ 8.27-8.10 (m, 2H), 7.99 (s, 2H), 7.83-7.67 (m, 2H), 7.55 (m, 6H), 4.95-4.77 (m, 1H), 1.45 (d, J=6.8 Hz, 3H). ES/MS m/z=495.6(M+H+);
(S)-2-(1-(6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 43a); 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.60 (s, 1H), 8.13 (d, J=12.6 Hz, 2H), 7.90-7.71 (m, 2H), 7.50 (ddd, J=91.6, 25.8, 8.8 Hz, 5H), 4.96 (s, 1H), 1.48 (d, J=6.6 Hz, 3H). ES/MS m/z=530.3 (M+H+);
(S)-2-(1-(6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 44a); 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=1.3 Hz, 1H), 8.62 (dd, J=4.9, 1.7 Hz, 1H), 8.30-8.03 (m, 2H), 7.98 (s, 1H), 7.87-7.69 (m, 2H), 7.66-7.30 (m, 6H), 4.93-4.69 (m, 1H), 1.44 (d, J=6.7 Hz, 3H)). ES/MS m/z=494.1 (M+H+);
(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 45a); 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=4.9 Hz, 1H), 8.09 (s, 1H), 7.94 (t, J=7.0 Hz, 1H), 7.89-7.78 (m, 3H), 7.73 (s, 1H), 7.62 (dd, J=6.9, 1.7 Hz, 1H), 7.46 (ddd, J=35.6, 32.4, 9.1 Hz, 6H), 5.03-4.84 (m, 1H), 1.43 (d, J=6.6 Hz, 3H). ES/MS m/z=529.3 (M+H+);
(S)-2-(1-(6-amino-5-((2-aminobenzo [d]thiazol-6-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 46a); 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.06 (s, 1H), 7.87 (s, 3H), 7.76 (t, J=7.6 Hz, 1H), 7.64-7.47 (m, 8H), 7.40 (d, J=8.2 Hz, 1H), 4.92-4.70 (m, 1H), 1.42 (d, J=6.6 Hz, 3H). ES/MS m/z=565.2 (M+H+);
(S)-2-(1-(6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 47a); 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.55 (dt, J=24.9, 7.1 Hz, 8H), 7.31-7.18 (m, 2H), 6.92 (d, J=11.1 Hz, 1H), 4.85-4.68 (m, 1H), 3.82 (d, J=1.0 Hz, 3H), 1.40 (d, J=6.7 Hz, 3H). ES/MS m/z=541.1 (M+H+);
(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 48a); 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=3.0 Hz, 1H), 7.88 (dd, J=8.0, 4.0 Hz, 1H), 7.85-7.71 (m, 4H), 7.64-7.35 (m, 6H), 7.11 (d, J=6.9 Hz, 1H), 6.83 (s, 2H), 4.67 (p, J=6.5 Hz, 1H), 1.24 (d, J=6.6 Hz, 3H). ES/MS m/z=512.1 (M+H+);
(S)-2-(1-(5-((1H-pyrazol-4-yl)ethynyl)-6-aminopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 49a); 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.01 (s, 2H), 7.76 (t, J=7.6 Hz, 2H), 7.66-7.48 (m, 6H), 4.87-4.69 (m, 2H), 1.39 (d, J=6.5 Hz, 3H). ES/MS m/z=483.1 (M+H+);
(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 50a); 1H NMR (400 MHz, dmso-d6) δ 8.75 (d, J=3.9 Hz, 1H), 8.32-8.10 (m, 1H), 8.12-7.70 (m, 5H), 7.73-7.31 (m, 6H), 4.85 (dd, J=13.0, 6.4 Hz, 1H), 1.40 (dd, J=19.9, 6.7 Hz, 3H). ES/MS m/z=494.1 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-hydroxy-3-phenylquinazolin-4(3H)-one (Compound 52a): 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.70 (d, J=2.9 Hz, 1H), 8.09 (s, 1H), 7.96-7.82 (m, 3H), 7.78 (t, J=8.2 Hz, 1H), 7.70-7.45 (m, 6H), 7.28 (dd, J=8.0, 1.0 Hz, 1H), 6.92 (dd, J=8.2, 1.0 Hz, 1H), 4.91-4.80 (m, 1H), 1.35 (d, J=6.5 Hz, 3H). ES/MS 494.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-8-methyl-3-phenylquinazolin-4(3H)-one (Compound 53a): 1H NMR (400 MHz, DMSO-d6) δ 8.65-8.62 (m, 1H), 8.00 (s, 1H), 7.94-7.88 (m, 1H), 7.88-7.80 (m, 1H), 7.65-7.60 (m, 1H), 7.60-7.47 (m, 5H), 7.44 (d, J=8.1 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 5.00-4.86 (m, 1H), 2.41 (s, 3H), 1.33 (d, J=6.5 Hz, 3H). ES/MS 526.1 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 54a): 1H NMR (400 MHz, DMSO-d6) δ 8.74-8.69 (m, 1H), 8.08 (s, 1H), 7.97-7.91 (m, 1H), 7.90-7.82 (m, 2H), 7.75 (dd, J=8.1, 7.3 Hz, 1H), 7.68 (dd, J=8.2, 1.3 Hz, 1H), 7.62-7.37 (m, 6H), 7.34-7.27 (m, 1H), 4.85-4.74 (m, 1H), 2.70 (s, 3H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 492.2 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile (Compound 55a): 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.5 Hz, 1H), 8.78 (dd, J=2.6, 1.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.14 (dd, J=7.6, 1.9 Hz, 1H), 8.11-8.00 (m, 3H), 7.72 (s, 1H), 7.64-7.41 (m, 6H), 4.90-4.74 (m, 1H), 1.36 (d, J=6.6 Hz, 3H). ES/MS 486.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-methyl-3-phenylquinazolin-4(3H)-one (Compound 56a): 1H NMR (400 MHz, DMSO-d6) δ 8.64 (dt, J=2.9, 0.7 Hz, 1H), 8.06 (s, 1H), 7.98-7.93 (m, 1H), 7.92-7.89 (m, 1H), 7.85 (td, J=8.6, 2.9 Hz, 1H), 7.69 (ddd, J=7.4, 1.6, 0.9 Hz, 1H), 7.59-7.46 (m, 7H), 7.43 (t, J=7.6 Hz, 1H), 5.07-4.95 (m, 1H), 2.45 (s, 3H), 1.36 (d, J=6.5 Hz, 3H). ES/MS 492.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-butylphenyl)-5-chloroquinazolin-4(3H)-one (Compound 57a): 1H NMR (400 MHz, DMSO) δ 8.77-8.67 (m, 1H), 8.11-7.97 (m, 1H), 7.97-7.74 (m, 3H), 7.62-7.54 (m, 1H), 7.48-7.37 (m, 2H), 7.37-7.24 (m, 3H), 4.90-4.75 (m, 1H), 2.62 (dt, J=26.3, 7.7 Hz, 2H), 1.55 (dq, J=24.3, 7.9 Hz, 2H), 1.38-1.22 (m, 5H), 0.87 (dtd, J=22.5, 7.4, 1.7 Hz, 3H). ES/MS 568.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-(methylsulfonyl)phenyl)quinazolin-4(3H)-one (Compound 58a): 1H NMR (400 MHz, DMSO) δ 8.67 (dd, J=6.9, 2.7 Hz, 1H), 8.22 (dt, J=9.4, 2.0 Hz, 1H), 8.09-7.96 (m, 1H), 7.96-7.72 (m, 6H), 7.58 (ddd, J=7.7, 3.8, 1.6 Hz, 1H), 7.06 (dd, J=35.8, 7.1 Hz, 1H), 6.82 (s, 2H), 4.72 (q, J=6.8 Hz, 1H), 3.29 (s, 1.5H), 3.21 (s, 1.5H), 1.36-1.28 (m, 3H). ES/MS 590.1 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-(tert-butyl)phenyl)-5-chloroquinazolin-4(3H)-one (Compound 59a): 1H NMR (400 MHz, DMSO) δ 8.77-8.68 (m, 1H), 8.11-7.98 (m, 1H), 7.99-7.74 (m, 3H), 7.66-7.55 (m, 2H), 7.55-7.40 (m, 3H), 7.41-7.29 (m, 1H), 4.95-4.70 (m, 1H), 1.37-1.20 (m, 12H). ES/MS 568.2 (M+H+);
