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nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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Nov 26th, 2019 12:00AM
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https://www.uspto.gov?id=US11312719-20220426
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9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use
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In its many embodiments, the present invention provides certain 9-substituted amino triazolo quinazoline compounds of the structural Formula (I):
and pharmaceutically acceptable salts thereof, wherein, ring A, R1 and R2 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutically active agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and/or A2b receptors, and in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.
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11312719
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1. A compound having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from F, Cl, (C1-C6)alkyl, and O(C1-C6)alkyl;
R2 is selected from H, F, Cl, (C1-C6)alkyl, and O(C1-C6)alkyl;
ring A is a moiety selected from:
R3 is selected from pyrazolyl, triazolyl, and pyridinyl, wherein said pyrazolyl and said triazolyl, are substituted with 1 or 2 R3A groups, and wherein said pyridinyl is substituted with 1, 2, or 3 R3A groups, wherein:
each R3A is independently selected from (C1-C6)alkyl, O(C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)haloalkyl, O(C1-C6)haloalkyl, oxo, (C1-C4)alkylC(O)(C1-C3)alkyl, (C1-C4)alkylCH(OH)(C1-C3)alkyl, (C1-C4)alkylS(O)2(C1-C3)alkyl, —(CH2)n(C3-C7)cycloalkyl, and —(CH2)n4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from oxygen and nitrogen, wherein said (C3-C7)cycloalkyl, and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2, or 3 groups independently selected from F, Cl, OH, (C1-C6)alkyl, and (C1-C6)haloalkyl;
n is 0, 1, or 2;
RA1 is selected from H, and (C1-C4)alkyl;
RA2 is selected from H, F, and (C1-C4)alkyl;
RA3 is selected from H, F, and (C1-C4)alkyl;
RA4 is selected from H and OH; and
RA5 is selected from H, F, and (C1-C4)alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from F, Cl, and OCH3; and
R2 is selected from H, F, Cl, CH3, and OCH3.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is a moiety selected from:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from
and
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
and
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
and
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
and
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
and
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
and each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each RAa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
11. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A compound having a structural Formula (I.1):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from F, Cl, and OCH3;
R2 is selected from H, F, Cl, CH3, and OCH3;
ring A is
R3 is selected from pyrazolyl, triazolyl, and pyridinyl, wherein said pyrazolyl and said triazolyl, are substituted with 1 or 2 R3A groups, and wherein said pyridinyl is substituted with 1, 2, or 3 R3A groups, wherein:
each R3A is independently selected from CH3,
RA1 is H RA1 is selected from H, and (C1-C4)alkyl;
RA2 is H;
RA3 is H; and
RA5 is H.
13. The compound of claim 12, wherein R1 is F and R2 is OCH3.
14. The compound of claim 12, wherein R3 is pyrazolyl, wherein said pyrazolyl is substituted with
15. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
16. A compound, wherein the compound is:
17. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
18. A compound, wherein the compound is:
19. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
20. A compound, wherein the compound is:
21. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
22. A compound, wherein the compound is:
23. A compound, and pharmaceutically acceptable salts thereof, wherein the compound is:
24. A compound, wherein the compound is:
25. A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier.
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25
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FIELD OF THE INVENTION
The present invention relates to novel compounds that inhibit at least one of the A2a and A2b adenosine receptors, and pharmaceutically acceptable salts thereof, and compositions comprising such compound(s) and salts, methods for the synthesis of such compounds, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor. Such diseases, conditions, and disorders include but are not limited to cancer and immune-related disorders. The invention further relates to combination therapies, including but not limited to a combination comprising a compound of the invention and a PD-1 antagonist.
BACKGROUND OF THE INVENTION
Adenosine is a purine nucleoside compound comprised of adenine and ribofuranose, a ribose sugar molecule. Adenosine occurs naturally in mammals and plays important roles in various biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also plays a causative role in processes associated with vasodilation, including cardiac vasodilation. It also acts as a neuromodulator (e.g., it is thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent to treat supraventricular tachycardia and other indications.
The adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. The four types of adenosine receptors in humans are referred to as A1, A2a, A2b, and A3. Modulation of A1 has been proposed for the management and treatment of neurological disorders, asthma, and heart and renal failure, among others. Modulation of A3 has been proposed for the management and treatment of asthma and chronic obstructive pulmonary diseases, glaucoma, cancer, stroke, and other indications. Modulation of the A2a and A2b receptors are also believed to be of potential therapeutic use.
In the central nervous system, A2a antagonists are believed to exhibit antidepressant properties and to stimulate cognitive functions. A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2a receptor antagonists are believed to be useful in the treatment of depression and to improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia (as in Alzheimer's disease), and in various psychoses of organic origin.
In the immune system, adenosine signaling through A2a receptors and A2b receptors, expressed on a variety of immune cells and endothelial cells, has been established as having an important role in protecting tissues during inflammatory responses. In this way (and others), tumors have been shown to evade host responses by inhibiting immune function and promoting tolerance. (See, e.g., Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441). Moreover. A2a and A2b cell surface adenosine receptors have been found to be upregulated in various tumor cells. Thus, antagonists of the A2a and/or A2b adenosine receptors represent a new class of promising oncology therapeutics. For example, activation of A2a adenosine receptors results in the inhibition of the immune response to tumors by a variety of cell types, including but not limited to: the inhibition of natural killer cell cytotoxicity, the inhibition of tumor-specific CD4+/CD8+ activity, promoting the generation of LAG-3 and Foxp3+ regulatory T-cells, and mediating the inhibition of regulatory T-cells. Adenosine A2a receptor inhibition has also been shown to increase the efficacy of PD-1 inhibitors through enhanced anti-tumor T cell responses. As each of these immunosuppressive pathways has been identified as a mechanism by which tumors evade host responses, a cancer immunotherapeutic regimen that includes an antagonist of the A2a and/or A2b receptors, alone or together with one or more other therapeutic agents designed to mitigate immune suppression, may result in enhanced tumor immunotherapy. (See, e.g., P. Beavis, et al., Cancer Immunol. Res. DOI: 10.1158/2326-6066. CIR-14-0211, Feb. 11, 2015; Willingham, S B., et al., Cancer Immunol. Res., 6(10), 1136-49; and Leone R D, et al., Cancer Immunol. Immunother., August 2018, Vol. 67, Issue 8, 1271-1284).
Cancer cells release ATP into the tumor microenvironment when treated with chemotherapy and radiation therapy, which is subsequently converted to adenosine. (See Martins, I., et al., Cell Cycle, vol. 8, issue 22, pp. 3723 to 3728.) The adenosine can then bind to A2a receptors and blunt the anti-tumor immune response through mechanisms such as those described above. The administration of A2a receptor antagonists during chemotherapy or radiation therapy has been proposed to lead to the expansion of the tumor-specific T-cells while simultaneously preventing the induction of tumor-specific regulatory T-cells. (Young, A., et al., Cancer Discovery (2014) 4:879-888).
The combination of an A2a receptor antagonist with anti-tumor vaccines is believed to provide at least an additive therapeutic effect in view of their different mechanisms of action. Further, A2a receptor antagonists may be useful in combination with checkpoint blockers. By way of example, the combination of a PD-1 inhibitor and an adenosine A2a receptor inhibitor is thought to mitigate the ability of tumors to inhibit the activity of tumor-specific effector T-cells. (See, e.g., Willingham, S B., et al., Cancer Immunol. Res.; 6(10), 1136-49; Leone, R D., et al., Cancer Immunol. Immunother., August 2018, Vol. 67, Issue 8, pp. 1271-1284; Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441; and Sitkovsky, M V., et al., (2014) Cancer Immunol. Res 2:598-605.)
The A2b receptor is a G protein-coupled receptor found in various cell types. A2b receptors require higher concentrations of adenosine for activation than the other adenosine receptor subtypes, including A2a. (Fredholm, B B., et al., Biochem. Pharmacol. (2001) 61:443-448). Conditions which activate A2b have been seen, for example, in tumors where hypoxia is observed. The A2b receptor may thus play an important role in pathophysiological conditions associated with massive adenosine release. While the pathway(s) associated with A2b receptor-mediated inhibition are not well understood, it is believed that the inhibition of A2b receptors (alone or together with A2a receptors) may block pro-tumorigenic functions of adenosine in the tumor microenvironment, including suppression of T-cell function and angiogenesis, and thus expand the types of cancers treatable by the inhibition of these receptors.
A2b receptors are expressed primarily on myeloid cells. The engagement of A2b receptors on myeloid derived suppressor cells (MDSCs) results in their expansion in vitro (Ryzhov, S. et al., J. Immunol. 2011, 187:6120-6129). MDSCs suppress T-cell proliferation and anti-tumor immune responses. Selective inhibitors of A2b receptors and A2b receptor knockouts have been shown to inhibit tumor growth in mouse models by increasing MDSCs in the tumor microenvironment (Iannone, R., et al., Neoplasia Vol. 13 No. 12, (2013) pp. 1400-1409; Ryzhov, S., et al., Neoplasia (2008) 10: 987-995). Thus, A2b receptor inhibition has become an attractive biological target for the treatment of a variety of cancers involving myeloid cells. Examples of cancers that express A2b receptors can be readily obtained through analysis of the publicly available TCGA database. Such cancers include lung, colorectal, head and neck, and cervical cancer, among others, and are discussed in further detail below.
Angiogenesis plays an important role in tumor growth. The angiogenesis process is highly regulated by a variety of factors and is triggered by adenosine under particular circumstances that are associated with hypoxia. The A2b receptor is expressed in human microvascular endothelial cells, where it plays an important role in the regulation of the expression of angiogenic factors such as the vascular endothelial growth factor (VEGF). In certain tumor types, hypoxia has been observed to cause an upregulation of the A2b receptors, suggesting that inhibition of A2b receptors may limit tumor growth by limiting the oxygen supply to the tumor cells. Furthermore, experiments involving adenylate cyclase activation indicate that A2b receptors are the sole adenosine receptor subtype in certain tumor cells, suggesting that A2b receptor antagonists may exhibit effects on particular tumor types. (See, e.g., Feoktistov, I., et al., (2003) Circ. Res. 92:485-492; and P. Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441).
In view of their promising and varied therapeutic potential there remains a need in the art for potent and selective inhibitors of the A2a and/or A2b adenosine receptors, for use alone or in combination with other therapeutic agents. The present invention addresses this and other needs.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds (hereinafter referred to as compounds of the invention) which, surprisingly and advantageously, have been found to be inhibitors of the adenosine A2a receptor and/or the adenosine A2b receptor. The compounds of the invention have a structure in accordance with the structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein ring A, R1, and R2 are as defined below.
In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier or diluent. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
In another aspect, the present invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e.g., an animal or human) in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents. These and other aspects and embodiments of the invention are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
For each of the following embodiments, any variable not explicitly defined in the embodiment is as defined in Formula (I). In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted.
In one embodiment, the compounds of the invention have the structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from F, Cl, (C1-C6)alkyl, and O(C1-C6)alkyl;
R2 is selected from H, F, Cl, (C1-C6)alkyl, and O(C1-C6)alkyl;
ring A is a moiety selected from:
R3 is selected from pyrazolyl, triazolyl, and pyridinyl, wherein said pyrazolyl and said triazolyl, are substituted with 1 or 2 R3A groups, and wherein said pyridinyl is substituted with 1, 2, or 3 R3A groups, wherein:
each R3A is independently selected from (C1-C6)alkyl, O(C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)haloalkyl. O(C1-C6)haloalkyl, oxo, (C1-C4)alkylC(O)(C1-C3)alkyl, (C1-C4)alkylCH(OH)(C1-C3)alkyl, (C1-C4)alkylS(O)2(C1-C3)alkyl, —(CH2)n(C3-C7)cycloalkyl, and —(CH2)n4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from oxygen and nitrogen, wherein said (C3-C7)cycloalkyl, and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2, or 3 groups independently selected from F, Cl, OH, (C1-C6)alkyl, and (C1-C6)haloalkyl;
n is 0, 1, or 2;
RA1 is selected from H, and (C1-C4)alkyl;
RA2 is selected from H, F, and (C1-C4)alkyl;
RA3 is selected from H, F, and (C1-C4)alkyl;
RA4 is selected from H and OH; and
RA5 is selected from H, F, and (C1-C4)alkyl.
In another embodiment, the compounds of the invention have the structural Formula (I.1):
or a pharmaceutically acceptable salt thereof, wherein ring A, R1, and R2 are as defined in Formula (I).
In another embodiment, the compounds of the invention have the structural Formula (I.2):
or a pharmaceutically acceptable salt thereof, wherein ring A, R1, and R2 are as defined in Formula (I).
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
R1 is selected from F, Cl, and OCH3;
R2 is selected from H, F, Cl, CH3, and OCH3.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
R1 is F; and
R2 is selected from H, F, Cl, CH3, and OCH3.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
R1 is C1; and
R2 is selected from H, F, Cl, CH3, and OCH3.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
R1 is F; and
R2 is OCH3.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
R1 is F; and
R2 is F.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
R1 is F; and
R2 is H.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is a moiety selected from:
wherein R3, RA1, RA2, RA3, and RA5 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is a moiety selected from:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each RAa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, RA3, and RA5 are as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is a moiety selected from:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, RA3, and RA5 are as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In an alternative of the immediately preceding embodiment:
RA1 is selected from H, CH3, and CH2CH3;
RA2 is selected from H, F, CH3, and CH2CH3;
RA3 is selected from H and F; and
RA5 is H.
In another alternative of the immediately preceding embodiment:
RA1 is selected from H and CH3;
RA2 is H;
RA3 is H; and
RA5 is H.
In another alternative of the immediately preceding embodiment:
RA1 is H;
RA2 is H;
RA3 is H; and
RA5 is H.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein R3 and RA3 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA3 is as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA3 is as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In an alternative of the immediately preceding embodiment:
RA3 is selected from H and F.
In another alternative of the immediately preceding embodiment:
RA3 is H.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein R3 is as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each R3A, is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein R3 is as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each R3A is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl; and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein R3, RA1, RA2, and RA3 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, and RA3 are as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, and RA3 are as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In an alternative of the immediately preceding embodiment:
RA1 is selected from H, CH3, and CH2CH3:
RA2 is selected from H, F, CH3, and CH2CH3; and
RA3 is selected from H and F.
In another alternative of the immediately preceding embodiment:
RA1 is selected from H and CH3:
RA2 is H; and
RA3 is H.
In another alternative of the immediately preceding embodiment:
RA1 is H;
RA2 is H; and
RA3 is H.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein R3, RA1, RA2, and RA3 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, and RA3 are as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, and RA3 are as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In an alternative of the immediately preceding embodiment:
RA1 is selected from H, CH3, and CH2CH3;
RA2 is selected from H, F, CH3, and CH2CH3; and
RA3 is selected from H and F.
In another alternative of the immediately preceding embodiment:
RA1 is selected from H and CH3;
RA2 is H; and
RA3 is H.
In another alternative of the immediately preceding embodiment:
RA1 is H;
RA2 is H; and
RA3 is H.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein R3, RA1, RA2, RA3 and RA4 are as defined in Formula (I); and wherein R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is as defined in Formula (I);
each R3Aa is independently selected from (C1-C4)alkyl, O(C1-C4)allyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, RA3 and RA4 re as defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In another embodiment, in each of Formulas (I), (I.1), and (I.2):
ring A is the moiety:
wherein:
R3 is selected from
wherein:
each R3A is a moiety selected from:
each RAa is independently selected from (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, and O(C1-C4)haloalkyl;
RA1, RA2, RA3 and RA4 are defined in Formula (I); and
R1 and R2 are as defined in Formula (I) or as defined in any of the alternative embodiments of R1 and R2 described above.
In an alternative of the immediately preceding embodiment:
RA1 is selected from H, CH3, and CH2CH3;
RA2 is selected from H, F, CH3, and CH2CH3;
RA3 is selected from H and F; and
RA4 is selected from H and OH.
In an alternative of the immediately preceding embodiment:
RA1 is H;
RA2 is H:
RA3 is H; and
RA4 is selected from H and OH.
In another embodiment, the compounds of the invention comprise those compounds identified herein as examples in the tables below, and pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt thereof. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.
In another aspect, the present invention provides a method for the manufacture of a medicament or a composition which may be useful for treating diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor, comprising combining a compound of the invention with one or more pharmaceutically acceptable carriers.
In another aspect, the present invention provides a method for treating or preventing a disease, condition, or disorder that is mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject (e.g., an animal or human) in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents. Specific non-limiting examples of such diseases, conditions, and disorders are described herein.
Oncology
In some embodiments, the disease, condition or disorder is a cancer. Any cancer for which a PD-1 antagonist and/or an A2a and/or A2b inhibitor are thought to be useful by those of ordinary skill in the art are contemplated as cancers treatable by this embodiment, either as a monotherapy or in combination with other therapeutic agents discussed below. Cancers that express high levels of A2a receptors or A2b receptors are among those cancers contemplated as treatable by the compounds of the invention. Examples of cancers that express high levels of A2a and/or A2b receptors may be discerned by those of ordinary skill in the art by reference to the Cancer Genome Atlas (TCGA) database. Non-limiting examples of cancers that express high levels of A2a receptors include cancers of the kidney, breast, lung, and liver. Non-limiting examples of cancers that express high levels of the A2b receptor include lung, colorectal, head & neck cancer, and cervical cancer.
Thus, one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2a receptor. A related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from kidney (or renal) cancer, breast cancer, lung cancer, and liver cancer.
Another embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is a cancer that expresses a high level of A2b receptor. A related embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said cancer is selected from lung cancer, colorectal cancer, head & neck cancer, and cervical cancer.
Additional non-limiting examples of cancers which may be treatable by administration of a compound of the invention (alone or in combination with one or more additional agents described below) include cancers of the prostate (including but not limited to metastatic castration resistant prostate cancer), colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma, and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including but not limited to small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), adrenal gland, thyroid, kidney, or bone. Additional cancers treatable by a compound of the invention include glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma, and Kaposi's sarcoma.
CNS and Neurological Disorders
In other embodiments, the disease, condition or disorder is a central nervous system or a neurological disorder. Non-limiting examples of such diseases, conditions or disorders include movement disorders such as tremors, bradykinesias, gait disorders, dystonias, dyskinesias, tardive dyskinesias, other extrapyramidal syndromes. Parkinson's disease, and disorders associated with Parkinson's disease. The compounds of the invention also have the potential, or are believed to have the potential, for use in preventing or reducing the effect of drugs that cause or worsen such movement disorders.
Infections
In other embodiments, the disease, condition or disorder is an infective disorder. Non-limiting examples of such diseases, conditions or disorders include an acute or chronic viral infection, a bacterial infection, a fungal infection, or a parasitic infection. In one embodiment, the viral infection is human immunodeficiency virus. In another embodiment, the viral infection is cytomegalovirus.
In other embodiments, the disease, condition or disorder is an immune-related disease, condition or disorder. Non-limiting examples of immune-related diseases, conditions, or disorders include multiple sclerosis and bacterial infections. (See, e.g., Safarzadeh, E. et al., Inflamm Res 2016 65(7):511-20; and Antonioli, L., et al., Immunol Lett S0165-2478(18)30172-X 2018).
Additional Indications
Other diseases, conditions, and disorders that have the potential to be treated or prevented, in whole or in part, by the inhibition of the A2a and/or A2b adenosine receptor(s) are also candidate indications for the compounds of the invention and salts thereof. Non-limiting examples of other diseases, conditions or disorders in which a compound of the invention, or a pharmaceutically acceptable salt thereof, may be useful include the treatment of hypersensitivity reaction to a tumor antigen and the amelioration of one or more complications related to bone marrow transplant or to a peripheral blood stem cell transplant. Thus, in another embodiment, the present invention provides a method for treating a subject receiving a bone marrow transplant or a peripheral blood stem cell transplant by administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, sufficient to increase the delayed-type hypersensitivity reaction to tumor antigen, to delay the time-to-relapse of post-transplant malignancy, to increase relapse-free survival time post-transplant, and/or to increase long-term post-transplant survival.
Combination Therapy
In another aspect, the present invention provides methods for the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, (or a pharmaceutically acceptable composition comprising a compound of the invention or pharmaceutically acceptable salt thereof) in combination with one or more additional agents. Such additional agents may have some adenosine A2a and/or A2b receptor activity, or, alternatively, they may function through distinct mechanisms of action. The compounds of the invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds of the invention or the other drugs described herein may have utility, where the combination of the drugs together are safer or more effective than either drug alone. The combination therapy may have an additive or synergistic effect. Such other drug(s) may be administered in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention or a pharmaceutically acceptable salt thereof. When a compound of the invention is used contemporaneously with one or more other drugs, the pharmaceutical composition may in specific embodiments contain such other drugs and the compound of the invention or its pharmaceutically acceptable salt in separate doses or in unit dosage form. However, the combination therapy may also include therapies in which the compound of the invention or its pharmaceutically acceptable salt and one or more other drugs are administered sequentially, on different or overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions comprising the compounds of the invention include those that contain one or more other active ingredients, in addition to a compound of the invention or a pharmaceutically acceptable salt thereof.