(S)-3-([1,1′-biphenyl]-3-yl)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloroquinazolin-4(3H)-one (Compound 60a): 1H NMR (400 MHz, DMSO) δ 8.72 (dd, J=6.0, 2.8 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.99-7.90 (m, 2H), 7.91-7.75 (m, 5H), 7.74-7.60 (m, 3H), 7.63-7.53 (m, 2H), 7.54-7.31 (m, 4H), 5.03-4.88 (m, 1H), 1.38 (dd, J=6.5, 2.9 Hz, 3H). ES/MS 588.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-ethylphenyl)quinazolin-4(3H)-one (Compound 61a): 1H NMR (400 MHz, DMSO) δ 8.72 (dd, J=13.0, 2.7 Hz, 1H), 8.03 (d, J=19.3 Hz, 1H), 7.97-7.72 (m, 3H), 7.62-7.53 (m, 1H), 7.48-7.39 (m, 3H), 7.32 (q, J=10.6, 9.2 Hz, 3H), 4.93-4.74 (m, 1H), 2.73-2.56 (m, 2H), 1.38-1.29 (m, 3H), 1.26-1.11 (m, 3H). ES/MS 540.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 62a): 1H NMR (400 MHz, DMSO) δ 8.63 (dt, J=2.8, 0.8 Hz, 1H), 8.08 (s, 1H), 7.93-7.79 (m, 2H), 7.74 (br s, 1H), 7.66-7.41 (m, 8H), 7.29 (ddd, J=8.3, 5.0, 1.0 Hz, 1H), 4.92-4.84 (m, 1H), 2.65 (s, 3H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 510.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 63a): 1H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.78 (td, J=9.6, 4.2 Hz, 1H), 7.65-7.41 (m, 7H), 7.34 (td, J=9.8, 3.7 Hz, 1H), 7.24-7.19 (m, 2H), 6.90 (dt, J=11.1, 2.4 Hz, 1H), 4.86-4.78 (m, 1H), 3.82 (s, 3H), 1.40 (d, J=6.7 Hz, 3H). ES/MS 543.2 (M+H+);
(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one (Compound 64a): 1H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.96-7.92 (m, 1H), 7.78-7.72 (m, 1H), 7.65-7.34 (m, 7H), 7.22-7.17 (m, 2H), 6.89 (dt, J=11.1, 2.4 Hz, 1H), 4.90-4.83 (m, 1H), 3.80 (s, 3H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 525.2 (M+H+);
(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound 65a): 1H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.81 (td, J=8.2, 5.4 Hz, 1H), 7.66-7.44 (m, 7H), 7.35-7.18 (m, 3H), 6.91 (dt, J=11.1, 2.4 Hz, 1H), 4.80-4.71 (m, 1H), 3.81 (s, 3H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 525.2 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 66a): 1H NMR (400 MHz, DMSO) δ 8.99 (d, J=1.6 Hz, 1H), 8.72 (dd, J=2.6, 1.5 Hz, 1H), 8.60 (d, J=2.6 Hz, 1H), 8.07-7.71 (m, 6H), 7.59-7.50 (m, 2H), 7.45-7.25 (m, 3H), 5.01-4.92 (m, 1H), 1.42 (d, J=6.6 Hz, 3H). ES/MS 547.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one (Compound 67a): 1H NMR (400 MHz, DMSO) δ 8.74 (dd, J=3.0, 0.7 Hz, 1H), 8.11-7.73 (m, 9H), 7.65-7.47 (m, 6H), 4.90-4.82 (m, 1H), 1.36 (d, J=6.6 Hz, 3H). ES/MS 528.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-phenyl-5-(trifluoromethyl)quinazolin-4(3H)-one (Compound 68a): 1H NMR (400 MHz, DMSO) δ 8.75 (dd, J=2.9, 0.8 Hz, 1H), 8.21-8.16 (m, 1H), 8.13-8.03 (m, 2H), 8.01-7.92 (m, 2H), 7.87 (td, J=8.7, 2.9 Hz, 1H), 7.62-7.49 (m, 6H), 4.87-4.78 (m, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 545.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-8-methyl-3-phenylquinazolin-4(3H)-one (Compound 69a): 1H NMR (400 MHz, DMSO) δ 8.64 (dd, J=3.0, 0.7 Hz, 1H), 8.03 (s, 1H), 7.91 (ddd, J=8.7, 4.8, 0.7 Hz, 1H), 7.85 (td, J=8.6, 2.9 Hz, 1H), 7.67 (dd, J=8.4, 5.5 Hz, 1H), 7.58-7.30 (m, 8H), 7.20 (dd, J=11.0, 8.3 Hz, 1H), 5.01-4.92 (m, 1H), 2.39 (s, 3H), 1.34 (d, J=6.6 Hz, 3H). ES/MS 510.2 (M+H+);
(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 70a): 1H NMR (400 MHz, DMSO) δ 8.67 (dd, J=3.1, 2.4 Hz, 1H), 8.20 (t, J=1.8 Hz, 1H), 8.11-7.80 (m, 11H), 7.77-7.66 (m, 1H), 4.90-4.82 (s, 1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS 553.2 (M+H+);
(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 71a): 1H NMR (400 MHz, DMSO) δ 9.00 (dd, J=1.6, 1.0 Hz, 1H), 8.72 (dt, J=2.6, 1.7 Hz, 1H), 8.59 (dd, J=2.6, 0.8 Hz, 1H), 8.21-8.17 (m, 1H), 8.06-7.82 (m, 8H), 7.75-7.65 (m, 1H), 4.92-4.84 (m, 1H), 1.40 (d, J=6.6 Hz, 3H). ES/MS 536.2 (M+H+);
(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 72a): 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.8 Hz, 1H), 8.15 (dd, J=2.1, 1.5 Hz, 1H), 8.00-7.78 (m, 6H), 7.72-7.55 (m, 2H), 7.34-7.25 (m, 2H), 4.93-4.87 (m, 1H), 2.64 (s, 3H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 535.2 (M+H+);
(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 73a): 1H NMR (400 MHz, DMSO) δ 8.96 (dd, J=2.9, 1.5 Hz, 1H), 8.66 (dd, J=2.6, 1.5 Hz, 1H), 8.58 (d, J=2.6 Hz, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.98-7.77 (m, 4H), 7.73-7.54 (m, 2H), 7.40-7.20 (m, 2H), 4.95-4.86 (m, 1H), 2.64 (s, 3H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 518.2 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 74a): 1H NMR (400 MHz, DMSO) δ 9.00 (d, J=1.6 Hz, 1H), 8.73 (dd, J=2.6, 1.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.04 (s, 1H), 8.03-7.70 (m, 4H), 7.65-7.50 (m, 3H), 7.43 (tt, J=9.4, 2.5 Hz, 1H), 7.37-7.29 (m, 1H), 4.92-4.83 (m, 1H), 2.01 (ddd, J=14.2, 7.4, 4.8 Hz, 1H), 1.79 (dq, J=15.2, 7.5 Hz, 1H), 0.79 (t, J=7.3 Hz, 3H). ES/MS 561.2 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 75a): 1H NMR (400 MHz, DMSO) δ 8.95 (d, J=1.5 Hz, 1H), 8.68 (dd, J=2.6, 1.5 Hz, 1H), 8.61 (d, J=2.6 Hz, 1H), 8.03 (s, 1H), 7.64 (s, 1H), 7.59-7.38 (m, 7H), 7.27 (ddd, J=8.4, 5.0, 1.0 Hz, 1H), 4.91-4.82 (m, 1H), 2.64 (s, 3H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 493.2 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one (Compound 76a): 1H NMR (400 MHz, DMSO) δ 9.02 (d, J=1.5 Hz, 1H), 8.77 (dd, J=2.6, 1.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.09-7.72 (m, 6H), 7.61-7.44 (m, 6H), 4.91-4.83 (m, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS 511.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 77a): 1H NMR (400 MHz, DMSO) δ 8.68 (dt, J=3.0, 0.7 Hz, 1H), 8.09-7.71 (m, 8H), 7.62-7.52 (m, 2H), 7.46-7.29 (m, 3H), 5.01-4.92 (m, 1H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 564.2 (M+H+);
(S)-5-chloro-2-(1-((2,6-diamino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 78a): 1H NMR (400 MHz, DMSO) δ 8.6 (m, 1H), 7.9-7.4 (m, 8H), 6.7 (m, 1H), 6.26 (bs, 1H), 5.98 (bs, 2H), 4.7 (m, 1H), 1.33 (d, J=4 Hz, 3H). ES/MS 563.9 (M+H+);
(S)-2-(1-((6-amino-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one. (Compound 79a): 1H NMR (400 MHz, DMSO) δ 8.54 (dt, J=4.7, 1.5 Hz, 1H), 8.08 (s, 1H), 7.90 (ddd, J=9.3, 8.5, 1.3 Hz, 1H), 7.76 (t, J=8 Hz, 1H), 7.65-7.4 (m, 8H), 4.85 (m, 1H), 1.36 (d, J=6.4 Hz, 3H). ES/MS 548.9 (M+H+);
(S)-2-(1-((6-amino-5-((3-methoxypyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one. (Compound 80a): 1H NMR (400 MHz, DMSO) δ 8.24 (dd, J=4.7, 1.3 Hz, 1H), 8.11 (s, 1H), 7.75 (dd, J=8.5, 7.6 Hz, 1H), 7.65-7.4 (m, 8H), 4.88 (m, 1H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 560.9 (M+H+);
(S)-2-(1-((6-amino-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-methoxy-2-methylphenyl)quinazolin-4(3H)-one (Compound 81a-1): 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dt, J=4.6, 1.5 Hz, 1H), 7.91-7.5 (m, 9H), 7.29 (t, J=8.2 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.17 (m, 1H), 3.78 (s, 3H), 1.86 (s, 3H), 1.42 (d, J=6.6 Hz, 3H). ES/MS 557.0 (M+H+);
(S)-2-(1-((6-amino-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-methoxy-2-methylphenyl)quinazolin-4(3H)-one (Compound 81a-2): 1H NMR (400 MHz, DMSO-d6) δ 8.55 (dt, J=4.7, 1.5 Hz, 1H), 8.09 (s, 1H), 7.91 (ddd, J=9.3, 8.5, 1.3 Hz, 1H), 7.83-7.4 (m, 6H), 7.28 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 2H), 4.96 (m, 1H), 3.85 (s, 3H), 1.89 (s, 3H), 1.26 (d, J=6.7 Hz, 3H). ES/MS 557.0 (M+H+);
(S)-2-(1-((6-amino-5-((3,5-difluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. (Compound 82a): 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=2.3 Hz, 1H), 8.16 (td, J=9.0, 2.4 Hz, 1H), 8.10 (s, 1H), 7.81-7.4 (m, 8H), 4.86 (p, J=6.7 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS 530.9 (M+H+)
(S)-5-chloro-2-(1-((2,6-diamino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one. (Compound 83a): 1H NMR (400 MHz, DMSO-d6) δ 8.64 (dt, J=2.9, 0.7 Hz, 1H), 7.93-7.71 (m, 4H), 7.65-7.51 (m, 5H), 6.82 (d, J=7.0 Hz, 1H), 6.28 (bs, 1H), 5.98 (s, 1H), 4.68 (q, J=6.6 Hz, 1H), 1.23 (d, J=6.4 Hz, 3H). ES/MS 527.9 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one (Compound 84a). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (dd, J=2.8, 0.9 Hz, 1H), 8.08 (s, 1H), 7.92-7.66 (m, 3H), 7.70-7.48 (m, 4H), 7.45-7.06 (m, 2H), 5.01 (p, J=6.8 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS 566.5 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 85a). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=1.5 Hz, 1H), 8.84-8.54 (m, 2H), 8.06 (s, 1H), 7.89-7.70 (m, 2H), 7.68-7.41 (m, 3H), 7.52-7.29 (m, 2H), 4.92 (t, J=6.7 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 531.6 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound 86a). 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=1.7 Hz, 1H), 8.88-8.76 (m, 1H), 8.70-8.56 (m, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.03-7.78 (m, 2H), 7.78-7.46 (m, 7H), 7.45-7.11 (m, 2H), 5.01-4.76 (m, 1H), 1.35 (dd, J=6.6, 2.2 Hz, 3H). ES/MS 479.3 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one (Compound 87a), 1H NMR (400 MHz, DMSO-d6) δ 9.00 (t, J=1.1 Hz, 1H), 8.74 (ddd, J=2.4, 1.5, 0.8 Hz, 1H), 8.62 (dd, J=2.6, 0.7 Hz, 1H), 8.07 (s, 1H), 7.99-7.80 (m, 1H), 7.75 (s, 1H), 7.70-7.46 (m, 3H), 7.48-7.13 (m, 3H), 4.94 (t, J=6.8 Hz, 2H), 1.42 (d, J=6.6 Hz, 3H). ES/MS 515.6 (M+H+);
(R)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 9b). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J=2.8 Hz, 1H), 8.11 (s, 1H), 7.98-7.68 (m, 4H), 7.70-7.50 (m, 3H), 7.50-7.06 (m, 3H), 4.92 (t, J=6.8 Hz, 1H), 1.40 (dd, J=6.4, 1.3 Hz, 3H). ES/MS 548.8 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-chlorophenyl)quinazolin-4(3H)-one (Compound 89a). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J=3.9, 1.4 Hz, 1H), 8.84-8.69 (m, 1H), 8.62 (q, J=2.5 Hz, 1H), 8.05 (d, J=19.0 Hz, 1H), 7.91-7.73 (m, 3H), 7.71-7.43 (m, 5H), 4.87 (q, J=6.2 Hz, 1H), 1.38 (t, J=6.5 Hz, 3H). ES/MS 530.4 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one (Compound 90a). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (dt, J=2.9, 0.7 Hz, 1H), 8.06 (s, 1H), 8.01-7.73 (m, 6H), 7.68-7.36 (m, 6H), 4.85 (q, J=6.6 Hz, 1H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 496.5 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one (Compound 91a). 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=1.5 Hz, 1H), 8.78 (dd, J=2.6, 1.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.06 (s, 1H), 8.01-7.70 (m, 4H), 7.71-7.20 (m, 7H), 4.85 (p, J=6.4 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 479.5 (M+H+);
(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 92a). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (tt, J=2.9, 0.7 Hz, 1H), 8.12-7.68 (m, 10H), 7.61 (dd, J=7.7, 1.3 Hz, 2H), 4.92-4.62 (m, 1H), 1.37 (dd, J=6.6, 1.9 Hz, 3H). ES/MS 537.5 (M+H+);
(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 93a). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J=1.5 Hz, 1H), 8.73 (ddd, J=2.6, 2.0, 1.5 Hz, 1H), 8.61 (dd, J=2.6, 0.8 Hz, 1H), 8.19 (ddd, J=2.1, 1.6, 0.5 Hz, 1H), 8.06-7.68 (m, 9H), 7.66-7.57 (m, 1H), 5.02-4.74 (m, 1H), 1.38 (dd, J=6.6, 2.0 Hz, 3H). ES/MS 521.1 (M+H+);
(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 94a). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (tt, J=2.9, 0.7 Hz, 1H), 8.21 (td, J=1.8, 0.5 Hz, 1H), 8.16-7.64 (m, 10H), 7.50 (s, 1H), 4.87 (d, J=6.5 Hz, 1H), 1.53-1.32 (m, 3H). ES/MS 521.6 (M+H+);
(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 95a). 1H NMR (400 MHz, DMSO-d6) δ 9.08-8.90 (m, 1H), 8.74 (dt, J=2.6, 1.7 Hz, 1H), 8.67-8.45 (m, 1H), 8.20 (ddd, J=2.1, 1.6, 0.5 Hz, 1H), 8.06-7.64 (m, 10H), 7.46 (s, 2H), 4.90 (q, J=6.4 Hz, 1H), 1.40 (dd, J=6.7, 0.9 Hz, 3H). ES/MS 504.4 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one (Compound 96a). 1H NMR (400 MHz, DMSO-d6) δ 8.71 (ddt, J=5.4, 2.9, 0.7 Hz, 1H), 8.06 (d, J=16.9 Hz, 1H), 8.01-7.75 (m, 6H), 7.66-7.38 (m, 6H), 4.92 (dd, J=8.3, 5.1 Hz, 1H), 1.38 (t, J=6.4 Hz, 3H). ES/MS 530.8 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one (Compound 97a). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J=4.4, 1.6 Hz, 1H), 8.76 (ddd, J=4.1, 2.6, 1.6 Hz, 1H), 8.63 (t, J=2.3 Hz, 1H), 8.06 (d, J=19.3 Hz, 1H), 7.99-7.71 (m, 5H), 7.70-7.38 (m, 5H), 5.01-4.88 (m, 1H), 1.40 (dd, J=6.7, 5.5 Hz, 3H). ES/MS 513.9 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 98a). 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.5 Hz, 1H), 8.86-8.69 (m, 1H), 8.63 (dd, J=2.7, 1.5 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.89-7.59 (m, 4H), 7.53 (dt, J=9.8, 3.6 Hz, 6H), 7.31 (d, J=7.2 Hz, 1H), 4.79 (t, J=6.9 Hz, 1H), 2.71 (s, 3H), 1.49-1.21 (m, 3H). ES/MS 475.3 (M+H+).