The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is used in combination with another agent, the weight ratio of the compound of the present invention to the other agent may generally range from about 1000:1 to about 1:1000, in particular embodiments from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should generally be used.
Given the immunosuppressive role of adenosine, the administration of an A2a receptor antagonist, an A2b receptor antagonist, and/or an A2a/A2b receptor dual antagonist according to the invention may enhance the efficacy of immunotherapies such as PD-1 antagonists. Thus, in one embodiment, the additional therapeutic agent comprises an anti-PD-1 antibody. In another embodiment, the additional therapeutic agent is an anti-PD-L1 antibody.
As noted above, PD-1 is recognized as having an important role in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T-cells, B-cells and NKT-cells and up-regulated by T-cell and B-cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe et al., Nature Immunology (2007); 8:239-245).
Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC) are expressed in human cancers arising in various tissues. In large sample sets of, for example, ovarian, renal, colorectal, pancreatic, and liver cancers, and in melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment. (Dong et al., Nat Med. 8(8):793-800 (2002); Yang et al., Invest Ophthamol Vis Sci. 49: 2518-2525 (2008); Ghebeh et al., Neoplasia 8:190-198 (2006); Hamanishi et al., Proc. Natl. Acad. Sci. USA 104: 3360-3365 (2007); Thompson et al., Cancer 5: 206-211 (2006) Nomi et al., Clin. Cancer Research 13:2151-2157 (2007); Ohigashi et al., Clin. Cancer Research 11: 2947-2953; Inman et al., Cancer 109: 1499-1505 (2007); Shimauchi et al., Int. J. Cancer 121:2585-2590 (2007); Gao et al., Clin. Cancer Research 15: 971-979 (2009); Nakanishi J., Cancer Immunol Immunother. 56: 1173-1182 (2007); and Hino et al., Cancer 00: 1-9 (2010)).
Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T-cells in breast cancer and melanoma (Ghebeh et al., BMC Cancer. 2008 8:5714-15 (2008); and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and to correlate with poor prognosis in renal cancer (Thompson et al., Clinical Cancer Research 15: 1757-1761(2007)). Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T-cells to attenuate T-cell activation and to evade immune surveillance, thereby contributing to an impaired immune response against the tumor.
Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers (Brahmer, et al., N Engl J Med 2012, 366: 2455-65; Garon et al., N Engl J Med 2015, 372: 2018-28; Hamid et al., N Engl J Med 2013, 369: 134-44: Robert et al., Lancet 2014, 384: 1109-17; Robert et al., N Engl J Med 2015, 372: 2521-32; Robert et al., N Engl J Med 2015, 372: 320-30; Topalian et al., N Engl J Med 2012, 366: 2443-54; Topalian et al., J Clin Oncol 2014, 32: 1020-30; and Wolchok et al., N Engl J Med 2013, 369: 122-33).
“PD-1 antagonist” means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T-cell, B-cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the treatment methods, medicaments and uses of the present invention in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD-L and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Kenilworth, N.J., USA). “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes referred to as “pembro”) is a humanized IgG4 mAb with the structure described in WHO Drug Information. Vol. 27, No. 2, pages 161-162 (2013). Additional examples of PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, N.J., USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, Calif., USA), durvalumab (IMFINZI®, Astra Zeneca Pharmaceuticals, LP, Wilmington, Del., and avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, N.Y.).
Examples of monoclonal antibodies (mAbs) that bind to human PD-1, and useful in the treatment methods, medicaments and uses of the present invention, are described in U.S. Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,168,757, WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.
Examples of mAbs that bind to human PD-L1, and useful in the treatment methods, medicaments and uses of the present invention, are described in WO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013/019906.
Other PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.
Thus, one embodiment provides for a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 antagonist to a subject in need thereof. In such embodiments, the compounds of the invention, or a pharmaceutically acceptable salt thereof, and PD-1 antagonist are administered concurrently or sequentially.
Specific non-limiting examples of such cancers in accordance with this embodiment include melanoma (including unresectable or metastatic melanoma), head & neck cancer (including recurrent or metastatic head and neck squamous cell cancer (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, and salivary cancer.
In one embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma and for the treatment of certain patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma, as described in the Prescribing Information for KEYTRUDA™ (Merck & Co., Inc., Whitehouse Station, N.J. USA; initial U.S. approval 2014, updated November 2018). In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with pembrolizumab, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma.
In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell cancer (HNSCC), Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.
In another embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, renal cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.
In one embodiment, there is provided a method of treating unresectable or metastatic melanoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating recurrent or metastatic head and neck squamous cell cancer (HNSCC) comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating classical Hodgkin lymphoma (cHL) comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating urothelial carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating gastric cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating cervical cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating primary mediastinal large-B-cell lymphoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating microsatellite instability-high (MSI-H) cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating non-small cell lung cancer comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In one embodiment, there is provided a method of treating hepatocellular carcinoma comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a person in need thereof, in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.
In another embodiment, the additional therapeutic agent is at least one immunomodulator other than an A2a or A2b receptor inhibitor. Non-limiting examples of immunomodulators include CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN-a/-13, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10 and indolamine 2,3-dioxygenase 1 (IDO1) inhibitors.
In another embodiment, the additional therapeutic agent comprises radiation. Such radiation includes localized radiation therapy and total body radiation therapy.
In another embodiment, the additional therapeutic agent is at least one chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents contemplated for use in combination with the compounds of the invention include: pemetrexed, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin, carboplatin and oxaliplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); anthracycline-based therapies (e.g., doxorubicin, daunorubicin, epirubicin and idarubicin); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin); antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea); tubulin interactive agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens; conjugated estrogens; ethynyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); luteinizing hormone releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide).
In another embodiment, the additional therapeutic agent is at least one signal transduction inhibitor (STI). Non-limiting examples of signal transduction inhibitors include BCR/ABL kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2/neu receptor inhibitors, and farnesyl transferase inhibitors (FTIs).
In another embodiment, the additional therapeutic agent is at least one anti-infective agent. Non-limiting examples of anti-infective agents include cytokines, non-limiting examples of which include granulocyte-macrophage colony stimulating factor (GM-CSF) and an flt3-ligand.
In another embodiment, the present invention provides a method for treating or preventing a viral infection (e.g., a chronic viral infection) including, but not limited to, hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).
In another embodiment, the present invention provides a method for the treatment of an infective disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a vaccine. In some embodiments, the vaccine is an anti-viral vaccine, including, for example, an anti-HTV vaccine. Other antiviral agents contemplated for use include an anti-HIV, anti-HPV, anti HCV, anti HSV agents and the like. In other embodiments, the vaccine is effective against tuberculosis or malaria. In still other embodiments, the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF). In another embodiment, the vaccine includes one or more immunogenic peptides and/or dendritic cells.
In another embodiment, the present invention provides for the treatment of an infection by administering a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein a symptom of the infection observed after administering both the compound of the invention (or a pharmaceutically acceptable salt thereof) and the additional therapeutic agent is improved over the same symptom of infection observed after administering either alone. In some embodiments, the symptom of infection observed can be reduction in viral load, increase in CD4+ T cell count, decrease in opportunistic infections, increased survival time, eradication of chronic infection, or a combination thereof.
Definitions
As used herein, unless otherwise specified, the following terms have the following meanings.
Unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein are assumed to have a hydrogen atom or atoms of sufficient number to satisfy the valences.
When a variable appears more than once in any moiety or in any compound of the invention (e.g., aryl, heterocycle, N(R)2), the selection of moieties defining that variable for each occurrence is independent of its definition at every other occurrence unless specified otherwise in the local variable definition.
As used herein, unless otherwise specified, the term “A2a receptor antagonist” (equivalently, A2a antagonist) and/or “A2b receptor antagonist” (equivalently, A2b antagonist) means a compound exhibiting a potency (IC50) of less than about 1 μM with respect to the A2a and/or A2b receptors, respectively, when assayed in accordance with the procedures described herein. Preferred compounds exhibit at least 10-fold selectivity for antagonizing the A2a receptor and/or the A2b receptor over any other adenosine receptor (e.g., A1 or A3).
As described herein, unless otherwise indicated, the use of a compound in treatment means that an amount of the compound, generally presented as a component of a formulation that comprises other excipients, is administered in aliquots of an amount, and at time intervals, which provides and maintains at least a therapeutic serum level of at least one pharmaceutically active form of the compound over the time interval between dose administrations.
The phrase “at least one” used in reference to the number of components comprising a composition, for example, “at least one pharmaceutical excipient” means that one member of the specified group is present in the composition, and more than one may additionally be present. Components of a composition are typically aliquots of isolated pure material added to the composition, where the purity level of the isolated material added into the composition is the normally accepted purity level for a reagent of the type.
Whether used in reference to a substituent on a compound or a component of a pharmaceutical composition the phrase “one or more”, means the same as “at least one”.
“Concurrently” and “contemporaneously” both include in their meaning (1) simultaneously in time (e.g., at the same time); and (2) at different times but within the course of a common treatment schedule.
“Consecutively” means one following the other.
“Sequentially” refers to a series administration of therapeutic agents that awaits a period of efficacy to transpire between administering each additional agent: this is to say that after administration of one component, the next component is administered after an effective time period after the first component; the effective time period is the amount of time given for realization of a benefit from the administration of the first component.
“Effective amount” or “therapeutically effective amount” is meant to describe the provision of an amount of at least one compound of the invention or of a composition comprising at least one compound of the invention which is effective in treating or inhibiting a disease or condition described herein, and thus produce the desired therapeutic, ameliorative, inhibitory or preventative effect. For example, in treating a cancer as described herein with one or more of the compounds of the invention optionally in combination with one or more additional agents, “effective amount” (or “therapeutically effective amount”) means, for example, providing the amount of at least one compound of the invention that results in a therapeutic response in a patient afflicted with the disease, condition, or disorder, including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and/or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition.
“Patient” and “subject” means an animal, such as a mammal (e.g., a human being) and is preferably a human being.
“Prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of a compound of the invention to a compound of the invention, or to a salt thereof. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes prodrugs of the novel compounds of this invention.
The term “substituted” means that one or more of the moieties enumerated as substituents (or, where a list of substituents are not specifically enumerated, the substituents specified elsewhere in this application) for the particular type of substrate to which said substituent is appended, provided that such substitution does not exceed the normal valence rules for the atom in the bonding configuration presented in the substrate, and that the substitution ultimate provides a stable compound, which is to say that such substitution does not provide compounds with mutually reactive substituents located geminal or vicinal to each other; and wherein the substitution provides a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
Where optional substitution by a moiety is described (e.g. “optionally substituted”) the term means that if substituents are present, one or more of the enumerated (or default) moieties listed as optional substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent, for example, a hydrogen atom on an alkyl chain can be substituted by one of the optional substituents, in accordance with the definition of “substituted” presented herein.
“Alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 10 carbon atoms. “(C1-C6)alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.
“Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl (up to and including each available hydrogen group) is replaced by a halogen atom. As appreciated by those of skill in the art, “halo” or “halogen” as used herein is intended to include chloro (Cl), fluoro (F), bromo (Br) and iodo (I), Chloro (Cl) and fluoro(F) halogens are generally preferred.
“Aryl” means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. “Monocyclic aryl” means phenyl.
“Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term “monocyclic heteroaryl” refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moieties include pyridyl, pyrazinyl furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
“Cycloalkyl” means a non-aromatic fully saturated monocyclic or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of multicyclic cycloalkyls include [1.1.1]-bicyclopentane, 1-decalinyl, norbornyl, adamantyl and the like.
“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkyl groups contain 4, 5 or 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide. S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein ═O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such ═O groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone);
As used herein, the term “monocyclic heterocycloalkyl” refers to monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S. S-oxide, S(O), and S(O)2. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limiting examples of lower alkyl-substituted oxetanyl include the moiety:
It is noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups on carbon adjacent to another heteroatom.
there is no —OH attached directly to carbons marked 2 and 5.
The line , as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example:
means containing both
The wavy line , as used herein, indicates a point of attachment to the rest of the compound. Lines drawn into the ring systems, such as, for example:
indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms.
“Oxo” is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,
As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:
represents
One or more compounds of the invention may also exist as, or optionally be converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous-based) and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I.R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form).
The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.
This invention also includes the compounds of the invention in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of the invention, and of the salts, solvates and prodrugs of the thereof, are intended to be included in the present invention. Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The inventive compounds include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.
In similar manner, unless indicated otherwise, presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such tautomeric forms of the compound. Accordingly, where compounds of the invention, their salts, and solvates and prodrugs thereof, may exist in different tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced by, and included within the scope of the invention. Examples of such tautomers include, but are not limited to, ketone/enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:
and
Where a reaction scheme appearing in an example employs a compound having one or more stereocenters, the stereocenters are indicated with an asterisk, as shown below:
Accordingly, the above depiction consists of the following pairs of isomers: (i) Trans-isomers ((2R,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-1) and ((2S,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-2); and (ii) Cis-isomers ((2R,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-3) and ((2S,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (Compound ABC-4).
All stereoisomers of the compounds of the invention (including salts and solvates of the inventive compounds and their prodrugs), such as those which may exist due to asymmetric carbons present in a compound of the invention, and including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may be isolated in a pure form, for example, substantially free of other isomers, or may be isolated as an admixture of two or more stereoisomers or as a racemate. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to salts, solvates and prodrugs of isolated enantiomers, stereoisomer pairs or groups, rotamers, tautomers, or racemates of the inventive compounds.
Where diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by known methods, for example, by chiral chromatography and/or fractional crystallization, simple structural representation of the compound contemplates all diastereomers of the compound. As is known, enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individually isolated diastereomers to the corresponding purified enantiomers.
As the term is employed herein, salts of the inventive compounds, whether acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, are included in the scope of the inventive compounds described herein. The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19: P. Gould, International J. of Pharmaceutics (1986) 33 201-217: Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York: in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference.
The present invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe” for use in the preparation of pharmaceutical formulations, termed herein as “pharmaceutically acceptable salts”. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates) undecanoates, and the like.
Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be converted to an ammonium ion or quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the scope of the invention.
A functional group in a compound termed “protected” means that the group is in modified form to preclude undesired side reactions at the protected site when the protected compound is subjected to particular reaction conditions aimed at modifying another region of the molecule. Suitable protecting groups are known, for example, as by reference to standard textbooks, for example, T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.
In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
The present invention also embraces isotopically-labeled compounds of the present invention which are structurally identical to those recited herein, but for the fact that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope usually found in nature, thus altering the naturally occurring abundance of that isotope present in a compound of the invention. Examples of isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 8F, and 36Cl, 123I and 125I. It will be appreciated that other isotopes also may be incorporated by known means.
Certain isotopically-labeled compounds of the invention (e.g., those labeled with 3H, 11C and 14C) are recognized as being particularly useful in compound and/or substrate tissue distribution assays using a variety of known techniques. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detection. Further, substitution of a naturally abundant isotope with a heavier isotope, for example, substitution of protium with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the reaction Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent, or by well-known reactions of an appropriately prepared precursor to the compound of the invention which is specifically prepared for such a “labeling” reaction. Such compounds are included also in the present invention.
The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The term “pharmaceutical composition” as used herein encompasses both the bulk composition and individual dosage units comprised of one, or more than one (e.g., two), pharmaceutically active agents such as, for example, a compound of the present invention (optionally together with an additional agent as described herein), along with any pharmaceutically inactive excipients. As will be appreciated by those of ordinary skill in the art, excipients are any constituent which adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid one, or more than one, pharmaceutically active agents. The bulk composition is material that has not yet been formed into individual dosage units.
It will be appreciated that pharmaceutical formulations of the invention may comprise more than one compound of the invention (or a pharmaceutically acceptable salt thereof), for example, the combination of two or three compounds of the invention, each present in such a composition by adding to the formulation the desired amount of the compound in a pharmaceutically acceptably pure form. It will be appreciated also that in formulating compositions of the invention, a composition may comprise, in addition to one or more of compounds of the invention, one or more other agents which also have pharmacological activity, as described herein.
While formulations of the invention may be employed in bulk form, it will be appreciated that for most applications the inventive formulations will be incorporated into a dosage form suitable for administration to a patient, each dosage form comprising an amount of the selected formulation which contains an effective amount of one or more compounds of the invention. Examples of suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties; (iii) a dosage form adapted for intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag; (iv) a dosage form adapted for administration through tissues of the oral cavity, for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachets or a needle array suitable for providing intramucosal administration; (v) a dosage form adapted for administration via the mucosa of the nasal or upper respiratory cavity, for example a solution, suspension or emulsion formulation for dispersion in the nose or airway; (vi) a dosage form adapted for transdermal administration, for example, a patch, cream or gel; (vii) a dosage form adapted for intradermal administration, for example, a microneedle array; and (viii) a dosage form adapted for delivery via rectal or vaginal mucosa, for example, a suppository.
For preparing pharmaceutical compositions comprising compounds of the invention, generally the compounds of the invention will be combined with one or more pharmaceutically acceptable excipients. These excipients impart to the composition properties which make it easier to handle or process, for example, lubricants or pressing aids in powdered medicaments intended to be tableted, or adapt the formulation to a desired route of administration, for example, excipients which provide a formulation for oral administration, for example, via absorption from the gastrointestinal tract, transdermal or transmucosal administration, for example, via adhesive skin “patch” or buccal administration, or injection, for example, intramuscular or intravenous, routes of administration. These excipients are collectively termed herein “a carrier”. Typically formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.
Pharmaceutical compositions can be solid, semi-solid or liquid. Solid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration. Liquid form preparations include, but are not limited to, solutions, suspensions and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for parenteral injection, for intranasal administration, or for administration to some other mucosal membrane. Formulations prepared for administration to various mucosal membranes may also include additional components adapting them for such administration, for example, viscosity modifiers.
Aerosol preparations, for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to a suspension or a solution, for example, for oral or parenteral administration. Examples of such solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.
The compounds of the invention may also be deliverable transdermally or transmucosally, for example, from a liquid, suppository, cream, foam, gel, or rapidly dissolving solid form. It will be appreciated that transdermal compositions can take also the form of creams, lotions, aerosols and/or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any know in the art, for example, a patch which incorporates either a matrix comprising the pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound.
Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions mentioned above may be found in A. Gennaro (ed.). Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
In accordance with the present invention, antagonism of adenosine A2a and/or A2b receptors is accomplished by administering to a patient in need of such therapy an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof.
In some embodiments it is preferred for the compound to be administered in the form of a pharmaceutical composition comprising the compound of the invention, or a salt thereof, and at least one pharmaceutically acceptable carrier (described herein). It will be appreciated that pharmaceutically formulations of the invention may comprise more than one compound of the invention, or a salt thereof, for example, the combination of two or three compounds of the invention, or, additionally or alternatively, another active agent such as those described herein, each present by adding to the formulation the desired amount of the compound or a salt thereof (or agent, where applicable) which has been isolated in a pharmaceutically acceptably pure form.
As mentioned above, administration of a compound of the invention to effect antagonism of A2a and/or A2b receptors is preferably accomplished by incorporating the compound into a pharmaceutical formulation incorporated into a dosage form, for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the invention), or a pharmaceutically acceptable salt thereof. Methods for determining safe and effective administration of compounds which are pharmaceutically active, for example, a compound of the invention, are known to those skilled in the art, for example, as described in the standard literature, for example, as described in the “Physicians' Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA), the Physician's Desk Reference, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, N.J. 07645-1742), or the Physician's Desk Reference, 57th Edition, 2003 (published by Thompson P D R, Montvale, N.J. 07645-1742); the disclosures of which is incorporated herein by reference thereto. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Compounds of the invention can be administered at a total daily dosage of up to 1,000 mg, which can be administered in one daily dose or can be divided into multiple doses per 24 hour period, for example, two to four doses per day.
As those of ordinary skill in the art will appreciate, an appropriate dosage level for a compound (or compounds) of the invention will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.
Those skilled in the art will appreciate that treatment protocols utilizing at least one compound of the invention can be varied according to the needs of the patient. Thus, compounds of the invention used in the methods of the invention can be administered in variations of the protocols described above. For example, compounds of the invention can be administered discontinuously rather than continuously during a treatment cycle.
In general, in whatever form administered, the dosage form administered will contain an amount of at least one compound of the invention, or a salt thereof, which will provide a therapeutically effective serum level of the compound in some form for a suitable period of time such as at least 2 hours, more preferably at least four hours or longer. In general, as is known in the art, dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention can be spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered. As will be appreciated the dosage form administered may also be in a form providing an extended release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals. As mentioned above, a composition of the invention can incorporate additional pharmaceutically active components or be administered simultaneously, contemporaneously, or sequentially with other pharmaceutically active agents as may be additionally needed or desired in the course of providing treatment. As will be appreciated, the dosage form administered may also be in a form providing an extended release period for the pharmaceutically active compound which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.