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one (Compound 99a). 1H NMR (400 MHz, DMSO-d6) δ 8.71 (dt, J=2.9, 0.7 Hz, 1H), 8.07 (d, J=3.8 Hz, 1H), 8.01-7.80 (m, 2H), 7.85-7.63 (m, 2H), 7.66-7.15 (m, 6H), 5.02-4.73 (m, 1H), 1.37 (d, J=6.6 Hz, 3H). ES/MS 514.5 (M+H+).
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one (Compound 100a). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J=1.5 Hz, 1H), 8.68 (dd, J=2.6, 1.5 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 8.05-7.85 (m, 1H), 7.85-7.68 (m, 2H), 7.55 (ddt, J=15.8, 7.9, 3.6 Hz, 3H), 7.46-7.32 (m, 1H), 7.32-7.17 (m, 1H), 5.05 (t, J=6.9 Hz, 1H), 1.47 (d, J=6.6 Hz, 3H). ES/MS 515.3 (M+H+).
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one (Compound 101a). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J=1.5 Hz, 1H), 8.76 (ddd, J=2.4, 1.4, 0.6 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.96-7.73 (m, 2H), 7.75-7.55 (m, 3H), 7.53-7.22 (m, 4H), 4.86 (dq, J=13.6, 6.8 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H). ES/MS 497.5 (M+H+);
(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 102a). 1H NMR (400 MHz, DMSO-d6) δ 9.02-8.84 (m, 1H), 8.07 (s, 1H), 7.92-7.75 (m, 2H), 7.73-7.48 (m, 7H), 7.45 (d, J=19.5 Hz, 2H), 4.80 (t, J=6.7 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 495.7 (M+H+);
(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 103a). 1H NMR (400 MHz, DMSO-d6) δ 9.06-8.78 (m, 2H), 8.10 (s, 1H), 7.97-7.72 (m, 3H), 7.75-7.51 (m, 3H), 7.51-7.31 (m, 3H), 4.93 (t, J=6.7 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 531.8 (M+H+);
(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one (Compound 104a). 1H NMR (400 MHz, DMSO-d6) δ 9.02-8.83 (m, 2H), 8.09 (s, 1H), 7.92 (s, 1H), 7.82-7.66 (m, 2H), 7.61-7.46 (m, 6H), 7.31 (ddd, J=7.3, 1.4, 0.9 Hz, 1H), 4.81 (p, J=6.6 Hz, 1H), 2.84-2.62 (m, 3H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 475.6(M+H+);
(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one (Compound 105a). 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J=4.9 Hz, 2H), 8.13 (s, 1H), 7.90 (s, 1H), 7.84-7.65 (m, 2H), 7.65-7.52 (m, 3H), 7.49-7.27 (m, 4H), 5.07-4.89 (m, 1H), 2.72 (d, J=5.9 Hz, 3H), 1.51-1.28 (m, 3H). ES/MS 511.3(M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-fluorophenyl)-5-methylquinazolin-4(3H)-one (Compound 106a). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J=1.4 Hz, 1H), 8.78 (ddd, J=2.5, 1.5, 0.8 Hz, 1H), 8.69-8.57 (m, 1H), 8.23-8.07 (m, 1H), 7.95 (s, 1H), 7.82-7.52 (m, 4H), 7.51-7.08 (m, 4H), 4.88 (tt, J=12.6, 6.6 Hz, 1H), 2.72 (d, J=6.2 Hz, 3H), 1.60-1.20 (m, 3H). ES/MS 493.5(M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one (Compound 107a). 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=1.5 Hz, 1H), 8.76 (dd, J=2.6, 1.5 Hz, 1H), 8.69-8.53 (m, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.98-7.80 (m, 1H), 7.70-7.29 (m, 8H), 4.86 (q, J=7.2 Hz, 1H), 2.15-1.92 (m, 1H), 1.79 (dt, J=14.5, 7.5 Hz, 1H), 0.80 (t, J=7.3 Hz, 3H). ES/MS 529.6(M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one (Compound 108a). 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.4 Hz, 1H), 8.86-8.69 (m, 1H), 8.76-8.58 (m, 1H), 8.15 (d, J=6.2 Hz, 1H), 7.93-7.70 (m, 3H), 7.66-7.51 (m, 2H), 7.49-7.24 (m, 3H), 4.88 (d, J=5.5 Hz, 1H), 2.72 (d, J=5.2 Hz, 3H), 2.09-1.92 (m, 1H), 1.80 (dt, J=14.7, 7.4 Hz, 1H), 0.80 (t, J=7.4 Hz, 3H). ES/MS 525.5(M+H+);
(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound 109a). 1H NMR (400 MHz, DMSO-d6) δ 9.04-8.86 (m, 2H), 8.01 (d, J=60.1 Hz, 1H), 7.98-7.72 (m, 2H), 7.77-7.63 (m, 1H), 7.66-7.49 (m, 4H), 7.43-7.22 (m, 3H), 4.83 (p, J=6.6 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 479.5(M+H+);
(S)-3-(2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile (Compound 110a). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=13.2 Hz, 1H), 8.04-7.78 (m, 4H), 7.81-7.63 (m, 3H), 7.68-7.17 (m, 8H), 4.86 (dd, J=9.8, 5.0 Hz, 1H), 1.44 (d, J=6.6 Hz, 3H). ES/MS 502.4 (M+H+);
(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one (Compound 111a). 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J=5.4, 2.0 Hz, 1H), 7.99-7.68 (m, 5H), 7.68-7.53 (m, 3H), 7.53-7.17 (m, 7H), 4.87 (q, J=7.6 Hz, 1H), 1.43 (dd, J=6.7, 2.0 Hz, 3H). ES/MS 435.6 (M+H+);
(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one (Compound 112a). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J=7.7, 1.3 Hz, 1H), 8.16-7.99 (m, 2H), 7.93 (dd, J=8.2, 1.3 Hz, 1H), 7.82-7.66 (m, 2H), 7.66-7.20 (m, 9H), 4.95-4.73 (m, 1H), 3.46 (s, 3H), 1.41 (d, J=6.8 Hz, 3H). ES/MS 536.3 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one (Compound 113a). 1H NMR (400 MHz, DMSO-d6) δ 9.11-8.91 (m, 1H), 8.76 (ddd, J=2.5, 1.6, 0.7 Hz, 1H), 8.72-8.52 (m, 1H), 8.42-8.21 (m, 1H), 8.24-7.96 (m, 3H), 7.75-7.22 (m, 7H), 4.83 (t, J=6.7 Hz, 1H), 3.63 (s, 3H), 1.35 (d, J=6.7 Hz, 3H). ES/MS 539.3(M+H+).
(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile (Compound 114a). 1H NMR (400 MHz, DMSO-d6) δ 8.16-8.01 (m, 1H), 8.01-7.80 (m, 3H), 7.82-7.64 (m, 3H), 7.68-7.29 (m, 10H), 4.94-4.71 (m, 1H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 484.6(M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 115a). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=1.5 Hz, 1H), 8.83-8.47 (m, 3H), 8.19-7.96 (m, 2H), 7.88 (td, J=8.2, 5.4 Hz, 2H), 7.70-7.39 (m, 3H), 7.46-7.22 (m, 2H), 4.76 (dt, J=20.3, 6.8 Hz, 1H), 1.36 (t, J=6.7 Hz, 3H). ES/MS 480.2(M+H+);
(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 116a). 1H NMR (400 MHz, DMSO-d6) δ 8.88-8.74 (m, 1H), 8.76-8.49 (m, 2H), 8.17-7.99 (m, 2H), 8.06-7.78 (m, 2H), 7.84-7.48 (m, 4H), 7.50-7.18 (m, 4H), 4.80 (q, J=6.8 Hz, 1H), 1.58-1.37 (m, 3H). ES/MS 478.4(M+H+).