PREPARATIVE EXAMPLES
The compounds of the present invention can be prepared readily according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions.
One general strategy for the synthesis of compounds of type G1.6 is via the four-step procedure shown in General Scheme 1, wherein R4 corresponds to ring A in Formula (I) and wherein R1, R2, and ring A are as defined in Formula (I). In the first step, amino benzonitriles G1.1 can be treated with 1-(isocyanatomethyl)-2,4-dimethoxybenzene in solvents such as the combination of dichloromethane and pyridine to form intermediate ureas G1.2. In the second step, these ureas can be dehydrated to the corresponding carbodiimides G1.3 in the presence of triphenylphosphine, carbon tetrabromide, and triethylamine in a solvent such as dichloromethane. In the third step, treatment of carbodiimides G1.3 with a hydrazide of the type G1.4 in the presence of acetic acid in a solvent such as dichloromethane or dioxane, produces products of the type G1.5. In the fourth step, the 2,4-dimethoxybenzyl group of G1.4 is removed under acidic conditions to provide products of type G1.6, which can be purified by silica gel chromatography, preparative reversed phase HPLC, and/or chiral SFC.
One general strategy for the synthesis of compounds of type G2.5 is via the three-step procedure shown in General Scheme 2, wherein RA(n) corresponds to RA1, RA2, RA3, and RA5 in Formula (I) and wherein R1, R2, R3 and RA(n) (as RA1, RA2, RA3, and RA5) are as defined in Formula (I). In the first step, protected cyclic amines G2.1 can be converted into unprotected amines G2.2 through carefully controlled treatment with acid. Acids such as formic acid in the absence of solvent or hydrochloric acid in the presence of MeOH or DCM, can be used. In the second step, intermediates of type G2.2 can be converted into intermediates of type G2.4 through a transition-metal catalyzed C—N coupling reaction with aryl bromides G2.3. The reaction is performed under deoxygenated conditions with palladium catalysts such as, tert-butyl X-Phos Third Generation Precatalyst, a base such as sodium tert-butoxide, and a solvent such as THF, at the appropriate temperature. In the third step, the 2,4-dimethoxybenzyl group of G2.4 is removed under acidic conditions to provide products of type G2.5, which can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
One general strategy for the synthesis of compounds of type G3.6 is via a four-step procedure shown in General Scheme 3, wherein R4 corresponds to ring A in Formula (I) and wherein R1, R2, and ring A are as defined in Formula (I). In the first step, amino benzoic acids G3.1 can be converted into amino quinazolines G3.2 via treatment with cyanamide in the presence of aqueous HCl in a solvent such as EtOH. In the second step, intermediates of type G3.2 can be converted into intermediates of type G3.3 through coupling with 1,2,4-triazole, following treatment of G3.2 with phosphorous(V) oxychloride in a solvent such as acetonitrile. In the third step, intermediates of type G3.3 can be treated with hydrazides G3.4 in a solvent such as THF, to provide products of type G3.5. In the fourth step, intermediates of type G3.5 can undergo a rearrangement upon heating in neat N,O-Bis(trimethylsilyl)acetamide (BSA) to form products of type G3.6. Products of type G3.6 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
One general strategy for the synthesis of compounds of type G4.5 is via a three-step procedure outlined in General Scheme 4, wherein R1, R2, R3, RA1, RA2, and RA3 are defined in Formula (I). Heteroaryl cyclohexanol G4.1 can be converted into the corresponding cyclohexanone G4.2 via oxidation with Dess-Martin periodinane. In the second step, intermediates of type G4.2 can undergo treatment with an R3—Li G4.3 at low temperature, to provide products of type G4.4. In the third step, the 2,4-dimethoxybenzyl group of G2.4 can be removed with DDQ to provide products of type G4.5, which can be purified by silica gel chromatography, preparative reversed-phase HPLC, and/or chiral SFC.
Experimentals
Abbreviations used in the experimentals may include, but are not limited to, the following:
18-crown-6
1,4,7,10,13,16-hexaoxacyclooctadecane
° C.
Degrees Celsius
AcOH
Acetic acid
aq.
Aqueous
Atm
Atmospheres
Boc2O
Di-tert-butyl dicarbonate
BSA
N,O-Bis(trimethylsilyl)acetamide
CD3OD
Deuterated Methanol-d4
DCM
Dichloromethane
DDQ
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DEA
Diethylamine
DIAD
Diisopropyl diazene-1,2-dicarboxylate
DIBAL
Diisobutylaluminium hydride
DIPEA
N,N-Diisopropylethylamine
DMAP
4-(dimethylamino)-pyridine
DMF
Dimethylformamide
DMP
Dess-Martin periodinane
DMSO
Dimethyl Sulfoxide
DMSO-d6
Deuterated Dimethyl Sulfoxide
dppf
Bis(diphenylphosphino)ferrocene
ES
Electrospray Ionization
Et2O
Diethylether
EtOAc
Ethyl Acetate
EtOH
Ethanol
h
Hours
HPLC
High Performance Liquid Chromatography
M
Molar
MeCN
Acetonitrile
MeOD-d4
Deuterated Methanol
MeOH
Methanol
MHz
Megahertz
min
Minutes
mL
Milliliters
MS
Mass Spectroscopy
MsC1
p-Toluenesulfonyl chloride
NaH
Sodium hydride
NBS
N-Bromosuccinimide
nm
Nanometers
NMR
Nuclear Magnetic Resonance
Pd/C
Palladium on Carbon
PPTS
Pyrdinium para-toluenesulfonate
p-TsOH
4-Methylbenzenesulfonic acid
Py
Pyridine
rac
racemic
SFC
Supercritical Fluid (CO2) Chromatography
T3P
Tripropyl phosphonic anhydride
tBuXPhos-Pd G3
[(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-
1,1′-biphenyl)-2-(T-amino-1,1′-biphenyl)]
palladium(II) methanesulfonate CAS# 1447963-75-8
Tf2O
Trifluoromethanesulfonic anhydride
TFA
Trifluoroacetic acid
TFE
2,2,2-Trifluoroethanol
THF
Tetrahydrofuran
THP
(tetrahydro-2H-pyran-2-yl)oxy
TLC
Thin Layer Chromatography
General Experimental Information:
Unless otherwise noted, all reactions were magnetically stirred and performed under an inert atmosphere such as nitrogen or argon.
Unless otherwise noted, diethyl ether used in the experiments described below was Fisher ACS certified material and stabilized with BHT.
Unless otherwise noted, “degassed” refers to a solvent from which oxygen has been removed, generally by bubbling an inert gas such as nitrogen or argon through the solution for 10 to 15 minutes with an outlet needle to normalize pressure.
Unless otherwise noted, “concentrated” means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump.
Unless otherwise noted, “evaporated” means evaporating using a rotary evaporator or vacuum pump.
Unless otherwise noted, silica gel chromatography was carried out on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as the column. Columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated on a Genevac® evaporator or were lyophilized.
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra and proton-decoupled carbon nuclear magnetic resonance (13C {1H} NMR) spectra were recorded on 400, 500, or 600 MHz Bruker or Varian NMR spectrometers at ambient temperature. All chemical shifts (δ) were reported in parts per million (ppm). Proton resonances were referenced to residual protium in the NMR solvent, which can include, but is not limited to, CDCl3, DMSO-d6, and MeOD-d4. Carbon resonances are referenced to the carbon resonances of the NMR solvent. Data are represented as follows: chemical shift, multiplicity (br=broad, br s=broad singlet, s=singlet. d=doublet, dd=doublet of doublets, ddd=doublet of doublet of doublets, t=triplet, q=quartet, m=multiplet), coupling constants (J) in Hertz (Hz), integration.
Intermediate 1: rac-3-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol
To a stirred solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol) in DMF (3.40 ml) was added cesium carbonate (2.22 g, 6.80 mmol) and 2,2,3-trimethyloxirane (820 mg, 9.52 mmol). The mixture was stirred and heated at 90° C. for 4 h. The mixture was cooled to room temperature, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 5-100% EtOAc in hexanes as eluent to afford rac-3-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C8H13BrN2O) (ES, m/z) [M+H]+: 233, 235.
The intermediates in the following Table 1 were prepared in a manner similar to that of Intermediate 1 from the appropriate pyrazole and epoxide.
TABLE 1
Inter-
Structure
Observed
mediate
Name
m/z [M + H]+
2
1-(3-bromo-1H-1,2,4-triazol-1-yl)- 2-methylpropan-2-ol
220, 222
3
1-(3-bromo-5-methyl-1H-1,2,4-triazol- 1-yl)-2-methylpropan-2-ol
234, 236
4
1-(4-bromo-1H-pyrazol-1-yl)- 2-methylpropan-2-ol
219, 221
5
2-(4-bromo-1H-pyrazol-1-yl) cyclopentan-1-ol
231, 233
6
2-(4-bromo-1H-pyrazol-1-yl)- 1-methylcyclopentan-1-ol
245, 247
7
mixture of 1-(4-bromo-3-methyl-1H-pyrazol- 1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5- methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
ND
8
mixture of rac-3-(4-bromo-3-methyl-1H-pyrazol- 1-yl)-2-methylbutan-2-ol and rac-3-(4-bromo-5- methyl-1H-pyrazol-1-yl)-2-methylbutan-2-ol
247, 249
9
3-(4-bromo-1H-pyrazol-1-yl)- 2,3-dimethylbutan-2-ol
247, 249
10
rat-3-(3-bromo-1H-1,2,4- triazol-1-yl)-2-methylbutan-2-ol
234, 236
Intermediate 11: 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Step 1: (1-hydroxycyclobutyl)methyl methanesulfonate
To a stirred solution of 1-(hydroxymethyl)cyclobutan-1-ol (9.00 g, 88.0 mmol) in DCM (260 mL) at 0° C. was added triethylamine (17.2 ml, 123 mmol) followed by methanesulfonyl chloride (7.0 mL, 90 mmol). The mixture was stirred at 0° C. for 10 min. The mixture was then warmed to room temperature and stirred for 15 min. The mixture was then partitioned with water. The layers were separated and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to afford (1-hydroxycyclobutyl)methyl methanesulfonate.
Step 2: 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
To a solution of 4-bromo-1H-pyrazole (7.70 g, 52.4 mmol) in DMF (60 ml) at 0° C. was added NaH (60% in mineral oil, 2.30 g, 57.6 mmol) portionwise. The mixture was stirred at 0° C. under nitrogen for 30 min. To the mixture was added a solution of (1-hydroxycyclobutyl)methyl methanesulfonate (13.1 g, 72.8 mmol) in DMF (20 ml). The mixture was stirred and heated at 90° C. for 16 h. The mixture was quenched with water (70 mL), then extracted with EtOAc three times. The organic layer was dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent, to afford 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol. LCMS (C8H11BrN2O) (ES, m/z): 231, 233 [M+H]+.
Intermediate 12: 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole
Step 1: (3-methyloxetan-3-yl)methyl methanesulfonate
Step 1 of the synthesis of Intermediate 12 was conducted similar to step 1 of the synthesis of Intermediate 11 from the appropriate starting materials to afford (3-methyloxetan-3-yl)methyl methanesulfonate.
Step 2: 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole
To a solution of 4-bromo-1H-pyrazole (5.04 g, 34.3 mmol) in DMF (114 mL) was added (3-methyloxetan-3-yl)methyl methanesulfonate (6.18 g, 34.3 mmol) and cesium carbonate (15.6 g. 48.0 mmol). The mixture was stirred and heated at 60° C. for 6 h. The solvents were evaporated. To the residue was added DCM (100 mL), and the mixture was filtered. The solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexane to afford 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole. LCMS (C8H11BrN2O) (ES, m/z): 231, 233 [M+H]+.
Intermediate 13, shown in the following Table 2, was prepared in a manner similar to that of Intermediate 12 from the appropriate starting materials.
TABLE 2
Structure
Observed
Intermediate
Name
m/z [M + H]+
13
4-bromo-1-((3-(f1uoromethyl) oxetan-3-yl)methyl)-1H-pyrazole
249, 251
Intermediate 14: (1s,3s)-3-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol
Step 1: 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole
To a solution of 2-bromo-5,8-dioxaspiro[3.4]octane (0.500 g, 2.59 mmol) and 4-bromo-1H-pyrazole (0.761 g. 5.18 mmol) in DMF (2.6 mL) in an 8 mL vial was added potassium carbonate (1.07 g, 7.77 mmol) and 18-crown-6 (0.137 g, 0.518 mmol). The mixture was stirred and heated at 90° C. After 5 min, the mixture was cooled to room temperature, and to the mixture was added additional 4-bromo-1H-pyrazole (400 mg, 2.72 mmol). The mixture was stirred and heated at 90° C. for 48 h. The mixture was then cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The layers were separated and the organic layer was washed with brine. The two aqueous layers were combined and extracted with EtOAc (15 mL). The organic layers were combined, washed with brine twice, dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-50% EtOAc in hexanes to afford 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole. LCMS (C9H12BrN2O2) (ES, m/z): 259, 261 [M+H]+.
Step 2: 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone
To a solution of 4-bromo-1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole (270 mg, 1.042 mmol) and PPTS (131 mg, 0.521 mmol) in dioxane (2.6 mL) was added water (2.6 mL). The mixture was stirred and heated at 85° C. for 95 h. The mixture was cooled to room temperature. The mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexane to afford 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone. LCMS (C7H8BrN2O) (ES, m/z): 215, 217 [M+H]+.
Step 3: (1s,3 s)-3-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol
A solution of 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (129 mg, 0.600 mmol) in diethyl ether (3.5 ml) was cooled to 0° C. To the stirred mixture was added methylmagnesium bromide (3 M in diethyl ether, 0.240 ml, 0.720 mmol) dropwise. The mixture was stirred for 16 h, allowing the ice bath to expire. The mixture was partitioned between EtOAc and 20% aqueous citric acid and stirred for 2 h. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-60% EtOAc in hexanes as eluent to afford (1s, 3s)-3-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol. LCMS (C8H12BrN2O) (ES, m/z): 231, 233 [M+H]+.
Intermediate 15: 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole
To a reaction vial were added 4-bromo-1H-pyrazole (1.50 g, 10.2 mmol). 4-iodotetrahydro-2H-pyran (2.16 g, 10.2 mmol), potassium carbonate (1.41 g, 10.2 mmol) and DMF (15 mL). The mixture was stirred and heated at 100° C. for 16 h. The mixture was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent, to afford 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole. LCMS (C8H11BrN2O) (ES, m/z): 231, 233 [M+H]+.
Intermediate 16: mixture of 4-bromo-5-methyl-1-trityl-1H-pyrazole and 4-bromo-3-methyl-1-trityl-1H-pyrazole
To a 200 mL round bottom flask was added 4-bromo-3-methyl-1H-pyrazole (1.00 g, 6.21 mmol) and THF (62.1 ml). The mixture was stirred under an atmosphere of nitrogen. The mixture was cooled at 0° C. To the mixture was added NaH (0.311 g, 7.76 mmol) portionwise. The mixture was slowly warmed to room temperature over 30 min. The mixture was then cooled at 0° C., and to the mixture was added trityl chloride (1.90 g, 6.83 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with water (60 mL) and diluted with EtOAc (60 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-25% EtOAc in hexanes as eluent to afford 4-bromo-3-methyl-1-trityl-1H-pyrazole and 4-bromo-5-methyl-1-trityl-1H-pyrazole as a mixture of regioisomers. LCMS (C23H19BrN2) (ES, m/z): 425, 427 [M+Na]+.
Intermediate 17: 4-bromo-3-(difluoromethyl)-1-trityl-1H-pyrazole
To a stirred mixture of 4-bromo-5-(difluoromethyl)-1H-pyrazole (250 mg, 1.27 mmol), trityl chloride (460 mg, 1.65 mmol) and pyridine (201 mg, 2.54 mmol) in DCM (4 mL) was added DMAP (15.5 mg, 0.127 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with water (5 mL) and aqueous saturated NH4Cl (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent to afford 4-bromo-5-(difluoromethyl)-1-trityl-1H-pyrazole. LCMS (C23H17BrF2N2) (ES, m/z): 461, 463 [M+Na]+.
Intermediate 18: mixture of 4-bromo-3-(difluoromethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole and 4-bromo-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole
To a solution of 4-bromo-5-(difluoromethyl)-1H-pyrazole (240 mg, 1.218 mmol) in DMF (60 ml) were added cesium carbonate (595 mg, 1.828 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (329 mg, 1.828 mmol). The mixture was stirred and heated at 80° C. under nitrogen for 3 h. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc three times. The organic layer was washed with water followed by brine, dried over anhydrous MgSO4, and filtered. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-90% EtOAc in hexanes as eluent to afford a mixture of 4-bromo-3-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole and 4-bromo-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole.
Intermediate 19: 2-(4-Bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Step 1: Methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate
To a solution of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) in DMF (20 mL) was added methyl 2-bromo-2-methylpropanoate (1.76 mL, 13.6 mmol) followed by cesium carbonate (8.87 g, 27.2 mmol). The mixture was heated at 80° C. for 18 h. The mixture was filtered, and the filter cake was washed with DCM. The combined filtrates were evaporated. The resulting residue was purified by silica gel chromatography with 10% EtOAc in hexanes as eluent to afford methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate. LCMS (C8H11BrN2O2) (ES, m/z): 247, 249 [M+H]+.
Step 2: 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol
To a solution of methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate (1.74 g, 7.04 mmol) in EtOH (35 ml) was added sodium borohydride (0.799 g, 21.1 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was diluted in DCM (50 mL), washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to afford 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol. LCMS (C7H11BrN2O) (ES, m/z): 219, 221 [M+H]+.
Intermediate 20 in the following Table 3 was prepared in a manner similar to that described for the synthesis of Intermediate 19 from the appropriate starting materials.
TABLE 3
Structure
Observed
Intermediate
Name
m/z [M + H]+
20
2-(4-bromo-3-methyl-1H-pyrazol- 1-yl)-2-methylpopan-1-ol
233, 235
Intermediate 21: 1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1 of the synthesis of Intermediate 21 was conducted in manner similar to that used in the synthesis of Intermediate 1 from the appropriate starting materials to afford 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol.
Step 2: 1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a solution of 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (1.55 g, 8.60 mmol) in DCM (86 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (1.23 g, 4.30 mmol). The mixture was stirred at room temperature for 30 min. The solvents were evaporated, and the resulting residue was purified by silica gel chromatography with 10-90% EtOAc in hexanes to afford 1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C10H15BrN2O) (ES, m/z): 259, 261 [M+H]+.
Intermediate 22: 4-bromo-1-ethyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole
Step 1: (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol
Step 1 of the synthesis of Intermediate 22 was conducted in a manner analogous to step 2 of the synthesis of Intermediate 21 from the appropriate starting materials to afford (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol. LCMS (C6H9BrN2O) (ES, m/z): 205, 207 [M+H]+.
Step 2: rac-4-bromo-1-ethyl-3-(((tetrahydro-2H-pyran-2-yl)oxymethyl)-1H-pyrazole
To a stirred solution of (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol (570 mg, 2.78 mmol) in DCM (27 mL) was added 3,4-dihydro-2H-pyran (468 mg, 5.56 mmol), followed by the addition of 4-methylbenzenesulfonic acid (polymer supported) (239 mg, 1.39 mmol). The mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was loaded directly onto a silica gel column and purified with 0-60% EtOAc in hexane as eluent to afford rac-4-bromo-1-ethyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole. LCMS (C11H17BrN2O2) (ES, m/z): 289, 291 [M+H]+.
Intermediate 23: rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl-1H-pyrazole
Step 1: rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl methanesulfonate
To a stirred solution of rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol (8.00 g, 43.0 mmol) in DCM (150 mL) at 0° C. was added triethylamine (8.38 mL, 60.1 mmol) followed by methanesulfonyl chloride (4.02 mL, 51.5 mmol). The mixture was stirred at 0° C. for 10 min and then warmed to room temperature and stirred for 40 min. The mixture was then partitioned with water. The layers were separated, and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to afford rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl methanesulfonate, LCMS (C11H20O5S) (ES, m/z): 287 [M+Na]+.
Step 2: rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole
To a solution of 4-bromo-1H-pyrazole (5.40 g, 36.7 mmol) in DMF (60 mL) at 0° C. was added NaH (60% in mineral oil, 1.62 g, 40.4 mmol) portionwise. The mixture was stirred at 0° C. under nitrogen for 1 h. To the mixture was added rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl methanesulfonate (10.7 g, 40.4 mmol). The mixture was stirred and heated at 90° C. under nitrogen for 16 h. The mixture was quenched with water (200 mL) and extracted with EtOAc three times. The combined organic layers were washed with water followed by brine. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent to afford rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23). LCMS (C13H19BrN2O2) (ES, m/z): 315, 317 [M+H]+.