(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 117a). 1H NMR (400 MHz, DMSO-d6) δ 8.95-8.56 (m, 3H), 8.17-7.92 (m, 1H), 7.91-7.31 (m, 6H), 7.27-6.88 (m, 3H), 5.02-4.67 (m, 1H), 1.54-1.17 (m, 3H). ES/MS 497.1(M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 118a). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=1.5 Hz, 1H), 8.91-8.45 (m, 4H), 8.14-7.91 (m, 2H), 7.87-7.64 (m, 2H), 7.68-7.36 (m, 4H), 4.88-4.65 (m, 1H), 1.36 (t, J=7.1 Hz, 3H). ES/MS 496.8 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-(pyridin-3-yl)quinazolin-4(3H)-one (Compound 119a). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (q, J=1.5 Hz, 1H), 8.95-8.37 (m, 4H), 8.02 (dddt, J=25.3, 8.1, 2.7, 1.4 Hz, 1H), 7.94-7.80 (m, 1H), 7.78-7.39 (m, 3H), 7.45-7.15 (m, 2H), 6.94 (s, 2H), 4.81-4.51 (m, 1H), 2.69 (s, 3H), 1.31 (ddd, J=8.1, 6.4, 1.2 Hz, 3H). ES/MS 476.6 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(5-fluoropyridin-3-yl)-5-methylquinazolin-4(3H)-one (Compound 120a). 1H NMR (400 MHz, DMSO-d6) δ 9.16-8.83 (m, 1H), 8.83-8.44 (m, 4H), 8.28-7.89 (m, 1H), 7.82 (dd, J=4.7, 1.7 Hz, 1H), 7.80-7.46 (m, 2H), 7.31 (dt, J=7.5, 1.3 Hz, 1H), 7.20-7.04 (m, 1H), 6.90 (s, 2H), 4.83 (dddd, J=15.4, 13.3, 7.4, 5.6 Hz, 1H), 2.69 (d, J=1.8 Hz, 3H), 1.36 (dd, J=7.1, 5.4 Hz, 3H). ES/MS 494.5 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-morpholinoquinazolin-4(3H)-one (Compound 121a): 1H NMR (400 MHz, DMSO) δ 8.71 (d, J=2.9 Hz, 1H), 8.18 (s, 1H), 7.97-7.73 (m, 5H), 7.53 (dt, J=7.3, 1.3 Hz, 1H), 5.63 (p, J=6.7 Hz, 1H), 4.03 (td, J=11.4, 3.1 Hz, 1H), 3.94-3.79 (m, 3H), 3.56 (dd, J=12.4, 10.0 Hz, 1H), 3.49-3.38 (m, 1H), 3.09 (d, J=10.7 Hz, 1H), 2.99 (dd, J=10.7, 2.4 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H). ES/MS 521.2 (M+H+);
(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-morpholinoquinazolin-4(3H)-one (Compound 122a): 1H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.83 (s, 1H), 7.67 (t, J=8.2 Hz, 1H), 7.55-7.43 (m, 4H), 7.24-7.16 (m, 2H), 6.90 (dt, J=11.2, 2.5 Hz, 1H), 5.73 (p, J=6.8 Hz, 1H), 4.06-3.76 (m, 5H), 3.55 (t, J=10.8 Hz, 1H), 3.48-3.37 (m, 1H), 3.12 (d, J=10.5 Hz, 1H), 2.98 (d, J=10.9 Hz, 1H), 2.51 (s, 1H), 2.46 (s, 4H), 1.56 (d, J=6.7 Hz, 3H). ES/MS 550.2 (M+H+);
(S)—N-(3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)methanesulfonamide (Compound 123a): 1H NMR (400 MHz, DMSO) δ 9.01 (dd, J=2.6, 1.5 Hz, 1H), 8.75 (ddt, J=9.9, 2.5, 1.1 Hz, 1H), 8.66-8.58 (m, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.86-7.40 (m, 10H), 4.83-4.70 (m, 1H), 4.20 (dd, J=20.5, 6.4 Hz, 2H), 2.84 (d, J=30.7 Hz, 3H), 1.38-1.29 (m, 3H). ES/MS 602.2 (M+H+);
2-((S)-1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H)-one (Compound 124a): 1H NMR (400 MHz, DMSO) δ 9.67 (d, J=5.7 Hz, 1H), 9.05 (d, J=1.5 Hz, 1H), 8.81 (dd, J=2.6, 1.5 Hz, 1H), 8.61 (d, J=2.6 Hz, 1H), 8.08 (s, 1H), 7.90 (dd, J=8.2, 1.3 Hz, 1H), 7.82 (t, J=8.0 Hz, 2H), 7.56 (dd, J=7.7, 1.3 Hz, 1H), 7.28 (s, 2H), 5.34 (p, J=6.4 Hz, 1H), 4.78 (p, J=9.7 Hz, 1H), 3.98-3.89 (m, 2H), 2.74-2.60 (m, 4H), 2.47 (dt, J=3.7, 1.9 Hz, 12H), 2.42-2.29 (m, 4H), 2.28-2.08 (m, 3H), 1.52 (d, J=6.4 Hz, 3H). ES/MS 542.2 (M+H+);
2-((S)-1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H)-one (Compound 125a): 1H NMR (400 MHz, DMSO) δ 9.77-9.54 (m, 1H), 9.05 (dd, J=4.6, 1.6 Hz, 1H), 8.88-8.75 (m, 1H), 8.62 (dd, J=4.6, 2.5 Hz, 1H), 8.08 (d, J=4.6 Hz, 1H), 7.91 (dd, J=7.7, 4.3 Hz, 1H), 7.82 (ddd, J=9.1, 6.8, 3.9 Hz, 2H), 7.63-7.45 (m, 1H), 7.26 (s, 2H), 5.35 (q, J=6.2 Hz, 1H), 4.86-4.65 (m, 2H), 3.93 (d, J=8.3 Hz, 3H), 2.77-2.57 (m, 4H), 2.34 (d, J=5.3 Hz, 1H), 2.14 (d, J=5.4 Hz, 1H), 1.52 (dd, J=6.5, 4.4 Hz, 3H), 1.21 (s, 1H). ES/MS 542.2 (M+H+);
(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(azepan-1-yl)-5-chloroquinazolin-4(3H)-one (Compound 126a): 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.5 Hz, 1H), 8.77 (ddd, J=2.5, 1.6, 0.6 Hz, 1H), 8.62 (d, J=2.6 Hz, 1H), 8.17 (s, 1H), 7.83-7.66 (m, 3H), 7.57 (s, 3H), 7.54-7.44 (m, 1H), 5.79 (p, J=6.6 Hz, 1H), 3.77 (td, J=8.0, 4.4 Hz, 1H), 3.62 (ddd, J=12.2, 8.9, 2.8 Hz, 1H), 3.17 (ddd, J=40.9, 12.6, 5.9 Hz, 3H), 1.78-1.45 (m, 15H). ES/MS 516.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(piperazin-1-yl)quinazolin-4(3H)-one (Compound 127a): 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=11.4 Hz, 1H), 8.61 (d, J=14.8 Hz, 1H), 8.13-8.04 (m, 1H), 7.97-7.73 (m, 3H), 7.64-7.48 (m, 2H), 7.37 (s, 2H), 7.28 (s, 1H), 5.64-5.56 (m, 1H), 4.17 (t, J=12.6 Hz, 1H), 4.04 (t, J=12.7 Hz, 1H), 3.46-3.25 (m, 4H), 3.14 (t, J=13.8 Hz, 1H), 2.97 (d, J=12.2 Hz, 1H), 2.47 (d, J=10.1 Hz, 1H), 2.38 (s, 1H), 1.55-1.43 (m, 3H). ES/MS 520.2 (M+H+);
(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-4-oxoquinazolin-3(4H)-yl)benzyl)-N-methylmethanesulfonamide (Compound 128a): 1H NMR (400 MHz, DMSO) δ 8.70 (dd, J=5.8, 2.9 Hz, 1H), 8.02 (d, J=9.6 Hz, 1H), 7.97-7.40 (m, 9H), 7.30 (dd, J=7.5, 4.1 Hz, 1H), 4.79 (td, J=7.0, 4.0 Hz, 1H), 4.35-4.19 (m, 2H), 2.94 (d, J=16.5 Hz, 3H), 2.73-2.62 (m, 6H), 1.31 (d, J=6.6 Hz, 3H). ES/MS 613.2 (M+H+);