Intermediate 24 and Intermediate 25: 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
The mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) was separated by SFC (Chiral Technologies IG 21×250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as cosolvent) to afford 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 24, first eluting peak) and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 25, second eluting peak).
For Intermediate 24: LCMS (C13H19BrN2O2) (ES, m/z): 233, 235 [M+H]+.
For Intermediate 25: LCMS (C8H13BrN2O) (ES, m/z): 233, 235 [M+H]+.
Intermediate 26 and Intermediate 27 in the following Table 4 were prepared in a manner analogous to the preparation of Intermediate 24 and Intermediate 25 by SFC separation of the racemic mixture Intermediate 1.
TABLE 4
Structure
SFC
Observed
Intermediate
Name
Conditions
m/z M + H
26
(S or R)-3-(4-bromo-1H- pyrazol-1-yl)-2- methylbutan-2-ol
Peak 1; Chiral Technologies AD-H 50 × 250 mm column with 35% MeOH as co-solvent
233, 235
27
(R or S)-3-(4-bromo-1H- pyrazol-1-yl)-2- methylbutan-2-ol
Peak 2; Chiral Technologies AD-H 50 × 250 mm column with 35% MeOH as co-solvent
233, 235
Intermediate 28: rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutan-1-one
To a solution of 2-bromocyclobutanone (16.2 g, 109 mmol) in MeCN (30 mL) was added 4-bromo-1H-pyrazole (8.00 g, 54.4 mmol) and potassium carbonate (30.1 g, 218 mmol). The mixture was stirred at 20° C. for 10 h. The mixture was filtered, and the solvents of the filtrate were evaporated. The residue was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/water (with 0.1% TFA modifier) as eluent) to afford rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone. LCMS (C7H7BrN2O) (ES, m/z) [M+H]+: 215, 217.
Intermediate 29: 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutane-1-ol
Methylmagnesium bromide (0.248 ml, 0.744 mmol, 3 M in diethyl ether) was added to a stirred mixture of rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (Intermediate 28) (80.0 mg, 0.372 mmol) in THF (2 mL) at −78° C., and the mixture was stirred at that temperature for 3 h. The reaction was quenched with aqueous saturated NH4Cl (2 mL), and the desired layer was extracted from the mixture with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The resulting residue was purified by preparative silica gel TLC with 30% EtOAc in petroleum ether as eluent to afford 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol. LCMS (C8H11BrN2O) (ES, m/z) [M+H]+: 231, 233.
Intermediate 30: rac-4-bromo-1-(2,2-dimethoxycyclobutyl)-1H-pyrazole
To a stirred mixture of trimethoxymethane (592 mg, 5.58 mmol) and rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (Intermediate 28) (600 mg, 2.79 mmol) in MeOH (5 mL) was added 4-methylbenzenesulfonic acid hydrate (53.1 mg, 0.279 mmol). The mixture was stirred at 28° C. for 12 h. The mixture was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% EtOAc in petroleum ether as eluent to afford rac-4-bromo-1-(2,2-dimethoxycyclobutyl)-1H-pyrazole. LCMS (C9H13BrN2O2) (ES, m/z) [M+H]+: 261, 263.
Intermediate 31: mixture of rac-4-bromo-5-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole and rac-4-bromo-3-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole
To a stirred solution of rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol (1.00 g, 5.37 mmol), 4-bromo-5-methyl-1H-pyrazole (0.864 g, 5.37 mmol) and triphenylphosphine (1.41 g, 5.37 mmol) in THF (10.2 mL) was added diisopropyl diazene-1,2-dicarboxylate (1.09 g, 5.37 mmol). The mixture was stirred and heated at 60° C. for 16 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-80% EtOAc in hexane to afford a mixture of rac-4-bromo-5-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole and rac-4-bromo-3-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole. LCMS (C14H21BrN2O2) (ES, m/z): 329, 331 [M+H]+.
Intermediate 32: rac-4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole
To a stirred solution of 2-(4-bromo-1H-pyrazol-1-yl)cyclopentanol (Intermediate 5) (3.00 g, 13.0 mmol) in DCM (45 mL) was added 3,4-dihydro-2H-pyran (2.4 mL, 26 mmol), followed by 4-methylbenzenesulfonic acid (polymer-bound, 2.0 g). The mixture was stirred at room temperature for 16 h. The mixture was filtered, and the solvents of the filtrate were evaporated. The residue was purified by reversed-phase C18 chromatography with 0-100% MeCN in water as eluent to afford rac-4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole. LCMS (C13H19BrN2O2) (ES, m/z): 315, 317 [M+H]+.
Intermediate 33: 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol
To a 500 mL round bottom flask was added 4-nitro-1H-pyrazole (15.0 g, 133 mmol), cesium carbonate (64.8 g, 199 mmol), and DMF (195 mL). To the mixture was added 2,2-dimethyloxirane (23.6 mL, 265 mmol). The mixture was heated at 80° C. for 16 h. The mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-80% EtOAc in hexanes, yielding 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol. LCMS (C7H11N3O3) (ES, m/z): 186 [M+H]+.
Step 2: 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 500 mL flask was added 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (18.8 g, 102 mmol), 10% palladium on carbon (1.08 g, 1.01 mmol), and EtOAc (300 mL). The mixture was degassed under vacuum and refilled with nitrogen three times. The mixture was degassed and refilled with hydrogen from a balloon. The mixture was stirred under an atmosphere of hydrogen for 21 h. The mixture was filtered through Celite® (diatomaceous earth). The solvents of the filtrate were evaporated, yielding 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C7H13N3O) (ES, m/z): 156 [M+H]+.
Intermediate 34: 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Step 1: ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate
To a stirred mixture of 4-nitro-1H-pyrazole (3.00 g, 26.5 mmol) and ethyl 2-bromo-2-methylpropanoate (5.69 g, 29.2 mmol) in DMF (50 mL) was added K2CO3 (11.00 g, 80.00 mmol). The mixture was stirred and heated at 80° C. for 10 h. The mixture was cooled, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography 5-20% EtOAc in petroleum ether as eluent to afford ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate. LCMS (C9H13N3O4) (ES, m/z): 228 [M+H]+.
Step 2: 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propan-1-ol
To a stirred mixture of ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate 3 g, 3.2 mmol) in EtOH (50 mL) was added NaBH4 (0.999 g, 26.4 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford 2-methyl-2-(4-nitro-1H-pyrazol-1-yl) propan-1-ol.
Step 3: 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Step 3 of the synthesis of Intermediate 34 was conducted in a manner similar to that of step 2 of the synthesis of Intermediate 33, using 2-methyl-2-(4-nitro-1H-pyrazol-1-yl) propan-1-ol as the starting material, to afford 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol. LCMS (C7H13N3O) (ES, m/z): 156 [M+H]+.
Intermediate 35: 2-amino-5-fluoro-4-methoxybenzonitrile
Step 1: 2-bromo-4-fluoro-5-methoxyaniline
A solution of 4-fluoro-3-methoxyaniline (350.0 g, 2.48 mol) in EtOAc (3.5 L) was cooled at 0-5° C. To the mixture was added tetra-n-butylammonium tribromide (14.0 kg, 2.90 mol) portionwise. The mixture was warmed to 15° C., and stirred at that temperature for 1 h. The mixture was adjusted to pH 8 with saturated aqueous Na2CO3. The mixture was extracted with EtOAc and the combined organic layers were washed with water (2×1.5 L) and dried with anhydrous Na2SO4. The solids were removed by filtration, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford 2-bromo-4-fluoro-5-methoxyaniline. LCMS (C7H7BrFNO) (ES, m/z): 220, 222 [M+H]+.
Step 2: 2-amino-5-fluoro-4-methoxybenzonitrile
To a solution of 2-bromo-4-fluoro-5-methoxyaniline (300 g, 1.36 mol) in DMF (2.1 L) was added Zn(CN)2 (327 g, 2.78 mol) and Pd(PPh3)4 (90.0 g, 0.0778 mol). The mixture was degassed under vacuum and purged with nitrogen. The mixture was stirred and heated at 130° C. for 1 h under nitrogen. The mixture was poured into ice water (4 L). The mixture was extracted with EtOAc (3 L, 2 L, 1 L), and the combined organic layers were washed with brine (2 L, 1.5 L). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford 2-amino-5-fluoro-4-methoxybenzonitrile. LCMS (C8H7FN2O) (ES, m/z): 167 [M+H]+.
Intermediate 36: 2-amino-4-chloro-5-fluorobenzonitrile
To a 20 mL microwave vial was added 2-bromo-5-chloro-4-fluoroaniline (1.00 g, 4.46 mmol), copper(I) cyanide (0.472 g, 4.90 mmol), and NMP (8 mL). The mixture was stirred and heated at 180° C. in a microwave for 1 h. The mixture was diluted in diethyl ether (100 mL) and filtered through Celite® (diatomaceous earth). The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvents of the filtrate were evaporated, to afford 2-amino-4-chloro-5-fluorobenzonitrile (LCMS (C7H4ClFN2) (ES, m/z): 171 [M+H]+.
Intermediate 37: 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile
Step 1: 1-(2-Cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea
To a 20 mL vial was added 2-amino-5-fluoro-4-methoxybenzonitrile (Intermediate 35) (817 mg, 4.92 mmol), DCM (6 mL), and pyridine (1 mL). The mixture was stirred. To the mixture was added 1-(isocyanatomethyl)-2,4-dimethoxybenzene (1425 mg, 7.380 mmol). The mixture was stirred and heated at 40° C. for 16 h. The solids were collected by filtration and washed with MeOH (3×3 mL), to afford 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea.
Step 2: 2-((((2,4-Dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile
To a 100 mL round bottom flask was added 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea (1.16 g, 3.22 mmol), triphenylphosphine (1.69 g, 6.44 mmol), triethylamine (1.80 ml, 12.9 mmol), and DCM (25 mL). The mixture was stirred and cooled at 0° C. To the mixture was added a solution of carbon tetrabromide (2.14 g, 6.44 mmol) in DCM (5 mL) dropwise. After 30 min, the mixture was concentrated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent, to afford 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile. LCMS (C18H16FN3O3) (ES, m/z) [M+Na]+: 364.
The intermediates in the following Table 5 were prepared in a manner similar to that of Intermediate 37 from the appropriate intermediates and starting materials.
TABLE 5
Observed
Inter-
Structure
m/z
mediate
Name
[M + H]+
38
2-((((2,4-dimethoxybenzyl)imino)methylene) amino)-5-fluoro-3-methoxybenzonitrile
364
39
4-chloro-2-((((2,4-dimethoxybenzyl) imino)methylene)amino)-5-fluorobenzonitrile
368
40
2-((((2,4-dimethoxybenzyl)imino)methylene)amino)- 5-fluoro-4-methylbenzonitrile
348
41
2-((((2,4-dimethoxybenzyl)imino)methylene)amino)- 3,5-difluorobenzonitrile
352
42
3,5-dichloro-2-((((2,4-dimethoxybenzyl) imino)methylene)amino)benzonitrile
384
Intermediate 43: 1-(tert-butyl) 3 ethyl (R)-piperidine-1,3-dicarboxylate
A solution of (R)-ethyl piperidine-3-carboxylate (200.0 g, 1270 mmol), triethylamine (257.5 g, 2540 mmol) and DMAP (15.5 g, 130 mmol) in DCM (2 L) was cooled at 0° C. To the mixture was added di-tert-butyl dicarbonate (305.4 g, 1400 mmol) portionwise. The mixture was stirred at room temperature for 3 h. Then the organic layer was washed with aqueous saturated sodium bicarbonate (3×1 L). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford 1-(tert-butyl) 3-ethyl (R)-piperidine-1,3-dicarboxylate.
Intermediate 44 in the following Table 6 was prepared in a manner similar to that of Intermediate 43 from the appropriate starting materials.
TABLE 6
Structure
Observed
Intermediate
Name
m/z [M + H]+
44
1-(tert-butyl) 3-methyl azepane- 1,3-dicarboxylate
280
Intermediate 45: 1-(tert-butyl) 3-methyl azepane-1,3-dicarboxylate
Step 1: 5-methylpiperidine-3-carboxylic acid
To a stirred mixture of 5-methylnicotinic acid (10 g, 72.9 mmol) and concentrated aqueous HCl (0.599 mL, 7.29 mmol) in MeOH (100 mL) at 20° C. was added platinum (IV) oxide (1.67 g, 7.29 mmol). The mixture was degassed and purged with nitrogen then pressurized to 50 psi with hydrogen. The mixture was stirred for 10 h. The mixture was filtered, and the solvents of the filtrate were evaporated to afford the 5-methylpiperidine-3-carboxylic acid.
Step 2: 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid
To a stirred mixture of di-tert-butyl dicarbonate (5.84 ml, 25.1 mmol) and 5-methylpiperidine-3-carboxylic acid (3.00 g, 21.0 mmol) in MeCN (20 mL) and water (20 mL) at 20° C. was added sodium bicarbonate (7.04 g. 84.0 mmol). The mixture was stirred at 20° C. for 5 h. The mixture was diluted with water (20 mL), adjusted with concentrated aqueous HCl to pH 5, and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid. LCMS (C12H21NO4) (ES, m/z) [M+H]+: 244.
Step 3: 1-(tert-butyl) 3-methyl 5-methylpiperidine-1,3-dicarboxylate
To a stirred mixture of 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid (5.00 g, 20.5 mmol) in DCM (10 mL) and MeOH (10 mL) at 0° C. was added trimethylsilyl-diazomethane (15.4 mL, 30.8 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to afford 1-tert-butyl 3-methyl 5-methylpiperidine-1,3-dicarboxylate. LCMS (C13H23NO4) (ES, m/z) [M+H]+: 258.
Intermediate 46: 1-(tert-butyl) 3-methyl 4-methylpiperidine-1,3-dicarboxylate
Step 1: Methyl 4-methylpiperidine-3-carboxylate
Step 1 of the synthesis of Intermediate 46 was conducted in a manner similar to that of step 1 of the synthesis of Intermediate 45 from the appropriate starting materials to afford methyl 4-methylpiperidine-3-carboxylate. LCMS (C8H15NO2) (ES, m/z) [M+H]+: 158.
Step 2: 1-(tert-butyl) 3-methyl 4-methylpiperidine-1,4-dicarboxylate
Step 2 of the synthesis of Intermediate 46 was conducted in a manner similar to step 2 of the synthesis of Intermediate 45 from the appropriate starting materials, with the exception that the crude material was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent to afford to 1-(tert-butyl) 3-methyl 4-methylpiperidine-1,4-dicarboxylate.
Intermediate 47: mixture of rac,cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate and rac,trans-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate
To a 250 mL round bottom flask containing rac, cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate (2.00 g, 7.26 mmol) was added EtOH (73 mL). To the mixture was added sodium tert-butoxide (7.26 mL, 14.5 mmol) (2 M solution in THF) dropwise with stirring. The mixture was stirred at room temperature for 3 h. The mixture was concentrated to about 10 mL of volume. To the mixture was added EtOAc (10 mL). The solvents were evaporated. The residue was dissolved in EtOAc (60 mL) and washed with water (3×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated to afford a mixture of rac, cis-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate and rac,trans-1-(tert-butyl) 3-ethyl-5-fluoropiperidine-1,3-dicarboxylate.
Intermediate 48 and 49: methyl (3S,6R)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate and methyl (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate
A 100 mL flask was charged with 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (4.66 g, 30.0 mmol), methyl 2-methylene-5-oxohexanoate1 (3.12 g, 20.0 mmol), and LiBF4 (1.88 g, 20.0 mmol). To the flask was added TFE (31.2 mL). The flask was fitted with a reflux condenser, which had an inlet for nitrogen. The mixture was heated at reflux for 48 h. The mixture was cooled to room temperature, and to the mixture was added 10% palladium on carbon (0.639 g, 6.00 mmol). The mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 6 h. The mixture was filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-4% MeOH in DCM as eluent, yielding the racemate with cis relative stereochemistry. The racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 21×250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as cosolvent), to afford methyl (3S,6R)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (Intermediate 48, first eluting peak) and methyl (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (Intermediate 49, second eluting peak).
For Intermediate 48: LCMS (C15H25N3O3) (ES, m/z): 296 [M+H]+. For Intermediate 49: LCMS (C15H25N3O3) (ES, m/z): 296 [M+H]+. 1Bizet, V.; Lefebvre, V.; Baudoux, J.; Lasne, M.; Boulange, A.; Leleu, S.; Franck, X.; Rouden, J. Eur. J. Org. Chem. 2011. 4170.
The intermediates in the following Table 7 were prepared in a manner similar to that of Intermediate 48 and Intermediate 49 from the appropriate intermediates and starting materials, with the exception that these compounds were isolated as racemic mixtures of diastereomers that were not resolved by SFC separation.
TABLE 7
Structure
Observed
Intermediate
Name
m/z [M + H]+
50
ethyl 1-(1-(1-hydroxy-2-methylpropan- 2-yl)-1H-pyrazo1-4-yl)-6- methylpiperidine-3-carboxylate
310
51
methyl 1-(1-(2-hydroxy-2-methylpropyl)- 3-methyl-1H-pyrazol-4-yl)- 6-methylpiperidine-3-carboxylate
310
Intermediate 52: ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carboxylate
Step 1: diethyl 2-(3-oxopentyl)malonate
A mixture of diethyl malonate (10.0 g, 62.4 mmol), pent-1-en-3-one (5.78 g, 68.7 mmol) and potassium carbonate (0.863 g, 6.24 mmol) was stirred at room temperature in a sealed tube for 3 days. The resulting mixture was filtered to provide the filtrate, which is neat diethyl 2-(3-oxopentyl) malonate. LCMS (C12H20O5) (ES, m/z): 245 [M+H]+. The crude material was used without further purification.
Step 2: rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate
To a stirred solution of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 33) (2.00 g, 12.9 mmol) in DCM (129 mL) was added diethyl 2-(3-oxopentyl)malonate (6.93 g, 28.4 mmol) and AcOH (0.077 mL, 1.3 mmol). The mixture was stirred at room temperature for 30 min. To the mixture was added sodium cyanoborohydride (1.62 g, 25.8 mmol) portionwise. The mixture was stirred at room temperature for an additional 30 min. The mixture was quenched with 1 M aqueous HCl (150 mL). The organic layer was separated, and the aqueous layer was extracted with DCM twice more. The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate. LCMS (C19H33N3O5) (ES, m/z): 384 [M+H]+.
Step 3: ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carboxylate
To a solution of rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate (1.70 g, 4.43 mmol) in toluene (22 mL) was added AcOH (0.530 mL, 8.87 mmol). The mixture was stirred at 90° C. for 2 days. The mixture was cooled to room temperature, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carboxylate. LCMS (C17H27N3O4) (ES, m/z): 338 [M+H]+.
Intermediate 53: ethyl 3-hydroxycyclohexanecarboxylate
To a solution of ethyl 3-oxocyclohexanecarboxylate (2.00 g, 11.7 mmol) in THF (20 mL) was added a solution of sodium borohydride (0.889 g, 23.5 mmol) in THF (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. To the mixture was added water (10 mL), and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford ethyl 3-hydroxycyclohexanecarboxylate.
Intermediate 54: tert-butyl (R)-3-(hydrazinocarbonyl)piperidine-1-carboxylate
The solution of (R)-1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (320.0 g, 1243 mmol) and hydrazine hydrate (311.3 g, 6217 mmol) in EtOH (1.6 L) was stirred and heated at 80° C. for 16 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography eluting with DCM to afford tert-butyl (R)-3-(hydrazinocarbonyl)piperidine-1-carboxylate. LCMS (C11H21N3O3) (ES, m/z): 244 [M+H]+.
The intermediates in the following Table 8 were prepared in a manner similar to that of Intermediate 54 from the appropriate intermediates and starting materials.
TABLE 8
Structure
Observed
Intermediate
Name
m/z [M + H]+
55
tert-butyl 3-(hydrazinecarbonyl) azepane-1-carboxylate
258
56
tert-butyl 3-(hydrazinecarbonyl)- 5-methylpiperidine-1-carboxylate
258
57
tert-butyl 3-(hydrazinecarbony1)- 4-methylpiperidine-1-carboxylate
258
58
tert-butyl 3-fluoro-5- (hydrazinecarbonyl)piperidine-1-carboxylate
206 [M + H]-C4H8]+
59
mixture of tert-butyl (3R,5R and 3S,5S)-3-fluoro-5- (hydrazinecarbonyl)piperidine4-carboxylate and tert- butyl (3S,5R and 3R,5S)-3-fluoro-5- (hydrazinecarbonyl)piperidine-1-carboxylate
206 [M + H]-C4H8]+
60
tert-butyl 3-fluoro-3-(hydrazinecarbonyl) pyrrolidine-1-carboxylate
248
61
(3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-6-methylpiperidine-3-carbohydrazide
296
62
1-(1-(1-hydroxy-2-methylpropan-2-yl)-1H- pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide
296
63
1-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol- 4-yl)-6-methylpiperidine-3-carbohydrazide
310
64
6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-2-oxopiperidine-3-carbohydrazide
324
65
3-hydroxycyclohexane-1-carbohydrazide
159
66
tert-butyl 5-(hydrazinecarbonyl)-2- methylpiperidine-1-carboxylate
258
Intermediate 67: (R)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
Step 1: ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate
A 40 mL reaction vial was charged with ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate (1.00 g, 6.36 mmol) and THF (15 mL). To the mixture was added 4-bromo-1-methyl-1H-pyrazole (4.96 mL, 48.0 mmol), followed by tBuXPhos-Pd G3 (2.02 g, 2.54 mmol) and sodium tert-butoxide (4.61 g, 48.0 mmol). Nitrogen was bubbled through the mixture for 10 min. The vial was sealed and heated at 65° C. for 24 h. The mixture was cooled to room temperature and diluted with EtOAc (40 mL). The mixture was filtered through Celite® (diatomaceous earth). The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to afford ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate. LCMS (C12H19N3O2) (ES, m/z): 238 [M+H]+.
Step 2: (R)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
A round bottom flask was charged with ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate (7.72 g, 32.5 mmol) and EtOH (77 mL). To the mixture was added hydrazine hydrate (31.7 mL. 651 mmol). The round bottom flask was fitted with a reflux condenser, and the mixture was heated at 80° C. for 16 h. The mixture was cooled to room temperature, and the solvents were evaporated to afford (R and S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide (Intermediate 67). The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AD-H 21×250 mm column with 40% (MeOH w/ 0.25% DEA modifier) as co-solvent to afford (R or S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide as the first eluting peak and (S or R)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide as the second eluting peak corresponding to Intermediate 67a and Intermediate 67b, respectively. LCMS (C10H17N5O) (ES, m/z): 224 [M+H]+.
Intermediate 68 in the following Table 9 was prepared in a manner similar to that of Intermediate 67, with the exception that no SFC separation was conducted. Thus, the compound was isolated as a mixture of isomers.
TABLE 9
Structure
Observed
Intermediate
Name
m/z [M + H]+
68
1-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-6- methylpiperidine-3-carbohydrazide
296
Intermediate 69: tert-butyl (R)-3-(hydroazinecarbonyl)pyrrolidine-1-carboxylate
To a 100 mL round bottom flask was added (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g, 9.29 mmol) and THF (18.6 mL). To the mixture was added 1,1′-carbonyldiimidazole (1.96 g, 12.1 mmol). The mixture was heated at 60° C. for 30 min. The mixture was cooled to room temperature and transferred to a stirring mixture of hydrazine hydrate (0.447 g, 13.9 mmol) in THF (10 mL) dropwise over 25 min. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford (R)-tert-butyl 3-(hydrazinocarbonyl)pyrrolidine-1-carboxylate. LCMS (C10H19N3O3) (ES, m/z): 230 [M+H]+.
The intermediates in the following Table 9A were prepared in a manner similar to that of the preparation of Intermediate 60.
Table 9A
Inter-
Structure
Observed
mediate
Name
m/z [M + H]+
70
tert-butyl 1-(hydrazinecarbonyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate
186 [M + H—C4H8]+
71
2-oxopiperidine-3-carbohydrazide
158
72
(R)-tert-butyl 2-(hydrazinecarbonyl) morpholine-4-carboxylate
268 [M + Na]+
73
tert-butyl 2-(hydrazinecarbonyl) thiomorpholine-4- carboxylate 1,1-dioxide
316 [M + Na]+
Intermediate 74: Benzyl 3-fluoro-3-(hydrazinocarbonyl)piperidine-1-carboxylate
To a stirred solution of hydrazine hydrate (0.155 mL, 7.11 mmol), 1-((benzyloxy)carbonyl)-3-fluoropiperidine-3-carboxylic acid (2.00 g, 7.11 mmol) and DIPEA (5.02 ml, 28.4 mmol) in DCM (70 mL) was added tripropyl phosphonic anhydride (50% v/v solution in EtOAc, 6.38 mL, 14.2 mmol) dropwise. The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate. The mixture was stirred for 5 min, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated to afford benzyl 3-fluoro-3-(hydrazinocarbonyl)piperidine-1-carboxylate. LCMS (C14H18FN3O3) (ES, m/z): 296 [M+H]+.
Intermediate 75 and Intermediate 76: tert-butyl (2R,5S or 2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate and tert-butyl (2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate
A solution of rac, cis-tert-butyl 5-(hydrazinocarbonyl)-2-methylpiperidine-1-carboxylate (Intermediate 66) (5.00 g, 19.4 mmol) in DCM (7 mL) was added AcOH (0.556 ml, 9.72 mmol). The mixture was stirred at room temperature. To the mixture was added 2-((((2,4-dimethoxybenzyl) imino) methylene) amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (6.63 g, 19.4 mmol). The mixture was stirred for 60 h. The mixture was filtered, and the filtrate was loaded directly onto a silica gel column and purified with 0-100% EtOAc in hexane as eluent to provide the racemic tert-butyl (2R,5S and 2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate. The racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 50×250 mm column, with 35% EtOH as cosolvent) to afford tert-butyl (2R,5S or 2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate (Intermediate 75, first eluting peak) and tert-butyl (2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidine-1-carboxylate (Intermediate 76, second eluting peak).
The intermediates in the following Table 10 were prepared in a manner similar to Intermediate 75 and Intermediate 76, from the appropriate intermediates and starting materials.
TABLE 10
Structure
SFC
Observed
Intermediate
Name
Conditions
m/z [M + H]+
77
tert-butyl (1R,5R or 1S,5S)-1-(5-((2,4-dimethoxybenzyl) amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Peak 1; Chiral Technologies AD-H 2 × 250 mm column with 50% (IPA w/0.2% DIPA modifier) as co-solvent
565
78
tert-butyl (1S,5S or 1R,5R)-1-(5-((2,4-dimethoxybenzyl) amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
Peak 2; Chiral Technologies AD-H 2 × 250 mm column with 50% (IPA w/0.2% DIPA modifier) as co-solvent
565
Intermediate 79-81: tert-butyl (3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate
Intermediates 79-81 were prepared from Intermediate 37 and Intermediate 58 in a manner similar to that used for the preparation of Intermediate 75 and Intermediate 76. The crude residue was purified by silica gel chromatography with 0-100% EtOAc in hexane as eluent to afford tert-butyl (3S,5R and 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (first eluting peak, mixture of Intermediate 79 and Intermediate 80) and tert-butyl (3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (second eluting peak, Intermediate 81). For Intermediate 81: LCMS (C29H34F2N6O5) (ES, m/z): 585 [M+H]+. The mixture of Intermediate 79 and Intermediate 80 was resolved by chiral SFC (Chiral Technologies AD-H 50×250 mm column with 35% MeOH as cosolvent) to afford tert-butyl (3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (Intermediate 79, first eluting peak) and tert-butyl (3R,5S or 3S, 5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate (Intermediate 80, second eluting peak). For Intermediate 79: LCMS (C29H34F2N6O5) (ES, m/z): 585 [M+H]+. For Intermediate 80: LCMS (C29H34F2N6O5) (ES, m/z): 585 [M+H]+.
Intermediate 82: (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: (R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
To a 40 mL vial was added (R)-tert-butyl 3-(hydrazinocarbonyl)piperidine-1-carboxylate (Intermediate 54) (596 mg, 2.45 mmol), DCM (7 mL) and AcOH (0.070 ml, 1.2 mmol). To the mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (836 mg, 2.45 mmol). The mixture was stirred for 16 h. The solution was loaded onto a silica gel column and purified with 0-80% EtOAc in hexane as eluent to afford (R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate LCMS (C29H35FN6O5) (ES, m/z) [M+H]+: 567.
Step 2: (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a 20 mL vial was added (R)-tert-butyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (1.40 g, 2.47 mmol) and formic acid (4 mL). The solution was stirred for 16 h. The mixture was diluted with DCM (50 mL) and washed with 2 M aqueous potassium carbonate (75 mL). The mixture was extracted with additional DCM (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvents of the filtrate were evaporated to afford (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82). LCMS (C24H27FN6O3) (ES, m/z) [M+H]+: 467.
The intermediates in the following Table 11 were synthesized in a manner similar to that used in the preparation of Intermediate 82 from the appropriate intermediates and starting materials. For the synthesis of Intermediate 89, the deprotection step in formic acid (step 2) was not necessary.
TABLE 11
Observed
Inter-
Structure
m/z
mediate
Name
[M + H]+
83
2-(azepan-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
481
84
2-(azepan-3-yl)-N-(2,4-dimethoxybenzyl)-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-5-amine
481
85
N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- 2-(5-methylpiperidin-3-yl)[1,2,4]triazolo [1,5-c]quinazolin-5-amine
481
86
N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- 2-(4-methylpiperidin-3-yl)-[1,2,4]triazolo [1,5-c]quinazolin-5-amine
481
87
(R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- 2-(morpholin-2-yl)-[1,2,4]triazolo[1,5-c] quinazolin-5-amine
469
88
2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)thiomorpholine 1,1-dioxide
517
89
3-(5-((2,4-dimethoxybenzyl)amino)-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yppiperidin-2-one
481
Intermediate 90 and Intermediate 91: (S or R)—N-(2,4-dimethoxybenzyl-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R or S)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: rac-benzyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1-carboxylate
To a stirred solution of rac-benzyl 3-fluoro-3-(hydrazinocarbonyl)piperidine-1-carboxylate (Intermediate 74) (1.73 g, 5.86 mmol) in DCM (25 mL) was added AcOH (0.201 mL, 3.52 mmol). The mixture was stirred at room temperature for 10 min. To the mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (Intermediate 38) (2.00 g, 5.86 mmol). The mixture was stirred and heated at 40° C. for 16 h. The mixture was cooled to room temperature. The mixture was diluted with DCM (100 mL) and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with EtOAc in isohexane as eluent to afford rac-benzyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1-carboxylate. LCMS (C32H32F2N6O5) (ES, m/z): 619 [M+H]+.
Step 2: (S or R)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R or S)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
A 200 mL round bottom flask was charged rac-benzyl 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1-carboxylate (2.00 g, 3.23 mmol), 10% Pd/C (800 mg, 3.23 mmol), and MeOH (50 mL). The mixture was stirred under an atmosphere of hydrogen for 16 h. The mixture was filtered through Celite® (diatomaceous earth), and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4H) as eluent to afford a racemic mixture that was resolved by chiral SFC separation (Chiral Technologies, IC 20×250 mm column with 50% (EtOH with 0.2% DEA modifier) as cosolvent) to afford (S or R)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (first eluting peak, Intermediate 90) and (R or S)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (second eluting peak, Intermediate 91). For Intermediate 90: LCMS (C24H26F2N6O3) (ES, m/z): 485 [M+H]+. For Intermediate 91: LCMS (C24H26F2N6O3) (ES, m/z): 485 [M+H]+.
Intermediate 92: (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: tert-butyl (R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
To a solution of tert-butyl (R)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (Intermediate 54) (1.52 g, 6.25 mmol) in DCM (25 mL) was added AcOH (0.201 mL, 3.52 mmol). The mixture was stirred at room temperature for 10 min. To this mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (Intermediate 38) (2.00 g, 5.86 mmol). The mixture was stirred for 16 h. The mixture was diluted with DCM (100 mL), washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous MgSO4, the solids were removed by filtration, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with EtOAc in isohexane as eluent to afford tert-butyl (R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C29H35FN6O5) (ES, m/z): 567 [M+H]+.
Step 2: (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a solution of tert-butyl (R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (2.12 g, 3.74 mmol) in DCM (30 mL) was added 4 M HCl in dioxane (10 mL, 40.0 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4OH) as eluent to afford (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 92). LCMS (C24H27FN6O3) (ES, m/z): 467 [M+H]+.
The intermediates in the following Table 12 were prepared in a manner similar to that used in the preparation of Intermediate 92 from the appropriate intermediates and starting materials.
TABLE 12
Inter-
Structure
Observed
mediate
Name
m/z [M + H]+
93
(R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8- methoxy-2-(pyrrolidin-3-yl)-[1,2,4]triazolo [1,5-c]quinazolin-5-amine
453
94
N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3- fluoropyrrolidin-3-yl)-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-5-amine
471
The intermediates in the following Table 12A were prepared in a manner similar to that used in step 2 of the preparation of Intermediate 92 from the appropriate intermediates and starting materials.
TABLE 12A
Structure
Observed
Intermediate
Name
m/z [M + H]+
95
N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2- ((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
481
96
N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)- 6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
481
97
2-((1R,5R or 1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)- N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
465
98
2-((1S,5S or 1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)- N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
465
99
N-(2,4-dimethoxybenzyl)-9-fluoro-2((3R,5S or 3S,5R)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
485
100
N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
485
101
N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R and 3S,5S)-5-fluoropiperidln-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
485
102
N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S and 3S,5R)-5-fluoropiperidln-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
485
103
N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R and 3S,5S)-5-fluoropiperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
485
Intermediate 104: rac-N-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
Step 1: 2-amino-6-fluoro-8-methoxyquinazolin-4-ol
To a stirred mixture of 2-amino-5-fluoro-3-methoxybenzoic acid (278 mg, 1.50 mmol) in EtOH (1.5 mL) was added cyanamide (158 mg, 3.75 mmol) and hydrochloric acid (325 μL, 1.95 mmol) (6 M, aqueous). The mixture was heated at reflux for 16 h. The mixture was cooled. The precipitate was collected by filtration and dried under high vacuum to afford 2-amino-6-fluoro-8-methoxyquinazolin-4-ol. LCMS (C9H8FN3O2) (ES, m/z): 210 [M+H]+.
Step 2: 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1-yl)quinazolin-2-amine
POCl3 (295 μL, 3.16 mmol) was added dropwise over 15 min to a stirred mixture of 1,2,4-triazole (524 mg, 7.59 mmol), 2-amino-6-fluoro-8-methoxyquinazolin-4-ol (264.7 mg, 1.265 mmol), and DIPEA (553 μL, 3.16 mmol) in acetonitrile (5 mL) at room temperature. The mixture was stirred and heated at 40° C. for 3 h and then at room temperature for 16 h. The mixture was filtered through Celite® (diatomaceous earth), washing with acetonitrile and diethyl ether to afford 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1-yl)quinazolin-2-amine. LCMS (C11H9FN6O) (ES, m/z): 261 [M+H]+.
Step 3: rac-N′-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
A 20 mL reaction vial was charged with 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1-yl)quinazolin-2-amine (41.1 mg, 0.158 mmol), (R and S)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide Intermediate 67) (38.8 mg, 0.174 mmol), THF (1 mL) and DIPEA (138 μl, 0.790 mmol). The mixture was stirred and heated at 50° C. for 4 h. The mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford rac-N-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide. LCMS (C19H23FN8O2) (ES, m/z): 415 [M+H]+.
The intermediates in the following Table 13 were prepared from the appropriate starting materials in a manner similar to Intermediate 104, with the exception that the enantiopure hydrazide, Intermediate 67b, was used.
TABLE 13
Structure
Observed
Intermediate
Name
m/z [M + H]+
105
(R or S)-N′-(2-amino-6,7-difluoroquinazolin-4-yl-1- (1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
403
106
(R or S)-N′-(2-amino-6-fluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
385
107
(R or S)-N′-(2-amino-6,8-difluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
403
108
(R or S)-N′-(2-amino-5,6-difluoroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
403
109
(R or S)-N′-(2-amino-6-chloroquinazolin-4-yl)-1-(1- methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
401
110
(R or S)-N′-(2-amino-6-chloro-8-methylquinazolin-4- yl)-1-(1-methyl-1H-pyrazol-4-yppiperidine-3-carbohydrazide
415
111
(R or S)-N′-(2-amino-6-chloro-8-methoxyquinazolin-4-yl)- 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide
431
112
(R or S)-N′-(2-amino-6-methoxyquinazolin-4-yl)-1-(1- methyl-1H-pyrazol--4-yl)piperidine-3-carbohydrazide
397
Intermediates 113-116: 1-(4-((2R or 2S,5S or 5R)-5(5-((2,4-dimethoxybenzyl)amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2R or 2S,5R or 5S)-5(5-((2,4-dimethoxybenzyl)amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one
To a solution of 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3-carbohydrazide (Intermediate 64) (270 mg, 0.835 mmol) in dioxane (7 mL) was added AcOH (0.024 mL, 0.42 mmol). The mixture was stirred at room temperature for 30 min. To this mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (285 mg, 0.835 mmol). The mixture was stirred at room temperature for 3 days. The mixture was filtered, and the filtrate was purified by silica gel chromatography with 0-100% 3:1 EtOAc:EtOH in hexanes as eluent to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C33H39FN8O5) (ES, m/z): 647 [M+H]+.
Step 2: 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2R or 2S,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To the solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one (320 mg, 0.495 mmol) in THF (4.9 mL) was added borane in THF (1.0 M, 2.47 mL, 2.47 mmol).
The mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with MeOH, and then the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column 19 mm×100 mm with MeCN/water (with 0.1% TFA) as eluent) to afford two racemic mixtures of the corresponding diastereomers. Each racemate was resolved by chiral SFC.
The first eluting racemate was resolved by chiral SFC separation (Chiral Technologies, AS-H, 21×250 mm column with 50% (IPA+0.2% DIPA) as co-solvent) to afford 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-]quinazolin-2-yl)-2-yl)-2-ethylpiperidin-1-yl)-H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((2S or 2R,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting) corresponding to Intermediate 113 and Intermediate 114, respectively.
For Intermediate 113: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+. For Intermediate 114: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+.
The second eluting racemate was resolved by chiral SFC separation (AS-H, 21×250 mm column with 50% (IPA+0.2% DIPA) as co-solvent) to afford 1-(4-((2S or 2R,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((2R or 2S,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting peak), corresponding to Intermediate 115 and Intermediate 116, respectively. For Intermediate 115: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+. For Intermediate 116: LCMS (C33H41FN8O4) (ES, m/z): 634 [M+H]+.
Intermediate 117: mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
A 20 mL microwave vial was charged with (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (500 mg, 1.07 mmol) and THF (6.7 mL). To the mixture was added the mixture of 4-bromo-5-methyl-1-trityl-1H-pyrazole and 4-bromo-3-methyl-1-trityl-1H-pyrazole (Intermediate 16) (865 mg, 2.14 mmol), followed by tBuXPhos-Pd G3 (412 mg, 4.29 mmol) and sodium tert-butoxide (412 mg, 4.29 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature. To the mixture was added Celite® (diatomaceous earth) and saturated aqueous NH4Cl. The mixture was stirred vigorously for 5 min. The mixture was filtered through Celite® (diatomaceous earth) topped with anhydrous MgSO4 and washed with DCM. The solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-20% MeOH in DCM to afford the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C47H45FN8O3) (ES, m/z): 789 [M+H]+.
Step 2: Mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-ylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a stirred solution of the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (565 mg, 0.716 mmol) in MeOH (7.2 mL) was added a 4 M solution of HCl in dioxane (1.79 mL, 7.16 mmol). The mixture was stirred at room temperature for 1 h. The solvents were evaporated, and the residue was dissolved in DCM (50 mL). To the mixture was added saturated aqueous sodium bicarbonate (50 mL). The biphasic mixture was separated, and the aqueous layer was extracted with additional DCM (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated to afford the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C28H31FN8O3) (ES, m/z): The intermediates in the following Table 14 were prepared in a manner similar to that used for the preparation of Intermediate 117, from the appropriate starting materials.