(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)-N-methylmethanesulfonamide (Compound 129a): 1H NMR (400 MHz, DMSO) δ 8.74-8.67 (m, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.97-7.69 (m, 5H), 7.61-7.40 (m, 6H), 4.79 (q, J=6.7, 6.2 Hz, 1H), 4.34-4.20 (m, 2H), 3.33 (s, 6H), 2.94 (d, J=17.3 Hz, 3H), 2.70 (s, 2H), 2.64 (s, 2H), 1.31 (dd, J=6.8, 2.2 Hz, 3H). ES/MS 633.2 (M+H+);
(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)methanesulfonamide (Compound 130a): 1H NMR (400 MHz, DMSO) δ 8.71 (dd, J=11.2, 2.9 Hz, 1H), 8.05 (d, J=3.1 Hz, 1H), 7.97-7.61 (m, 7H), 7.61-7.39 (m, 7H), 7.33 (s, 3H), 4.84-4.72 (m, 1H), 4.21 (dd, J=19.7, 6.4 Hz, 2H), 2.84 (d, J=30.6 Hz, 3H), 1.33 (dd, J=8.5, 6.5 Hz, 3H), 1.20 (dt, J=12.5, 6.7 Hz, 1H). ES/MS 619.2 (M+H+);
(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)-2-methylpropane-1-sulfonamide (Compound 131a): 1H NMR (400 MHz, DMSO) δ 8.70 (dd, J=16.9, 2.9 Hz, 1H), 8.03 (d, J=10.0 Hz, 1H), 7.97-7.66 (m, 5H), 7.63-7.35 (m, 7H), 4.77 (dt, J=13.3, 6.7 Hz, 1H), 4.19 (dd, J=20.8, 6.4 Hz, 2H), 2.89-2.67 (m, 2H), 2.01 (dh, J=27.2, 6.8 Hz, 1H), 1.33 (dd, J=12.5, 6.7 Hz, 3H), 1.01-0.85 (m, 7H). ES/MS 661.2 (M+H+);
(S)-2-(1-((6-amino-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 132a): 1H NMR (400 MHz, DMSO-d6) δ 9.09-9.03 (m, 1H), 8.32 (dd, J=8.3, 2.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.90-7.82 (m, 2H), 7.67-7.42 (m, 6H), 7.36 (s, 2H), 4.78 (t, J=6.7 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 562.1 (M+H+);
(S)-2-(1-((6-amino-5-((5-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 133a): 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=1.8 Hz, 1H), 7.91-7.79 (m, 3H), 7.76-7.64 (m, 2H), 7.63-7.49 (m, 5H), 7.16 (d, J=7.0 Hz, 1H), 6.82 (s, 2H), 4.72 (t, J=6.7 Hz, 1H), 2.35 (s, 3H), 1.29 (d, J=6.6 Hz, 3H).). ES/MS 508.1 (M+H+);
(S)-2-(1-((6-amino-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 134a): 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.33-8.25 (m, 1H), 8.11-8.04 (m, 1H), 7.99 (s, 1H), 7.91-7.76 (m, 2H), 7.60 (dt, J=7.7, 1.3 Hz, 1H), 7.57-7.23 (m, 4H), 4.96-4.80 (m, 1H), 4.23-3.43 (brs, 2H), 1.39 (dd, J=6.8, 1.2 Hz, 4H). ES/MS 598.1 (M+H+).
(S)-6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinamide (Compound 135a): 1H NMR (400 MHz, DMSO-d6) δ 9.12-9.06 (m, 1H), 8.31-8.20 (m, 2H), 8.05 (s, 1H), 7.96-7.89 (m, 1H), 7.90-7.80 (m, 2H), 7.69 (s, 1H), 7.61 (ddd, J=5.7, 3.3, 0.7 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.47-7.33 (m, 3H), 4.90 (t, J=6.8 Hz, 1H), 4.12 (brs, 5H), 1.40 (d, J=6.6 Hz, 3H). ES/MS 537.1 (M+H+);
(S)-6-((4-amino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinamide (Compound 136a): 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J=2.2 Hz, 1H), 8.33-8.21 (m, 2H), 8.03 (s, 1H), 7.99-7.79 (m, 3H), 7.70 (s, 1H), 7.63-7.49 (m, 6H), 4.86-4.69 (m, 1H), 4.37-3.20 (br m, 2H), 1.32 (dd, J=6.9, 1.3 Hz, 3H). ES/MS 573.1 (M+H+).
(S)-isopropyl 6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinate (Compound 137a): 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J=5.1 Hz, 1H), 8.33 (dd, J=7.9, 5.1 Hz, 1H), 8.00 (t, J=6.7 Hz, 2H), 7.83 (dd, J=13.8, 6.4 Hz, 2H), 7.67-7.05 (m, 6H), 5.25-5.08 (m, 1H), 4.78 (dd, J=13.5, 6.2 Hz, 1H), 4.13-3.35 (m, 4H), 2.35 (d, J=28.1 Hz, 6H), 1.42-1.21 (m, 3H). ES/MS 580.1 (M+H+).
(S)-6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinic acid (Compound 138a): 1H NMR (400 MHz, DMSO-d6) δ 9.19-9.04 (m, 1H), 8.32 (dd, J=8.2, 2.3 Hz, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.89-7.73 (m, 2H), 7.61-7.45 (m, 7H), 4.77 (s, 1H), 3.55 (brs, 4H), 1.38-1.27 (m, 3H). ES/MS 538.1 (M+H+);
(R)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)-2-hydroxyethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 139a): 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=2.9 Hz, 1H), 8.03 (s, 1H), 8.01-7.93 (m, 1H), 7.93-7.80 (m, 3H), 7.68-7.25 (m, 12H), 4.87 (q, J=5.2 Hz, 1H), 4.02-3.43 (m, 2H). ES/MS 528.1 (M+H+);
(S)-2-(1-((6-amino-5-((5-fluoro-6-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 140a): 1H NMR (400 MHz, DMSO-d6) δ 10.36 (d, J=2.7 Hz, 1H), 9.22 (s, 1H), 8.49 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.71-7.39 (m, 6H), 7.30 (m, 4H), 7.07 (td, J=7.3, 2.5 Hz, 1H), 4.38 (d, J=6.9 Hz, 1H), 1.56-1.05 (m, 6H). ES/MS 526.1 (M+H+);
(S)-2-(1-((6-amino-5-((6-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 141a): 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.86-7.67 (m, 3H), 7.67-7.46 (m, 7H), 7.33 (d, J=7.6 Hz, 1H), 4.78 (m, 1H), 3.52 (s, 7H), 1.33 (dd, J=6.5, 1.9 Hz, 3H). ES/MS 508.1 (M+H+);
(S)-2-(1-((6-amino-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 142a): 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dt, J=5.2, 0.8 Hz, 1H), 8.33-8.24 (m, 1H), 8.01 (s, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.69-7.40 (m, 9H), 7.12 (m, 1H), 4.84 (t, J=6.7 Hz, 1H), 4.31-3.56 (m, 2H), 1.33 (dd, J=6.7, 0.9 Hz, 3H). ES/MS 562.1 (M+H+);
(S)-2-(1-((6-amino-5-((3-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 143a)1H NMR (400 MHz, DMSO-d6) δ 8.58-8.49 (m, 1H), 8.04 (s, 1H), 7.85-7.80 (m, 1H), 7.80-7.73 (m, 1H), 7.64 (dd, J=8.2, 1.2 Hz, 1H), 7.60-7.46 (m, 7H), 7.39 (dd, J=7.8, 4.9 Hz, 1H), 4.91-4.75 (m, 1H), 3.69 (s, 3H), 2.54-2.49 (m, 3H), 1.34 (d, J=6.6 Hz, 3H). ES/MS 508.1 (M+H+).