TABLE 14
Structure
Observed
Intermediate
Name
m/z [M + H]+
533
(R)-2-(1-(1H-pyrazol-4-yl)piperidin-3-yl)-N- (2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
118
119
(R)-2-(1-(3-(difluoromethyl)-1H-pyrazol- 4-yl)piperidin-3-yl)-N- (2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
583
Intermediate 120 and Intermediate 121: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S, 6R)-6-methyl-1-(1-((1R,2R or 1S,2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S, 6R)-6-methyl-1-(1-((1S,2S or 1R,2R)-2-(tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial containing of solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 95) (150 mg, 0.312 mmol) in THF (4 mL) was added 4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole (Intermediate 32) (177 mg, 0.562 mmol), followed by tBuXPhos-Pd G3 (124 mg, 0.156 mmol) and sodium tert-butoxide (105 mg, 1.09 mmol). The mixture was sparged with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 16 h. To the mixture was added additional 4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole (Intermediate 32) (88.5 mg, 0.281 mmol), tBuXPhos-Pd G3 (62 mg, 0.078 mmol) and sodium tert-butoxide (52.5 mg, 0.547 mmol). The mixture was stirred and heated at 90° C. for 16 h. The mixture was purified by preparative silica gel TLC with 4% MeOH in DCM as eluent to afford a mixture of isomers. The mixture was resolved by chiral SFC separation (ID 21×250 mm column with 50% (MeOH w/ACN 1:1+0.2% DIPA) as co-solvent) to afford N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1R,2R or 1S,2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (first eluting peak, Intermediate 120) and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S, 6R)-6-methyl-1-(1-((1S,2S or 1R,2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (fourth eluting peak, Intermediate 121), corresponding to Intermediate 120 and Intermediate 121, respectively. (NOTE: peaks 2 and 3 had poor separation). For Intermediate 120: LCMS (C38H47FN8O5) (ES, m/z): 715 [M+H]+. For Intermediate 121: LCMS (C38H47FN8O5) (ES, m/z): 715 [M+H]+.
Intermediate 122 and Intermediate 123: 1-(4-((3R,5S and 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a stirred mixture of sodium tert-butoxide (300 mg, 3.12 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (274 mg, 1.25 mmol) and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 85) (300 mg, 0.624 mmol) in THF (2 mL) was added tBuXPhos-Pd G3 (149 mg, 0.187 mmol) under a nitrogen atmosphere in a glove box. The mixture was stirred and heated at 100° C. for 14 h. The mixture was purified by preparative silica gel TLC with 10% MeOH in DCM as eluent to afford the two diastereomers: 1-(4-((3R,5S and 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, corresponding to Intermediate 122 and Intermediate 123, respectively. For Intermediate 122, LCMS (C32H39FN8O4) (ES, m/z): 619 [M+H]+. For Intermediate 123, LCMS (C32H39FN8O4) (ES, m/z): 619 [M+H]+.
Intermediate 124: (R)-5-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one
To a stirred mixture of sodium tert-butoxide (66.5 mg, 0.692 mmol), (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (89.0 mg, 0.190 mmol), 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol (Intermediate 29) (40.0 mg, 0.173 mmol) in THF (2 mL) was added tBuXPhos-Pd G3 (41.3 mg, 0.0520 mmol). The mixture was stirred and heated at 80° C. for 12 h. The mixture was cooled, diluted with EtOAc (10 mL), and washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with EtOAc as eluent, affording the ring-opened product (R)-5-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one. LCMS (C32H37FN8O4) (ES, m/z): 617 [M+H]+.
Intermediate 125: 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutan-1-one
Step 1: N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a stirred mixture of sodium tert-butoxide (177 mg, 1.84 mmol), (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (236 mg, 0.506 mmol), 4-bromo-1-(2,2-dimethoxycyclobutyl)-1H-pyrazole (Intermediate 30) (120 mg, 0.460 mmol) in THF (4 mL) was added tBuXPhos-Pd G3 (110 mg, 0.138 mmol). The mixture was stirred and heated at 80° C. for 12 h under nitrogen. The mixture was cooled, diluted with EtOAc (10 mL), and then washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to afford N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C33H39FN8O5) (ES, m/z): 647 [M+H]+.
Step 2: 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutan-1-one
A mixture of N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (130 mg, 0.201 mmol) and formic acid (2 mL) was stirred and heated at 40° C. for 15 h. The mixture was cooled and adjusted to pH=8 with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by preparative silica gel TLC with EtOAc as eluent to afford 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutan-1-one. LCMS (C22H23FN8O2) (ES, m/z): 451 [M+H]+.
Intermediate 126 and Intermediate 127: rac-(1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and rac-(1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-cyclohexan-1-ol
Step 1: 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexan-1-ol
To a stirred mixture of 3-hydroxycyclohexanecarbohydrazide (Intermediate 65) (0.556 g, 3.52 mmol) in DCM (30 mL) was added AcOH (0.084 mL, 1.5 mmol). To the solution was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (1.00 g, 2.93 mmol). The mixture was stirred and heated at 35° C. for 10 h. The mixture was concentrated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanol. LCMS (C25H28FN5O4) (ES, m/z) [M+H]+: 482.
Step 2: 3-(5-((2,4-Dimethoxybenzylamino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexan-1-one
To a stirred solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanol (780 mg, 1.62 mmol) in DCM (10 mL) was added DMP (1.37 g, 3.24 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate (5 mL), and the mixture was filtered. The filtrate was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanone. LCMS (C25H26FN5O4) (ES, m/z) [M+H]+: 480.
Step 3: 3-(5-((2,4-dimethoxybenzyl)aminol-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol
To a stirred solution of 4-bromo-1-ethyl-1H-pyrazole (621 mg, 3.55 mmol) in THF (3 mL) was added n-butyllithium (1.42 mL, 3.55 mmol, 2.5 M in hexane) at −78° C. The mixture was stirred at −78° C. for 20 min. To the mixture was added a solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanone (340 mg, 0.709 mmol) in THF (3 mL) at −78° C., and the mixture was stirred at this temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl). LCMS (C30H34FN7O4) (ES, m/z) [M+H]+: 576.
Step 4: rac-(1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and rac-(1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol
To a solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexanol (180 mg, 0.313 mmol) in DCM (4 mL) and water (2 mL) was added DDQ (106 mg, 0.469 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was diluted with DCM (10 mL) and was washed with Na2SO3 (2 M aqueous solution, 5 mL) and brine (2×10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by reversed-phase HPLC (Waters XBridge C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/ 10 mM NH4HCO3 modifier) as eluent) to afford two diastereomers rac-(1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(l-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and rac-(1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol, corresponding to Intermediate 126 and Intermediate 127, respectively. For Intermediate 126: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. For Intermediate 127: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426.
Intermediate 128: (2S,3S and 2R,3R)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-ol
To a mixture of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) and cesium carbonate (13.3 g, 40.8 mmol) in MeCN (20 mL) was added cis-2,3-dimethyloxirane (2.38 ml, 27.2 mmol). The mixture was stirred and heated at 80° C. for 16 h. The mixture was cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated, and the residue was diluted with DCM and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford (2S,3S and 2R,3R)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-ol. LCMS (C7H11BrN2O) (ES, m/z) [M+H]+: 219, 221.
The intermediates in the following Table 15 were prepared from the appropriate starting materials in a manner similar to Intermediate 128.
TABLE 15
Structure
Observed
Intermediate
Name
m/z [M + H]+
129
racemic, anti-3-(4-bromo-1H-pyrazol- 1-yl)butan-2-ol
219, 221
130
racemic, syn-3-(4-bromo-3-methyl- 1H-pyrazol-1-yl)butan-2-ol
233, 235
131
racemic-syn-3-(4-bromo-5-methyl- 1H-pyrazol-1-yl)butan-2-ol
233, 235
132
racemic-syn-3-(4-nitro-1H-pyrazol- 1-yl)butan-2-ol
186
133
rac-2-methyl-3-(4-nitro-1H-pyrazol- 1-yl)propane-1,2-diol
202
134
2-methyl-1-(5-methyl-4-nitro- 1H-pyrazol-1-yl)propan-2-ol
200
135
2-methyl-1-(3-methyl-4-nitro-1H- pyrazol-1-yl)propan-2-ol
200
Intermediate 136: ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate
To a stirred mixture of 4-bromo-1H-pyrazole (0.500 g, 3.40 mmol) in DMF (10 mL) was added K2CO3 (1.18 g, 8.50 mmol) and ethyl 3-bromopropanoate (0.924 g, 5.10 mmol). The mixture was stirred and heated at 60° C. for 8 h. The mixture was diluted with water (30 mL), filtered, and the filtrate was extracted with EtOAc (2×30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel column chromatography with 3-25% EtOAc in petroleum ether as eluent to afford ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate. LCMS (C8H11BrN2O2) (ES, m/z) [M+H]+: 247, 249.
The intermediates in the following Table 16 were prepared from the appropriate pyrazole and alkyl halide or mesylate in a manner similar to that used in the preparation of Intermediate 136.
TABLE 16
Structure
Observed
Intermediate
Name
m/z [M + H]+
137
3-(4-bromo-1H-pyrazol-1- yl)-3-methylbutan-2-one
231, 233
138
3-(4-bromo-3-methyl-1H-pyrazol- 1-yl)-3-methylbutan-2-one
245, 247
139
methyl 2-(4-bromo-3-methy1-1H- pyrazol-1-yl)-2-methylpropanoate
261, 263
140
methyl 2-(4-bromo-5-methyl-1H- pyrazol-1-yl)-2-methylpropanoate
261, 263
141
methyl 2-(4-bromo-5-methyl-1H- pyrazol-1-yl)-2-methylpropanoate
203, 205
142
tert-butyl (2-methyl-1-(4-nitro-1H- pyrazol-1-yl)propan-2-yl)carbamate
307 [M + Na]+
143
3-methyl-3-(4-nitro-1H-pyrazol- 1-yl)butan-2-one
198
144
diethyl 2-methyl-2-(4-nitro-1H- pyrazol-1-yl)malonate
—
Intermediate 145: rac-1-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol
To a solution of 1-(4-bromo-1H-pyrazol-1-yl)propan-2-one (Intermediate 141) (2.00 g, 9.85 mmol) in Et2O (22 mL) was added a 3 M solution of ethylmagnesium bromide (9.85 mL, 29.6 mmol) dropwise at 0° C. under a nitrogen atmosphere. The solution was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for 15 h. The mixture was quenched with saturated aqueous ammonium chloride (50 mL), diluted with EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and the solvents were evaporated. The resulting residue was purified by reversed phase HPLC (MeCN/water with 0.05% TFA) to afford rac-1-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C8H13BrN2O) (ES, m/z) [M+H]+: 233, 235.
Intermediate 146: 1-((5-methyl-2-phenyl-1,3-dioxan-5-yl)methyl)-4-nitro-1H-pyrazole
To a solution of (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol (4.00 g, 19.2 mmol) in THF (20 mL) was added 4-nitro-1H-pyrazole (2.61 g, 23.1 mmol), triphenylphosphine (10.1 g, 38.4 mmol). To the mixture was slowly added DIAD (5.83 g. 28.8 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 15 h. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether to afford 1-((5-methyl-2-phenyl-1,3-dioxan-5-yl)methyl)-4-nitro-1H-pyrazole. LCMS (C15H17N3O4) (ES, m/z) [M+H]+: 304.
The intermediate in the following Table 17 was prepared from the appropriate pyrazole and alcohol in a manner similar to that described for the synthesis of Intermediate 146.
TABLE 17
Structure
Observed
Intermediate
Name
m/z [M + H]+
147
4-nitro-1((1-((tetrahydro-2H-pyran-2-yl) oxy)cyclopropyl)methyl)-1H-pyrazole
528 [2M + Na]+
Intermediate 148: rac-3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-ol
To a suspension of 3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-one (Intermediate 138) (1.27 g, 5.18 mmol) in EtOH (25.9 ml) was added sodium borohydride (0.588 g, 15.5 mmol). The mixture was stirred for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and aqueous potassium hydroxide (1 M, 20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent of the filtrate was evaporated to afford 3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-ol, which was taken forward without further purification. LCMS (C9H15BrN2O) (ES, m/z) [M+H]+: 247, 249.
The intermediates in the following Table 18 were prepared from the appropriate ketone or ester containing pyrazole in a manner similar to that described in the preparation of Intermediate 148.
TABLE 18
Intermediate
Structure
Observed
Name
m/z [M + H]+
149
2-(4-bromo-3-methyl-1H-pyrazol- 1-yl)-2-methylpropan-1-ol
233, 235
150
2-(4-bromo-5-methyl-1H-pyrazol- 1-yl)-2-methylpropan-1-ol
233, 235
151
rac-3-methyl-3-(4-nitro-1H- pyrazol-1-yl)butan-2-ol
200
152
4-nitro-1((1-((tetrahydro-2H-pyran-2-yl) oxy)cyclopropyl)methyl)-1H-pyrazole
202
Intermediate 153: 4-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol
To a solution of ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate (100 mg, 0.405 mmol) (Intermediate 136) in THF (4 mL) was added a 3 M solution of MeMgBr in diethyl ether (1.35 mL, 4.05 mmol) at 15° C. under a nitrogen atmosphere. The mixture was stirred at 15° C. for 1 h. The mixture was cooled at 0° C., diluted with water (5 mL), extracted with EtOAc (2×5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with 25% EtOAc in petroleum ether as eluent to afford 4-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C8H13BrN2O) (ES, m/z) [M+H]+: 233, 235.
Intermediate 154: 4-bromo-1-((racemic, anti)-3-((rac-tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-1H-pyrazole
To a solution of Intermediate 129 (9.40 g, 42.9 mmol) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (19.6 mL, 215 mmol) and PPTS (10.8 g, 42.9 mmol). The mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM (15 mL), washed with saturated aqueous NaHCO3 and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford rac-4-bromo-1-((2S,3R)-3-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-1H-pyrazole. LCMS (C12H19BrN2O2) (ES, m/z) [M+H]+: 303, 305.
The intermediate in the following Table 19 was prepared from the appropriate starting materials in a manner similar to that described for the synthesis of Intermediate 154.
TABLE 19
Structure
Observed
Intermediate
Name
m/z [M + H]+
155
rac-4-bromo-1-(2-methyl-1-((tetrahydro- 2H-pyran-2-yl)oxy)propan-2-yl)- 1H-pyrazole
303, 305
Intermediate 156: rac-3-(4-amino-1H-pyrazol-1-yl)-3-methylbutan-2-ol
A 100 mL round-bottom flask was charged with 10% Pd/C (200 mg, 0.188 mmol), 3-methyl-3-(4-nitro-1H-pyrazol-1-yl)butan-2-ol (Intermediate 151) (750 mg, 3.76 mmol), and EtOH (31.4 mL). The mixture was degassed by evacuating and backfilling with nitrogen three times. The mixture was then evacuated and refilled with hydrogen from a balloon. The mixture was stirred for 3 h. The mixture was filtered through Celite, and the solvents of the filtrate were evaporated to afford 3-(4-amino-1H-pyrazol-1-yl)-3-methylbutan-2-ol. LCMS (C8H15N3O) (ES, m/z) [M+H]+: 170.
The intermediates in the following Table 20 were prepared from the appropriate nitro-pyrazole in a manner similar to that described for the preparation of Intermediate 156.
TABLE 20
Structure
Observed
Intermediate
Name
m/z [M + H]+
157
tert-butyl (1-(4-amino-1H-pyrazol-1-yl)- 2-methylpropan-2-yl)carbamate
255
158
2-(4-amino-1H-pyrazol-1-yl)- 2-methylpropane-1,3-dial
—
159
rac-3-(4-amino-1H-pyrazol-1-yl)- 2-methylpropane-1,2-
172
160
racemic, syn-3(4-amino-1H-pyrazol- 1-yl)butan-2-ol
156
161
rac-1-((1-((tetrahydro-2H-pyran-2-yl)oxy) cyclopropyl)methyl)-1H-pyrazol-4-amine
238
162
1((5-methyl-2-phenyl-1,3-dioxan- 5-yl)methyl)-1H-pyrazol-4-amine
274
163
1-(4-amino-5-methyl-1H-pyrazol- 1-yl)-2-methylpropan-2-ol
170
164
1-(4-amino-3-methyl-1H-pyrazol- 1-yl)-2-methylpropan-2-ol
170
Intermediate 165: tert-butyl (1-(4-((2S,5R and 2R,5S)-5-(hydrazinecarbonyl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate
Step 1: methyl (3R,6S and 3S,6R)-1-(1-(2-(tert-butoxycarbonyl)amino-2-methylpropyl-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate
To a 20 mL vial was added tert-butyl (1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (Intermediate 157) (85.0 mg, 0.334 mmol), sodium triacetoxyborohydride (106 mg, 0.501 mmol), and DCE (1.5 mL). The mixture was stirred. To the mixture was added methyl 2-methylene-5-oxohexanoate (0.063 ml, 0.40 mmol). After 20 minutes, to the mixture was added 1 M aqueous KOH (3 mL), water (3 mL), and DCM (3 mL). The organic layer was collected with a phase separator. The solvents were evaporated. To the resulting residue was dissolved in MeOH (1 mL), and water (0.4 mL). The mixture was stirred at room temperature for 72 h. To the mixture was added water (20 mL). The mixture was extracted with DCM (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to afford methyl (3R,6S and 3S, 6R)-1-(1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate. LCMS (C20H34N4O4) (ES, m/z) [M+H]+: 395.
Step 2: tert-butyl (1-(4-((2S,5R and 2R,5S)-5-(hydrazinecarbonyl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate
To a 20 mL vial was added methyl (3R,6S and 3S, 6R)-1-(1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (99.1 mg, 0.251 mmol), EtOH (1 mL), and hydrazine hydrate (0.175 ml, 3.77 mmol). The mixture was heated at 90° C. for 16 h. The solvents were evaporated to afford tert-butyl (1-(4-((2S,5R and 2R,5S)-5-(hydrazinocarbonyl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate. LCMS (C19H34N6O3) (ES, m/z) [M+H]+: 395.
The intermediates in the following Table 21 were prepared from the appropriate amino-pyrazole in a manner similar to that described for the preparation of Intermediate 165.
TABLE 21
Observed
Structure
m/z
Intermediate
Name
[M + H]+
166
1-(1-(1,3-dihydroxy-2-methylpropan-2-yl)- 1H-pyrazol-4-yl)-6-methylpiperidine- 3-carbohydrazide
312
167
1-(1-(2,3-dihydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-6-methylpiperidine- 3-carbohydrazide
312
168
6-methyl-1-(1((5-methyl-2-phenyl- 1,3-dioxan-5-yl)methyl)-1H-pyrazol-4-yl) piperidine-3-carbohydrazide
414
169
6-methyl-1-(1-((1-((tetrahydro-2H-pyran- 2-yl)oxy)cyclopropyl)methyl)-1H-pyrazol- 4-y1)piperidine-3-carbohydrazide
378
170
(3R,6S and 3S, 6R)-6-methyl-1-(1H- pyrazol-4-yl)piperidine-3-carbohydrazide
224
Intermediate 171: 1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide
Step 1: methyl 4-methyl-2-methylene-5-oxopentanoate
A solution of methyl 2-(bromomethyl)acrylate (6.04 ml, 50.3 mmol) and DMAP (6.76 g, 55.3 mmol) in DCM (201 mL) was stirred at room temperature for 30 minutes. To the mixture were added propionaldehyde (5.41 ml, 75 mmol) and L-proline (5.79 g, 50.3 mmol). The mixture was stirred at 23° C. for 48 hours. The mixture was washed with water (200 mL), 1 M aqueous HCl (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-2.5% MeOH in DCM as eluent to afford methyl 4-methyl-2-methylene-5-oxopentanoate.
Step 2: methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate
1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 163) (1.43 g, 8.45 mmol) was dissolved in MeOH (25.6 mL). To the mixture was added sodium triacetoxyborohydride (6.51 g, 30.7 mmol), followed by methyl 4-methyl-2-methylene-5-oxopentanoate (1.20 mL, 7.68 mmol). The mixture was stirred for 5 min (until the sodium triacetoxyborohydride went into solution). The mixture was quenched with 1 M aqueous sodium hydroxide (30.7 mL, 30.7 mmol) and allowed to stir for 48 h. The MeOH was evaporated, and to the mixture was added DCM (30 mL). The layers were separated and the DCM layer was dried with anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-10% MeOH in DCM to afford methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate. LCMS (C16H27N3O3) (ES, m/z) [M+H]+: 310.
Step 3: Mixture of methyl (3S,5R and 3R,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate and methyl (3R,5R and 3S, 55)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate
Methyl (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate (1.39 g, 4.49 mmol) was stirred in MeOH (35.9 ml) with potassium tert-butoxide (1.01 g, 8.98 mmol) for 18 h at 60° C. The mixture was cooled to room temperature, and the solvents were evaporated. The resulting residue was dissolved in DCM and quenched with saturated aqueous NH4Cl. The layers were separated using a Biotage Isolute® phase separator and the DCM layer was concentrated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to afford a mixture of methyl (3S,5R and 3R, 55)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate and methyl (3R,5R and 3S, 5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carboxylate. LCMS (C16H27N3O3) (ES, m/z) [M+H]+: 310.
Step 4: (3R,5S and 3S, 5R)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide and (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide
To a solution of the product from step 3 (1.18 g, 3.81 mmol) in ethanol (15.3 mL) was added hydrazine hydrate (1.87 mL, 38.1 mmol). The mixture was stirred and heated at 80° C. for 16 h. The mixture was cooled to room temperature and the solvents were evaporated to afford (3R,5S and 3S,5R)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide and (3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5-methylpiperidine-3-carbohydrazide LCMS (C18H27N5O2) (ES, m/z) [M+H]+: 310.
Intermediate 172 and Intermediate 173: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,5S and 3S, 5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 85) (2.52 g, 5.24 mmol) was subjected to chiral SFC separation (Phenomenex Lux-3 21×250 mm column with 20% MeOH (w/ 0.1% NH4OH) as cosolvent) to afford rac-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,5S)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (combination of peaks 2 and 3) and rac-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,5S)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (combination of peaks 1 and 4). LCMS (C25H29FN6O3) (ES, m/z) [M+H]+: 481.
Intermediate 174 and Intermediate 175: N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R,5S and 3S,5R)-5-methylpiperid ii-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: tert-butyl (3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate and tert-butyl (3S,5S and 3R,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate
To a 100 mL round bottom flask was added tert-butyl 3-(hydrazinocarbonyl)-5-methylpiperidine-1-carboxylate (Intermediate 56) (1.56 g, 6.07 mmol), 1,4-dioxane (20 mL), and acetic acid (0.174 mL, 3.04 mmol). The mixture was stirred. To this stirring mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-3,5-difluorobenzonitrile (Intermediate 41) (2.00 g, 6.07 mmol). The mixture was stirred at 75° C. for 16 h. The mixture was purified by silica gel chromatography with 0-50% EtOAc in hexanes as eluent to afford tert-butyl (3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate (first eluting) and tert-butyl (3S,5S and 3R, 5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate (second eluting). LCMS (C29H34F2N6O4) (ES, m/z) [M+H]+: 569.
Step 2: N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R,5S and 3S, 5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
tert-butyl (3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate and tert-butyl (3S,5S and 3R, 5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1-carboxylate from Step 1 were converted to N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R,5S and 3S, 5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 174) and N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3S,5S and 3R, 5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 175) (LCMS (C24H26F2N6O2) (ES, m/z) [M+H]+: 469) with formic acid in a manner similar to the synthesis of Intermediate 82.
The intermediates in the following Table 22 were prepared in a similar manner to that described for the synthesis of Intermediate 174 from the appropriate hydrazide and carbodiimide.
TABLE 22
Inter-
Observed
medi-
Structure
m/z
ate
Name
[M + H]+
176
N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2- ((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
481
177
N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2((3R,6S and 3S,6R)-6-methyl-1-(1H-pyrazol-4-yl)piperidin -3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
547
Intermediate 178: (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile
To a mixture of 2-bromo-5-(difluoromethoxy)-4-fluoroaniline (1.40 g, 5.47 mmol) and zinc cyanide (1.28 g, 10.9 mmol) in NMP (4 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.699 g, 1.37 mmol). The mixture was stirred and heated at 160° C. under nitrogen for 1 h in a microwave reactor. The mixture was cooled to room temperature. To the mixture was added brine (60 mL), and the mixture was extracted with petroleum ether:ethyl acetate (3:1) (3×25 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were, evaporated. The resulting residue was purified by silica gel chromatography with 25% EtOAc in petroleum ether to afford 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile.
Step 2: methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate
A solution of 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile (500 mg, 2.47 mmol) in methyl carbonochloridate (3.04 g, 32.2 mmol) was stirred and heated at 75° C. under a nitrogen atmosphere for 15 h. The mixture was cooled, diluted with water (10 mL), extracted with EtOAc (3×20 mL), dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography to afford methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate.
Step 3: (R)-tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
To a solution of methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate (400 mg, 1.537 mmol) in NMP (4 mL) was added (R)-tert-butyl 3-(hydrazinocarbonyl)piperidine-1-carboxylate (411 mg, 1.691 mmol) (Intermediate 54). The mixture was stirred and heated at 170° C. for 30 min. The mixture was cooled, diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in hexanes as eluent to afford (R)-tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C20H22F3N5O4) (ES, m/z) [M+H]+: 454.
Step 4: tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate
To a solution of tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (1.00 g, 2.21 mmol) in MeCN (10 mL) was added DBU (0.831 mL, 5.51 mmol), PyBroP (1.34 g, 2.87 mmol) and (2,4-dimethoxyphenyl)methanamine (0.553 g, 3.31 mmol) at 90° C. under a nitrogen atmosphere. The mixture was stirred at 90° C. for 12 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-50% EtOAc in hexanes as eluent to afford tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C29H33F3N6O5) (ES, m/z) [M+H]+: 603.
Step 5: (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a solution of tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate (700 mg, 1.16 mmol) in DCM (7 mL) was added TFA (0.7 mL) at 15° C. under a nitrogen atmosphere. The mixture was stirred at 15° C. for 2 h. The mixture was cooled, diluted with NaHCO3 (15 mL), extracted with DCM (3×20 mL), dried over anhydrous Na2SO4, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent to afford (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C24H25F3N6O3) (ES, m/z) [M+H]+: 503.
Example 1: (R)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol
A 5 mL microwave vial was charged with (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (100 mg, 0.214 mmol), tBuXPhos-Pd G3 (68.1 mg, 0.086 mmol) and sodium tert-butoxide (82 mg, 0.86 mmol). To the mixture was added 1-(3-bromo-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol (Intermediate 2) (94 mg, 0.429 mmol) in THF (1.4 mL). The mixture was sparged with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature, and the solids were removed by filtration and washed with DCM. The solvents of the filtrate were evaporated. To the resulting residue was added TFA (0.5 mL). The mixture was stirred and heated at 50° C. for 3 h. The mixture was cooled to room temperature, and the solvents were evaporated. The residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/1H2O with 0.1% TFA as eluent) to afford (R)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol. LCMS (C21H26FN9O2) (ES, m/z): 458 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.89 (d, J=10.9 Hz. 1H), 7.81 (s, 2H), 7.19 (d, J=7.9 Hz, 1H), 4.31 (d, J=12.8 Hz, 1H), 3.97 (s, 4H), 3.91 (s, 2H), 3.15 (ddt, J=10.9, 6.7, 3.4 Hz, 1H), 3.11-3.04 (m, 1H), 2.86 (td, J=12.5, 2.7 Hz, 1H), 2.23 (d, J=12.1 Hz, 1H), 1.92-1.77 (m, 2H), 1.75-1.63 (m, 1H), 1.10 (d, J=2.4 Hz, 6H).
The example compounds of the invention in the following Table 15 were prepared in a manner similar to that described in Example 1, from the appropriate starting aryl halide and amine intermediates.
TABLE 15
Structure
Observed
Example
Name
m/z [M + H]+
2
(R)-9-fluoro-8-methoxy-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
397
3
(R)-2-(1-(1-(tert-butyl)-1H-pyrazol-4-yl)piperidin-3-yl)-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
439
4
(R)-9-fluoro-2-(1-(1-isopropyl-1H-pyrazol-4-yl)piperidin-3-yl)- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
425
5
(R)-9-fluoro-8-methoxy-2-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol- 4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine
465
6
(R)-9-fluoro-8-methoxy-2-(1-(1-methyl-1H-1,2,3-triazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
398
7
(R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-l-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
455
8
(R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-l-yl)-5-methyl-1H-pyrazol- 1-yl)-2-methylpropan-2-ol
469
9
(R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-3-methyl-1H- pyrazol-1-yl)-2-methylpropan-2-ol
469
10
(R)-1-((4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1- yl)methyl)cyclobutan-1-ol
467
11
(R)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
469
12
(S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
469
13
(R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-l-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
469
14
(1s,3s)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-l-yl)-1H- pyrazol-1-yl)-methylcyclobutan-1-ol
467
15
(R)-9-fluoro-8-methoxy-2-(1-(1-((3-methyloxetan-3-yl) methyl)-1H-pyrazol-4-yl)piperidin-3-yl)[1,2,4] triazolo[1,5-c]quinazolin-5-amine
467
16
(R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin- 3-yl)-[1,2,4]triazolo[1,5-c]quinazoliu-5-amine
481
17
(R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl) [1,2,4]triazolo[1,5-c]quinazolin-5-amine
481
18
(R)-2-(1-(5-(difluoromethyl)-1-(tettahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
517
19
(R)-2-(1-(3-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) piperidin-3-yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
517
20
(R)-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-1-yl)-ethyl-1H-pyrazol-3-yl)methanol
441
21
(R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-1-yl)-3-cyclopropyl- 1H-pyrazol-1-yl)-2-methylpropan-2-ol
495
22
(R)-2-(1-(6-(difluoromethoxy)pyridin-3-yl)piperidin-3-yl)- 9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-5-amine
460
23
(R)-9-fluoro-2-(1-(6-isopropoxypyridin-3-yl)piperidin-3-yl)- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
452
24
(R)-2-(1-(6-(difluoromethoxy)-5-methylpyridin-3-yl)piperidin-3-yl)- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
474
25
(R)-5-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)piperidin-1-yl)-1-(difluoromethyl)-3-methylpyridin-2(1H)-one
474
26
(R)-9-fluoro-8-methoxy-2-(1-(6-methoxypyridin-3-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
424
27
(R)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-1-yl)-5-methyl-1H-1,2,4-triazol- 1-yl)-2-methylpropan-2-ol
470
28
(R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol
455
29
(R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-5-methyl- 1H-pyrazol-1-yl)-2-methylpropan-2-ol
469
30
(R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-l-yl)-3-methyl- 1H-pyrazol-1-yl)-2-methylpropan-2-ol
469
31
(R)-1-((4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-l-yl)-1H- pyrazol-1-yl)methyl)cyclobutan-1-ol
467
32
(R)-2-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
455
33
(R)-2-(1-(6-(difluoromethoxy)pyridin-3-yl)piperidin-3-yl)- 9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
460
34
(R)-9-fluoro-7-methoxy-2-(1-(6-methoxypyridin-3-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
424
35
(R)-9-fluoro-2-(1-(6-isopropoxypyridin-3-yl)piperidin-3-yl)- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
452
36
(R)-1-(3-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol
456
37
(R)-1-(3-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]trazolo[1,5-c] quinazolin-2-yl)piperidin-1-yl)-5-methyl-1H-1,2,4-triazol-1-yl)- 2-methylpropan-2-ol
470
38
(R)-1((4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)prrolidin-l-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
453
39
rac-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5-c]quinazoln-2-yl)azepan-1-yl)-1H-pyrazol- 1-yl)-2-methylpropan-2-ol
469
Example 40: 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial containing of solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 95) (600 mg, 1.25 mmol) in THF (12 ml) was added rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23) (590 mg, 1.87 mmol) followed by tBuXPhos-Pd G3 (298 mg, 0.375 mmol) and sodium tert-butoxide (420 mg, 4.37 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 4 h. The mixture was cooled to room temperature. To the mixture was added additional tBuXPhos-Pd G3 (149 mg, 0.188 mmol) followed by sodium tert-butoxide (210 mg, 2.19 mmol). Nitrogen was bubbled through the mixture for an additional 10 min. The mixture was stirred and heated at 90° C. for 18 h. The mixture was cooled to room temperature, and then the solvents were evaporated. The residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous MgSO4, and the solids were removed by filtration. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexane as eluent. The obtained residue was further purified by preparative silica gel TLC with 4% MeOH in DCM as eluent to afford N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C38H47FN8O5) (ES, m/z): 715 [M+H]+.
Step 2: 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (1.40 g, 2.22 mmol) and TFA (1.65 mL, 22.2 mol). The mixture was stirred and heated at 60° C. for 1 h. The mixture was cooled to room temperature, and then the solvents were evaporated. The residue was purified by silica gel chromatography with 6% (7 M ammonia solution in MeOH) in DCM as eluent to afford 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol (Example 40). LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.87 (d, J=10.9 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 4.14 (s, 2H), 3.99 (s, 3H), 3.73 (d, J=4.9 Hz, 1H), 3.47 (d, J=9.2 Hz, 1H), 3.36-3.20 (m, 3H), 2.11 (d, J=7.9 Hz, 3H), 2.02 (p, J=10.7, 9.6 Hz, 2H), 1.89-1.69 (m, 2H), 1.55 (dq, J=19.0, 9.6 Hz, 1H), 1.37-1.20 (m, 2H), 1.12 (d, J=6.6 Hz, 3H), 0.96-0.82 (m, 2H).
The example compounds of the invention in the following Table 16 were prepared in a manner similar to that described for the preparation of Example 40 from the appropriate starting aryl halide and Intermediate 95.
TABLE 16
Structure
Observed
Example
Name
m/z [M + H]
41
1-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
483
42
1-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
483
43
3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2,3-dimethylbutan-2-ol
497
44
9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
481
45
9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1- (5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
495
46
9-fluoro-8-methoxy-24(3R,6S or 3S,6R)-6-methyl-1-(3-methyl- 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl) [1,2,4]triazolo[1,5-c]quinazolin-5-amine
495
47
9-fluor-2-((3R,6S or 3S,6R)-1-(1((3-(fluoromethyl)oxetan-3-yl) methyl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
499
Example 48 and Example 49: (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
Step 1: (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzylamino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
Step 1 of the synthesis of Example 48 and Example 49 was conducted with Intermediate 95 and Intermediate 1 in a manner similar to that described in step 1 of the synthesis of Example 40. The resulting diastereomeric mixture was purified by SFC (Chiral Technologies AD-H 21×250 mm column with 55% (IPA+0.2% DIPA) as co-solvent), to afford peak 1 and peak 2 corresponding to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol. For peak 1, LCMS (C33H41FN8O4) (ES, m/z): 633 [M+H]+. For peak 2, LCMS (C33H41FN8O4) (ES, m/z): 633 [M+H]+.
Step 2: (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
Step 2 of the synthesis of Example 48 and Example 49 was conducted in a manner similar to that described in step 2 of Example 40, where peak 1 was converted to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Example 48) and peak 2 was converted to (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Example 49).
For Example 48: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.99 (d, J=10.7 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.74 (s, 2H), 4.14 (s, 1H), 4.02 (m, 1H), 4.00 (s, 3H), 3.74 (m, 1H), 3.49 (s, 1H), 3.45 (dd, J=11.6, 3.8 Hz, 1H), 3.32 (dd, J=11.3, 4.0 Hz, 1H), 3.20 (t, J=11.3 Hz, 1H), 2.18-2.00 (m, 3H), 1.78 (d, J=9.9 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.14 (s, 3H), 1.11 (d, J=6.7 Hz, 2H), 1.01 (s, 3H).
For Example 49: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.99 (d, J=10.8 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.78 (s, 2H), 4.18 (s, 1H), 4.03 (m, 1H), 4.00 (s, 4H), 3.74 (m, 1H), 3.49 (s, 1H), 3.44 (dd, J=11.6, 3.9 Hz, 1H), 3.33 (dd, J=11.0, 4.2 Hz, 1H), 3.21 (t, J=11.3 Hz, 1H), 2.18-2.00 (m, 3H), 1.78 (d, J=9.7 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.14 (s, 3H), 1.11 (m, J=6.9 Hz, 3H), 1.02 (s. 3H).
Example 50 and Example 51: 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl-9-fluoro-8-methoxy-2-((3S,6R, or 3R,6S)-6-methyl-(5-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial was added N-(2,4-dimethoxybenz)-9-fluoro-8-methoxy-2-((3S,6R, or 3R,6S)-6-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 96) (240 mg, 0.499 mmol, tBuXPhos-Pd G3 (119 mg, 0.150 mmol), rac-4-bromo-3-methyl-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 31) (329 mg, 0.999 mmol), sodium tert-butoxide (288 mg, 3.00 mmol) and THF (5 mL). The mixture was sparged with nitrogen for 5 min. The mixture was stirred and heated at 100° C. for 19 h. The solvents were evaporated and the residue was purified by preparative silica gel TLC with 4% (7 M ammonia in MeOH) in DCM as eluent to afford a mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S′)-6-methyl-1-(3-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(5-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.
Step 2: 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
To the mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(5-methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (12.0 mg, 0.0186 mmol) was added TFA (2 mL). The mixture was stirred and heated at 60° C. for 1 h. The mixture was cooled to room temperature. The mixture was concentrated and the residue was purified by preparative silica gel TLC with 4% (7 M ammonia in MeOH) in DCM as eluent followed by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/water w/ 0.1% TFA modifier as eluent) to afford 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol (Example 50) and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol (Example 51).
For Example 50: LCMS (C25H31FN8O2) (ES, m/z): 495 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.95 (d J=10.8 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 4.22 (s, 2H), 4.18 (d, J=12.9 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 2H), 3.74 (s, 1H), 3.57-3.43 (m, 1H), 2.46 (s, 3H), 2.36-2.26 (m, 1H), 2.22-2.12 (m, 3H), 2.04 (q, J=9.7 Hz, 3H), 1.84-1.73 (m, 1H), 1.68-1.58 (m, 1H), 1.27 (d, J=6.5 Hz, 3H).
For Example 51: LCMS (C25H31FN8O2) (ES, m/z): 495 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.98-7.91 (m, 1H), 7.82 (s, 1H), 7.26 (d, J=7.7 Hz, 1H), 4.27 (s, 2H), 4.03 (s, 3H), 3.96 (d, J=11.8 Hz, 2H), 3.76 (d, J=20.2 Hz, 1H), 2.61 (s, 2H), 2.45 (d, J=15.4 Hz, 2H), 2.40-2.29 (m, 2H), 2.26 (s, 1H), 2.15 (d, J=10.4 Hz, 3H), 2.11-1.97 (m, 3H), 1.89-1.74 (m, 1H), 1.75-1.58 (m, 1H), 1.28 (d, J=6.6 Hz, 3H).
The example compounds of the invention in the following Table 17 were prepared in a manner similar to that described for Example 50 and Example 51 from the appropriate starting aryl halide and Intermediate 96.
TABLE 17
Ex-
Observed
am-
Structure
m/z
ple
Name
[M + H]+
52
1-(4-((2R,5S, or 2S,5R)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)-5-methyl-1H- pyrazol-1-yl)-2-methylpropan-2-ol
483
53
1-(4-((2R,5S, or 2S,5R)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)-3- methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
483
Example 54: 1-((4-((3R,5S or 3S5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial containing of solution of N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 99) (80.0 mg, 0.165 mmol) in THF (1.5 mL) was added 4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23) (83.0 mg, 0.260 mmol) followed by tBuXPhos-Pd G3 (39.3 mg, 0.0500 mmol) and sodium tert-butoxide (47.6 mg, 0.495 mmol). The mixture was flushed with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 2 h. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexanes as eluent to afford N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C37H44F2N8O5) (ES, m/z): 719 [M+H]+.
Step 2: 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (105 mg, 0.146 mmol) in TFA (1.2 mL) was stirred and heated at 60° C. for 1 h. The mixture was concentrated. The residue was purified by preparative silica gel TLC with 5% (7 M ammonia in MeOH) in DCM as eluent to afford 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol. LCMS (C23H26F2N8O2) (ES, m/z): 485 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.96 (d, J=10.7 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J=3.8 Hz, 2H), 5.91 (s, 2H), 4.90 (dtt, J=48.1, 9.9, 4.7 Hz, 1H), 4.13 (s, 2H), 4.00 (s, 3H), 3.74-3.64 (m, 2H), 3.42 (d, J=12.6 Hz, 1H), 2.86 (t, J=11.4 Hz, 1H), 2.71 (dq, J=10.3, 7.2, 5.2 Hz, 2H), 2.17-1.92 (m, 3H), 1.88-1.73 (m, 2H), 1.57 (dq, J=18.2, 9.1 Hz, 2H).
The example compounds of the invention in the following Table 18 were prepared in a manner similar to that described for the preparation of Example 54 from the appropriate starting aryl halide and Intermediate 99.
TABLE 18
Structure
Observed
Example
Name
m/z [M + H]+
55
1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
473
56
9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
485
Example 57: 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial containing of solution of 2-((1R,5R or 1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 97) (60.0 mg, 0.129 mmol) in THF (1.5 mL) was added 4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (Intermediate 23) (61.1 mg, 0.194 mmol) followed by tBuXPhos-Pd G3 (30.8 mg, 0.039 mmol) and sodium tert-butoxide (43.4 mg, 0.452 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 18 h. The mixture was cooled to room temperature. The solvents were evaporated, and the resulting residue was purified by preparative silica gel TLC with 5% MeOH in DCM as eluent to afford N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C37H43FN8O5) (ES, m/z): 699 [M+H]+.