(S)-2-(1-((6-amino-5-(cyclopentylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 144a): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=3.3 Hz, 1H), 7.81 (dd, J=8.3, 7.7 Hz, 1H), 7.60 (p, J=1.2 Hz, 1H), 7.58-7.55 (m, 2H), 7.52 (td, J=3.3, 1.9 Hz, 3H), 7.24 (brs, 2H), 4.79 (t, J=6.7 Hz, 1H), 3.55 (d, J=41.9 Hz, 3H), 3.02 (p, J=7.7 Hz, 1H), 2.03 (t, J=8.4 Hz, 2H), 1.85-1.69 (m, 4H), 1.62 (m, 2H), 1.31 (d, J=6.6 Hz, 3H). ES/MS 485.2 (M+H+);
(S)-2-(1-((6-amino-5-(cyclohexylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 145a): 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=3.6 Hz, 1H), 7.80 (dd, J=8.3, 7.7 Hz, 1H), 7.62-7.46 (m, 9H), 7.18 (brs, 2H), 4.87-4.72 (m, 1H), 2.75 (d, J=9.8 Hz, 1H), 1.93 (m, 2H), 1.72 (d, J=6.9 Hz, 2H), 1.57 (m, 4H), 1.44-1.27 (m, 5H). ES/MS 499.2 (M+H+);
(R)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)-2-methoxyethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 146a): 1H NMR (400 MHz, DMSO-d6) δ 8.03 (t, J=2.9 Hz, 1H), 7.52-7.48 (m, 1H), 7.41-7.15 (m, 5H), 7.09 (ddt, J=8.2, 2.6, 1.2 Hz, 1H), 6.96 (ddt, J=7.8, 2.6, 1.2 Hz, 1H), 6.89-6.82 (m, 1H), 6.76 (ddd, J=11.7, 8.7, 2.6 Hz, 1H), 6.70-6.59 (m, 1H), 5.62-4.73 (brs, 2H), 4.54 (td, J=6.7, 5.4, 3.1 Hz, 1H), 3.17 (m, 1H), 3.11-3.01 (m, 1H), 1.83 (dt, J=3.7, 1.8 Hz, 3H). ES/MS 578.1 (M+H+);
(S)-2-(1-((6-amino-5-((4-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 147a);
(S)-2-(1-((6-amino-5-((4-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 148a): 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.42 (d, J=6.9 Hz, 1H), 7.82 (td, J=8.0, 0.9 Hz, 1H), 7.74-7.51 (m, 8H), 6.55 (brs, 1H), 4.95-4.84 (m, 1H), 2.54-2.43 (m, 4H), 1.34 (dd, J=6.5, 1.0 Hz, 3H). ES/MS 562.1 (M+H+);
(S)-2-(1-((6-amino-5-((4-(difluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 149a);
(S)-2-(1-((6-amino-5-((4-ethylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 150a);
(S)-2-(1-((6-amino-5-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 151a);
(S)-2-(1-((5-((3-acetylpyridin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 152a);
(S)-2-(1-((5-((6-acetylpyridin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 153a);
(S)-2-(1-((6-amino-5-((4-(hydroxymethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 154a);
(S)-2-(1-((6-amino-5-((6-(hydroxymethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 155a);
(S)-2-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinamide (Compound 156a): 1H NMR (400 MHz, DMSO-d6) δ 8.87 (dt, J=5.1, 0.8 Hz, 1H), 8.34 (s, 1H), 8.28 (dt, J=1.8, 1.0 Hz, 1H), 8.13 (d, J=6.6 Hz, 1H), 8.01-7.77 (m, 5H), 7.74-7.45 (m, 7H), 4.90-4.75 (m, 1H), 1.36 (dd, J=6.6, 1.1 Hz, 3H), 1.24 (s, 2H). ES/MS 536.2 (M+H+);
2-((1S)-1-((6-amino-5-((6-(1-hydroxyethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 157a): 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.07 (t, J=8.6 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.91-7.82 (m, 1H), 7.83-7.68 (m, 3H), 7.65-7.48 (m, 9H), 4.85 (m, 2H), 1.48-1.34 (m, 7H). ES/MS 538.1 (M+H+);
(S)-methyl 2-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinate (Compound 158a): 1H NMR (400 MHz, DMSO-d6) δ 8.97 (dd, J=5.1, 1.0 Hz, 1H), 8.40 (dt, J=1.7, 0.9 Hz, 1H), 8.20 (s, 1H), 7.96 (ddd, J=8.2, 1.3, 0.5 Hz, 1H), 7.92-7.83 (m, 3H), 7.67-7.51 (m, 9H), 4.86 (t, J=7.2 Hz, 1H), 3.94 (s, 3H), 1.37 (dd, J=6.7, 1.9 Hz, 3H). ES/MS 552.1 (M+H+);
(S)-2-(1-((6-amino-5-((6-(aminomethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 159a): 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 3H), 8.02-7.92 (m, 2H), 7.87 (d, J=7.7 Hz, 1H), 7.77 (td, J=8.0, 0.8 Hz, 1H), 7.66-7.45 (m, 8H), 7.17 (s, 1H), 7.08 (s, 2H), 4.74 (p, J=6.6 Hz, 1H), 4.25 (q, J=5.8 Hz, 2H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 522.2 (M+H+);
(S)-2-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinic acid (Compound 160a): 1H NMR (400 MHz, DMSO-d6) δ 8.92 (dt, J=5.1, 0.9 Hz, 1H), 8.36 (dt, J=1.7, 0.8 Hz, 1H), 8.07 (s, 1H), 7.96 (dt, J=8.3, 1.0 Hz, 1H), 7.91-7.70 (m, 3H), 7.66-7.47 (m, 10H), 4.81 (t, J=6.6 Hz, 1H), 1.34 (d, J=6.6 Hz, 3H). ES/MS 538.2 (M+H+);
(S)-2-(1-((5-((3-acetylphenyl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 161a): 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J =5.4 Hz, 1H), 7.82-7.69 (m, 4H), 7.68-7.46 (m, 9H), 7.46-7.31 (m, 2H), 4.87-4.77 (m, 1H), 4.55 (s, 3H), 1.38 (d, J=6.5 Hz, 3H). ES/MS 536.1 (M+H+);
(S)-2-(1-((6-amino-5-((3-(hydroxymethyl)phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 162a): 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.29 (m, 1H), 8.10 (s, 1H), 8.02 (dt, J=8.1, 2.1 Hz, 2H), 7.77 (m, 3H), 7.67-7.48 (m, 10H), 4.80 (q, J=6.8 Hz, 1H), 2.63 (d, J=0.8 Hz, 2H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 524.1 (M+H+);
(S)-2-(1-((6-amino-5-((3-(hydroxymethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Compound 163a): 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.56 (s, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.54-7.26 (m, 5H), 7.11 (m, 1H), 5.93 (d, J=0.9 Hz, 1H), 5.47 (s, 2H), 4.87 (m, 1H), 3.84 (brs, 2H), 1.39 (d, J=7.1 Hz, 3H). ES/MS 524.1 (M+H+); and
(S)-2-(1-((6-amino-5-((5-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 164a).
Biological Examples
Activity testing was conducted in the Examples below using methods described herein and those well known in the art.
EXAMPLE B1
Enzymatic Activity of PI3K Isoforms
Enzymatic activity of the class I PI3K isoforms was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay that monitors formation of the product 3,4,5-inositol triphosphate molecule (PIP3), as it competes with fluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homology domain protein. An increase in phosphatidylinositide 3-phosphate product results in a decrease in TR-FRET signal as the labeled fluorophore is displaced from the GRP-1 protein binding site.
Class I PI3K isoforms were expressed and purified as heterodimeric recombinant proteins. All assay reagents and buffers for the TR-FRET assay were purchased from Millipore. PI3K isoforms were assayed under initial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2×Km ATP (100-300 μM), 10 μM PIP2, 5% glycerol, 5 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, 1% (v/v) DMSO at the following concentrations for each isoform: PI3K α, β, δ, and γ at 50 picomolar (pM) and PI3Kγ at 2 nanomolar (nM). After an assay reaction time of 30 minutes at 25° C., reactions were terminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRET on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 μs delay and 500 μs read window).
Data are normalized based on a positive (1 uM wortmanin) and negative (DMSO) controls PI3K α, β, δ, and γ IC50 values were calculated from the fit of the dose-response curves to a four-parameter equation. IC50 are reported in units of nM. These assays generally produced results within 3-fold of the reported mean. The data collected from these assays are summarized in Table 2 below.
TABLE 2
Summary of IC50 data
Compound No.
IC50-PIP-α
IC50-PIP-β
IC50-PIP-δ
IC50-PIP-γ
1a
>1
uM
>1
uM
<100
nM
>1
uM
2a
>1
uM
>1
uM
<100
nM
>1
uM
3a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
4a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
5a
>1
uM
>1
uM
<100
nM
>1
uM
6a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
7a
>1
uM
>1
uM
<100
nM
>1
uM
8a
>1
uM
>1
uM
<100
nM
>1
uM
9a
>1
uM
>1
uM
<100
nM
>1
uM
10a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
11a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
12a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
13a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
14a
>1
uM
>1
uM
<1 uM and >100 nM
>1
uM
15a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
16a
>1
uM
<100
nM
<100
nM
<1 uM and >100 nM
17a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
<100
nM
18a
<100
nM
<100
nM
<100
nM
<100
nM
19a
>1
uM
>1
uM
<100
nM
>1
uM
19b
>1
uM
>1
uM
<100
nM
>1
uM
20a
>1
uM
>1
uM
<100
nM
>1
uM
20b
>1
uM
>1
uM
<100
nM
>1
uM
23a
>1
uM
>1
uM
<100
nM
>1
uM
24a
>1
uM
>1
uM
<100
nM
>1
uM
25a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
<100
nM
26a
>1
uM
>1
uM
<1 uM and >100 nM
>1
uM
27a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
28a
>1
uM
>1
uM
<100
nM
>1
uM
29a
>1
uM
>1
uM
<100
nM
>1
uM
30a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
31a
<100
nM
<100
nM
<100
nM
<100
nM
32a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
33a
<100
nM
<100
nM
<100
nM
<100
nM
34a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
35a
<100
nM
<100
nM
<100
nM
<100
nM
36a
>1
uM
>1
uM
<1 uM and >100 nM
>1
uM
37a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
38a
<1 uM and >100 nM
<100
nM
<100
nM
>1
uM
39a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
40a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
41a
>1
uM
>1
uM
<100
nM
>1
uM
42a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
43a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
44a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
<100
nM
45a
>1
uM
>1
uM
<100
nM
>1
uM
46a
<1 uM and >100 nM
<100
nM
<100
nM
<100
nM
47a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
48a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
49a
<1 uM and >100 nM
<100
nM
<100
nM
<100
nM
50a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
51a
<1 uM and >100 nM
<100
nM
<100
nM
<100
nM
52a
>1
uM
>1
uM
<100
nM
>1
uM
53a
>1
uM
>1
uM
<100
nM
>1
uM
54a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
55a
>1
uM
>1
uM
<100
nM
>1
uM
56a
>1
uM
>1
uM
<100
nM
>1
uM
57a
>1
uM
>1
uM
<100
nM
>1
uM
58a
>1
uM
>1
uM
<1 uM and >100 nM
>1
uM
59a
>1
uM
>1
uM
<1 uM and >100 nM
>1
uM
60a
>1
uM
>1
uM
<100
nM
>1
uM
61a
>1
uM
>1
uM
<100
nM
>1
uM
62a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
63a
>1
uM
>1
uM
<100
nM
>1
uM
64a
>1
uM
>1
uM
<100
nM
>1
uM
65a
>1
uM
>1
uM
<100
nM
>1
uM
66a
>1
uM
>1
uM
<100
nM
>1
uM
67a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
68a
>1
uM
>1
uM
<100
nM
>1
uM
69a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
70a
>1
uM
>1
uM
<100
nM
>1
uM
71a
>1
uM
>1
uM
<100
nM
>1
uM
72a
>1
uM
>1
uM
<100
nM
>1
uM
73a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
74a
>1
uM
>1
uM
<100
nM
>1
uM
75a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
76a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
77a
>1
uM
>1
uM
<100
nM
>1
uM
78a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
79a
>1
uM
<100
nM
<100
nM
<1 uM and >100 nM
80a
<100
nM
<100
nM
<100
nM
<100
nM
81-1a
>1
uM
>1
uM
<100
nM
>1
uM
81-2a
>1
uM
>1
uM
<100
nM
>1
uM
82a
>1
uM
>1
uM
<100
nM
>1
uM
83a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
84a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
85a
>1
uM
>1
uM
<100
nM
>1
uM
86a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
87a
>1
uM
>1
uM
<100
nM
>1
uM
88a
>1
uM
>1
uM
<100
nM
>1
uM
89a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
90a
>1
uM
>1
uM
<100
nM
>1
uM
91a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
92a
>1
uM
>1
uM
<100
nM
>1
uM
93a
>1
uM
>1
uM
<100
nM
>1
uM
94a
>1
uM
>1
uM
<100
nM
>1
uM
95a
>1
uM
>1
uM
<100
nM
>1
uM
96a
>1
uM
>1
uM
<100
nM
>1
uM
97a
>1
uM
>1
uM
<100
nM
>1
uM
98a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
99a
>1
uM
>1
uM
<100
nM
>1
uM
100a
>1
uM
>1
uM
<100
nM
>1
uM
101a
>1
uM
>1
uM
<100
nM
>1
uM
102a
>1
uM
<1 uM and>100 nM
<100
nM
<1 uM and >100 nM
103a
>1
uM
>1
uM
<100
nM
>1
uM
104a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
105a
>1
uM
>1
uM
<100
nM
>1
uM
106a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
107a
>1
uM
>1
uM
<100
nM
>1
uM
108a
>1
uM
>1
uM
<100
nM
>1
uM
109a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
110a
>1
uM
>1
uM
<100
nM
>1
uM
111a
>1
uM
<1 uM and>100 nM
<100
nM
<1 uM and >100 nM
112a
<1 uM and >100 nM
>1
uM
<100
nM
<1 uM and >100 nM
113a
>1
uM
>1
uM
<100
nM
>1
uM
114a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
115a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
116a
<1 uM and >100 nM
<1 uM and >100 nM
<100
nM
>1
uM
117a
>1
uM
>1
uM
<100
nM
>1
uM
118a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
119a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
120a
>1
uM
>1
uM
<100
nM
>1
uM
121a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
122a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
123a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
124a
>1
uM
>1
uM
<100
nM
>1
uM
125a
>1
uM
>1
uM
<100
nM
>1
uM
126a
>1
uM
>1
uM
<100
nM
>1
uM
127a
>1
uM
<100
nM
<100
nM
>1
uM
128a
>1
uM
>1
uM
<100
nM
>1
uM
129a
>1
uM
>1
uM
<100
nM
>1
uM
130a
>1
uM
>1
uM
<100
nM
>1
uM
131a
>1
uM
>1
uM
<100
nM
>1
uM
132a
>1
uM
>1
uM
<100
nM
<100
nM
133a
>1
uM
<1 uM and >100 nM
<100
nM
<100
nM
134a
>1
uM
>1
uM
<1 uM and >100 nM
<1 uM and >100 nM
135a
>1
uM
<1 uM and >100 nM
<100
nM
<100
nM
136a
>1
uM
>1
uM
<100
nM
>1 uM and >100 nM
137a
>1
uM
>1
uM
<1 uM and >100 nM
>1
uM
138a
>1
uM
>1
uM
<100
nM
>1
uM
139b
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
140a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
141a
>1
uM
<100
nM
<100
nM
<1 uM and >100 nM
142a
>1
uM
<100
nM
<100
nM
<1 uM and >100 nM
143a
>1
uM
<100
nM
<100
nM
<1 uM and >100 nM
144a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
145a
>1
uM
>1
uM
<100
nM
>1
uM
146b
>1
uM
>1
uM
<100
nM
>1
uM
147a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
148a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
149a
>1
uM
<100
nM
<100
nM
<100
nM
150a
>1
uM
<1 uM and >100 nM
<100
nM
<100
nM
151a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
152a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
153a
>1
uM
<1 uM and >100 nM
<100
nM
<1 uM and >100 nM
154a
<1 uM and >100 nM
<100
nM
<100
nM
<100
nM
155a
<1 uM and >100 nM
>1
nM
<100
nM
<100
nM
156a
<1 uM and >100 nM
<100
nM
<100
nM
<1 uM and >100 nM
157a
>1
uM
<100
nM
<100
nM
<1 uM and >100 nM
158a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
159a
>1
uM
>1
uM
<100
nM
>1
uM
160a
<1 uM and >100 nM
<100
nM
<100
nM
>1
uM
161a
<100
nM
<100
nM
<100
nM
<100
nM
162a
>1
uM
<1 uM and >100 nM
<100
nM
>1
uM
163a
>1
uM
>1
uM
>1
uM
>1
uM
164a
>1
uM
>1
uM
<100
nM
<1 uM and >100 nM
|
14686418
|
gilead calistoga llc
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
|
|
Mar 31st, 2022 02:23PM
|
Mar 31st, 2022 02:23PM
|
Gilead
|
Health Care
|
Pharmaceuticals & Biotechnology
|