Step 2: 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol 2,2,2-trifluoroacetate
A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (59 mg, 0.084 mmol) and TFA (1.0 mL) was stirred and heated at 60° C. for 1 h. The mixture was cooled to room temperature. The solvents were evaporated. The resulting residue was purified by preparative silica gel TLC with 8% (7 M ammonia in MeOH) in DCM as eluent. The obtained residue was further purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA modifier as eluent) to afford 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol 2,2,2-trifluoroacetate). LCMS (C23H25FN8O2) (ES, m/z): 465 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.96 (d, J=10.0 Hz, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.06 (s, 1H), 4.18 (s, 2H), 4.08 (s, 3H), 3.79 (d, J=8.6 Hz, 1H), 3.69 (d, J=8.7 Hz, 1H), 3.54 (d, J=8.6 Hz, 2H), 3.35 (s, 2H), 3.20 (dd, J=8.8, 3.8 Hz, 2H), 2.32 (s, 1H), 2.13-2.04 (m, 3H), 1.75 (d, J=3.8 Hz, 2H), 1.58 (d, J=4.9 Hz, 1H).
Example 58 in the following Table 19 was prepared in a manner similar to that described for the preparation of Example 57 from Intermediate 97 and the appropriate starting aryl halide.
TABLE 19
Ex-
Observed
am-
Structure
m/z
ple
Name
[M + H]+
58
453
1-(4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-
[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3.1.0]
hexan-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Example 59: 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-1)-1-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 100) (50.0 mg, 0.103 mmol), tBuXPhos-Pd G3 (24.6 mg, 0.0310 mmol), 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (Intermediate 15) (23.9 mg, 0.103 mmol), sodium tert-butoxide (59.5 mg, 0.619 mmol) and THF (1 mL). The mixture was flushed with nitrogen for 5 min. The mixture was stirred and heated at 100° C. for 4 h. The solvents were evaporated, and the resulting residue was purified by silica gel chromatography with 0-100% (30% MeOH in EtOAc) in hexanes, yielding N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.
Step 2: 9-fluoro-2-((3S,5R or 3R,5S5-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
To a reaction vial was added N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (85.0 mg, 0.130 mmol) was added TFA (2 mL). The mixture was stirred and heated at 60° C. for 1 h. The solvents were evaporated, and the residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA modifier as eluent), to afford 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C23H26F2N8O2) (ES, m/z): 485 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.93 (d, J=10.7 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=7.5 Hz, 1H), 4.95 (dt, J=10.3, 5.4 Hz, 1H), 4.32 (dq, J=11.0, 6.1, 5.6 Hz, 1H), 4.13-3.95 (m, 4H), 3.78 (d, J=11.1 Hz, 2H), 3.65-3.52 (m, 2H), 3.46 (t, J=11.2 Hz, 1H), 2.89 (t, J=11.4 Hz, 1H), 2.82-2.59 (m, 2H), 2.12-1.92 (m, 4H).
Example 60 and Example 61: (R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
A 5 mL microwave vial was charged with rac-2-(azepan-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 83) (100 mg, 0.208 mmol) and THF (1.3 mL). To the mixture was added 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (91.0 mg, 0.420 mmol), followed by tBuXPhos-Pd G3 (66.1 mg, 0.0830 mmol) and sodium tert-butoxide (80.0 mg, 0.832 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 12 h. The mixture was cooled to room temperature, and then the solids were removed by filtration and washed with DCM. The solvents of the filtrate were evaporated. The resulting residue was dissolved in TFA (802 μL, 10.4 mmol) and heated at 50° C. for 3 h. The mixture was cooled to room temperature, and the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA modifier as eluent) to yield the racemic product. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21×250 mm column with 25% (isopropanol w/ 0.1% NH4OH modifier) as co-solvent), to afford (R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 60, first eluting peak) and (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 61, second eluting peak).
For Example 60: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.88 (d, J=11.0 Hz, 1H), 7.72 (d, J=26.0 Hz, 2H), 7.18 (d, J=7.9 Hz, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 4.63 (s, 1H), 3.97 (s, 3H), 3.87 (s, 2H), 3.75 (dd, J=14.3, 3.9 Hz, 1H), 3.53 (dd, J=14.3, 10.0 Hz, 1H), 3.45 (dq, J=9.7, 5.0, 4.6 Hz, 1H), 3.37 (dd, J=14.0, 6.1 Hz, 1H), 3.23 (ddd, J=13.3, 7.6, 5.1 Hz, 1H), 2.07-1.82 (m, 3H), 1.71 (s, 1H), 1.58-1.45 (m, 2H), 1.03 (d, J=3.5 Hz, 6H).
For Example 61: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.88 (d, J=11.0 Hz, 1H), 7.70 (s, 2H), 7.18 (d, J=7.7 Hz, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 4.62 (s, 1H), 3.97 (s, 3H), 3.87 (s, 2H), 3.75 (dd, J=14.4, 3.8 Hz, 1H), 3.53 (dd, J=14.2, 10.2 Hz, 1H), 3.45 (dt, J=9.5, 4.9 Hz, 1H), 3.38 (s, 1H), 3.24 (dd, J=13.6, 5.5 Hz, 2H), 2.08-1.84 (m, 3H), 1.71 (s, 1H), 1.50 (d, J=12.7 Hz, 2H), 1.03 (d, J=3.4 Hz, 6H).
The example compounds of the invention in the following Table 20 were prepared in a manner similar to that described for the preparation of Example 60 and Example 61 from the appropriate starting amine and aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 20
Structure
SFC
Observed m/z
Example
Name
Conditions
[M + H ]+
62
(R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3- fluoropyrrolidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 50% (IPA w/ 0.2% DIPA modifier) as co-solvent
459
63
(S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3- fluoropyrrolidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 50% (IPA w/ 0.2% DIPA modifier) as co-solvent
459
64
(R or S)-3-(3-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- 1,2,4-triazolo-1-yl)-2-methylbutan-2-ol
Peak 1; Chiral Technologies IC 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
470
65
(S or R)-3-(3-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-1,2,4-triazolo-1-yl)-2-methylbutan-2-ol
Peak 2; Chiral Technologies IC 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
470
66
1-(4-((3S or 3R,4S or 4R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Chiralcel OJ- H 4.6 × 150 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent
469
67
1-(4-((3R or 3S,4R or 4S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4] methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Chiralcel OJ- H 4.6 × 150 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent
469
Example 68 and Example 69: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 40 mL vial was added rac-N-(2,4-diethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 102) (736 mg, 1.52 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (998 mg, 4.56 mmol), tBuXPhos-Pd G3 (965 mg, 1.22 mmol), sodium tert-butoxide (876 mg, 9.11 mmol), and THF (15.0 mL). The mixture was purged with nitrogen for 5 min. The mixture was stirred and heated at 80° C. for 6 h. The mixture was cooled to room temperature. The solvents were evaporated, and the resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
Step 2: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 20 mL vial was added rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (550 mg, 0.883 mmol), and TFA (8.83 mL, 115 mmol). The mixture was stirred and heated at 50° C. for 2 h. The solvents were evaporated. To the resulting residue was added MeOH and the mixture was filtered. The solvents of the filtrate were evaporated. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AS-H 21×250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent) to afford 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 68, first eluting peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[12.4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 69, second eluting peak).
For Example 68: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.82 (s, 2H), 7.43 (dd. J=8.3, 2.6 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.18 (dd, J=11.0, 2.6 Hz. 1H), 4.94 (dtt, J=48.3, 10.3, 4.8 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.89 (s, 2H), 3.78-3.71 (m, 1H), 3.66 (d, J=11.5 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 2.75 (t, J=11.5 Hz, 1H), 2.66 (d, J=6.1 Hz, 1H), 2.58 (td, J=10.4, 5.2 Hz, 1H), 1.92 (p, J=11.3 Hz, 1H), 1.04 (s, 6H).
For Example 69: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.44 (dd, J=8.3, 2.7 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.19 (dd, J=11.1, 2.7 Hz, 1H), 4.95 (ddt, J=48.3, 10.4, 5.2 Hz, 1H), 4.64 (s, 1H), 3.94 (s, 2H), 3.89 (s, 1H), 3.74 (d, J=10.6 Hz, 1H), 3.66 (d, J=11.9 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 2.74 (d, J=11.5 Hz, 1H), 2.65 (s, 1H), 2.58 (dt, J=10.3, 5.2 Hz, 1H), 1.97-1.89 (m, 1H), 1.04 (s, 6H).
The example compounds of the invention in the following Table 21 were prepared in a manner similar to that described for the preparation of Example 68 and Example 69 from Intermediate 102 and the appropriate starting aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 21
Structure
SFC
Observed m/z
Example
Name
Conditions
[M + H]+
70
1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Phenomenex Lux-2 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
487
71
1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] fltriazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Phenomenex Lux-2 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
487
72
1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Peak 1; ES Industries CCA 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
485
73
1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Peak 2; ES Industries CCA 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
485
Example 74 and Example 75: 1-(4-((3R,5R or 3S,5S) 3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: rac-1-(4-((3R,5R or 3S,5S)-3 (5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 20 mL vial was added rac-N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R or 3S,5S)-5-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 102) (434 mg, 0.896 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (589 mg, 2.69 mmol), tBuXPhos-Pd G3 (569 mg, 0.717 mmol), sodium tert-butoxide (517 mg, 5.37 mmol) and THF (9.0 mL). The mixture was purged with nitrogen for 5 min. The mixture was stirred and heated at 80° C. for 6 h. The mixture was cooled to room temperature. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 30-50% EtOAc:EtOH (3:1) in hexane as eluent, yielding rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
Step 2: 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 20 mL vial containing rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (439 mg, 0.705 mmol) was added TFA (7.05 mL, 92.0 mmol). The mixture was stirred and heated at 50° C. for 2 h. The solvents were evaporated. To the residue was added MeOH. The mixture was filtered, and then the solvents of the filtrate were evaporated. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AS-H 21×250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent), yielding 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 74, first eluting peak) and 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 75, second eluting peak).
For Example 74: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.83 (s. 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=10.0 Hz, 1H), 5.11 (d, J=46.5 Hz, 1H), 4.64 (s, 1H), 3.94 (s, 3H), 3.89 (s, 2H), 3.69-3.48 (m, 3H), 2.97-2.89 (m, 1H), 2.90-2.79 (m, 1H), 2.40 (s, 1H), 2.14 (dt, J=40.9, 11.8 Hz, 1H), 1.04 (s, 6H).
For Example 75: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.83 (s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=8.9 Hz, 1H), 5.11 (d, J=47.5 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 2H), 3.67-3.50 (m, 3H), 2.97-2.90 (m, 1H), 2.90-2.79 (m, 1H), 2.41 (s, 1H), 2.14 (dt, J=40.8, 12.8 Hz, 1H), 1.04 (s, 6H).
The example compounds of the invention in the following Table 22 were prepared in a manner similar to that described for the preparation of Example 74 and Example 75 from Intermediate 103 and the appropriate starting aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 22
Structure
SFC
Observed m/z
Example
Name
Conditions
[M + H]+
76
1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
487
77
1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Phenomenex Lux-2 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
487
78
1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
485
79
1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 1H-pyrazol-1-yl)methyl)cyclobutan-1-ol
Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
485
Example 80 and Example 81: 1-(4-((3R,5S or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R) 3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan 2-ol
Step 1 of Example 80 and Example 81 was conducted in a manner similar to step 1 of Example 74 and Example 75, with Intermediate 101 and Intermediate 4 to afford rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
Step 2: 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 2 of Example 80 and Example 81 was conducted in a manner similar to step 2 of Example 74 and Example 75, where rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol is converted to the racemic mixture of the corresponding final compounds. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21×250 mm column with 25% (MeOH w/ 0.2% DIPA modifier) as co-solvent), to afford 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 80, first eluting peak) and 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 81, second eluting peak).
For Example 80: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.94 (d, J=10.8 Hz. 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 5.12 (d, J=46.8 Hz, 1H), 4.02 (d, J=3.8 Hz, 3H), 3.84 (d, J=12.4 Hz, 1H), 3.82-3.74 (m, 1H), 3.74-3.62 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 3.08-2.95 (m, 1H), 2.67 (s, 1H), 2.59 (s, 1H), 2.31-2.12 (m, 1H), 1.16 (s, 6H).
For Example 81: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.94 (d, J=10.8 Hz, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 5.13 (d, J=47.0 Hz, 1H), 4.02 (d, J=4.8 Hz, 3H), 3.85 (d, J=11.0 Hz, 1H), 3.82-3.73 (m, 1H), 3.73-3.60 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 3.04 (dd, J=36.0, 12.9 Hz, 1H), 2.59 (s, 1H), 2.30-2.12 (m, 1H), 1.16 (s, 6H).
Example 82 and Example 83: (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol
Step 1: (1R or 1R,1S,2R or 2S)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol
To a reaction vial containing a solution of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (150 mg, 0.322 mmol) in THF (3.0 mL) was added 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclopentanol 2,2,2-trifluoroacetate (Intermediate 6) (184 mg, 0.514 mmol) followed by tBuXPhos-Pd G3 (77.0 mg, 0.0960 mmol) and sodium tert-butoxide (93.0 mg, 0.965 mmol). Nitrogen was bubbled through the mixture for 10 min. The mixture was stirred and heated at 90° C. for 4 h. The mixture was cooled to room temperature, and then the resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexane as eluent, yielding a diastereomeric mixture of products. The mixture was purified by SFC separation (Chiral Technologies OJ-H 21×250 mm column with 30% MeOH as co-solvent), yielding peak 1 and peak 2 corresponding to (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol. For peak 1, LCMS (C33H39FN8O4) (ES, m/z): 631 [M+H]+. For peak 2, LCMS (C33H39FN8O4) (ES, m/z): 631 [M+H]+.
Step 2: (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol
Step 2 of Example 82 and Example 83 was conducted in a manner similar to step 2 of Example 40, where peak 1 and peak 2 obtained from step 1 were converted to (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol, which are the final compounds of Example 82 and Example 83, respectively.
For Example 82: LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.97 (d, J=10.7 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 5.89 (s, 2H), 4.36 (t, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.68 (dd, J=11.5, 3.6 Hz, 1H), 3.38 (tt, J=7.5, 3.8 Hz, 2H), 2.95 (t, J=11.1 Hz, 1H), 2.67 (td, J=11.3, 4.4 Hz, 1H), 2.40-2.07 (m, 3H), 1.99-1.73 (m, 7H), 0.88 (s, 3H).
For Example 83: LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.97 (d, J=10.7 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 5.88 (s, 2H), 4.35 (t, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.74-3.64 (m, 1H), 3.43-3.31 (m, 2H), 2.95 (t, J=11.1 Hz, 1H), 2.67 (td, J=11.2, 4.5 Hz, 1H), 2.39-2.10 (m, 3H), 2.00-1.74 (m, 7H), 0.88 (s, 3H).
The example compounds of the invention in the following Table 23 were prepared in a manner similar to that described for the preparation of Example 82 and Example 83 from the appropriate intermediates and starting materials. In each case, an SFC separation was conducted on the intermediate mixture formed from the first step. The SFC conditions to isolate these intermediates are shown with the corresponding final products formed from the second step.
TABLE 23
SFC Conditions
Observed
Structure
for intermediate
m/z
Example
Name
from step 1
[M + H]+
84
(1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)cyclopentan-1-ol
Peak 1; Whielko-1 21 × 250 mm column with 50% (MeOH w/ 0.2% DIPA modifier) as co-solvent
467
85
(1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)- 1H-pyrazol-1-yl)cyclopentan-1-ol
Peak 2; Whielko-1 21 × 250 mm column with 50% (MeOH w/ 0.2% DIPA modifier) as co-solvent
467
86
(S or R)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-3-methyl- 1H-pyrazol-1-yl)-2-methylbutan-2-ol
Peak 1: Chiral Technologies AD-H 21 × 250 mm column with 45% (IPA 1:1 w/ 0.2% DIPA modifier) as co-solvent
483
87
(R or S)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-3-methyl- 1H-pyrazol-1-yl)-2-methylbutan-2-ol
Peak 2: Chiral Technologies AD-H 21 × 250 mm column with 45% (IPA 1:1 w/ 0.2% DIPA modifier) as co-solvent
483
Example 88: (1R or 1S,2R or 2S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-1H-pyrazol-1-yl)cyclopentan-1-ol
The mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1R or 1S,2R or 2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 120) (5.0 mg, 7.0 μmol) in TFA (0.3 mL) was heated at 60° C. for 25 min. The mixture was concentrated. The residue was purified by preparative silica gel TLC eluting with 5% (7 M ammonia in MeOH) in DCM to afford (1R or 1S,2R or 2S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclopentan-1-ol. LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.99 (d, J=10.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 5.87 (s, 2H), 4.35 (d, J=7.5 Hz, 1H), 4.21 (d, J=8.7 Hz, 1H), 4.01 (s, 3H), 3.74 (d, J=6.5 Hz, 1H), 3.47-3.41 (m, 1H), 3.32 (d, J=11.0 Hz, 1H), 3.23 (d, J=11.3 Hz, 1H), 2.26 (m, 1H), 2.16-2.08 (m, 3H), 2.08-2.00 (m, 2H), 1.90-1.71 (m, 4H), 1.13 (d, J=6.7 Hz, 3H).
Example 89: (1S or 1R,2S or 2R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclopentan-1-ol
Example 89 was prepared from Intermediate 121 in a manner similar to Example 88 to afford (1S or 1R,2S or 2R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclopentan-1-ol. LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, Chloroform-d6) δ 7.99 (d, J=10.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.81 (s, 2H), 4.36 (q, J=7.1 Hz, 1H), 4.27-4.15 (m, 1H), 4.00 (s, 3H), 3.79-3.67 (m, 1H), 3.44 (dd, J=11.5, 4.2 Hz, 1H), 3.37-3.28 (m, 1H), 3.22 (t, J=11.1 Hz, 1H), 2.34-2.21 (m, 1H), 2.19-1.96 (m, 4H), 1.94-1.62 (m, 6H), 1.12 (d, J=6.7 Hz, 3H).
Example 90 and 91: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a solution of rac-1-(4-((3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 122) (150 mg, 0.242 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 50° C. for 10 h. The mixture was concentrated. The racemic mixture was purified and resolved by chiral SFC (Phenomenex Lux-2 4.6×150 mm column with 0-40% (EtOH w/ 0.05% DEA) as cosolvent), to yield 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluting peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting peak), corresponding to Example 90 and Example 91, respectively
For Example 90: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, METHANOL-d4) 6=7.66 (d, J=10.8 Hz, 1H), 7.32 (d, J=10.0 Hz, 2H), 6.94 (d, J=7.8 Hz, 1H), 3.98 (s, 2H), 3.91 (s, 3H), 3.81-3.71 (m, 1H), 3.38 (br d, J=9.0 Hz, 1H), 3.32-3.22 (m, 2H), 2.69 (t, J=11.6 Hz, 1H), 2.32-2.13 (m, 2H), 2.02-1.89 (m, 1H), 1.36 (q, J=12.5 Hz, 1H), 1.14 (s, 6H), 1.00 (d, J=6.6 Hz, 3H).
For Example 91: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, METHANOL-d4) 5=7.68 (d, J=10.8 Hz, 1H), 7.37 (d, J=19.1 Hz. 2H), 6.98 (d, J=7.8 Hz, 1H), 3.99 (s, 2H), 3.93 (s, 3H), 3.84-3.76 (m, 1H), 3.42 (br d, J=10.3 Hz. 1H), 3.34-3.26 (m, 2H), 2.77 (t, J=11.6 Hz, 1H), 2.32-2.20 (m, 2H), 1.99 (br d, J=6.6 Hz, 1H), 1.40 (q, J=12.5 Hz, 1H), 1.19-1.09 (m, 7H), 1.02 (d, J=6.6 Hz, 3H).
Example 92: rac-1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a solution of 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 123) (20 mg, 0.032 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred and heated at 45° C. for 5 h. The mixture was concentrated. The residue was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/ 0.1% TFA as modifier) as eluent), to yield 1-(4-((3R,5R and 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, METHANOL-d4) δ=8.02-7.90 (m, 2H), 7.73 (s, 1H), 7.27-7.15 (m, 1H), 4.22 (br d, =11.2 Hz, 1H), 4.13-4.07 (m, 2H), 4.00 (s. 4H), 3.78-3.65 (m, 2H), 3.57-3.47 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 2.54 (br d, J=13.7 Hz, 1H), 2.27-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.17 (s. 6H), 1.11 (d, J=6.8 Hz. 3H).
Example 93: (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one
To a stirred mixture of TFA (0.5 mL) in DCM (0.5 mL) was added (R)-5-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[12.4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one (Intermediate 124) (28.0 mg, 0.0450 mmol). The mixture was stirred and heated at 50° C. for 15 h. The mixture was cooled, and the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/ 0.1% TFA as modifier) as eluent), to yield (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one. LCMS (C23H27FN8O2) (ES, m/z) [M+H]+: 467. 1H NMR (400 MHz, CD3OD) δ: 7.90 (d, J=10.96 Hz, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.19 (d, J=7.45 Hz, 1H), 4.62 (br s, 1H), 4.05 (t, J=6.80 Hz, 2H), 3.99 (s, 3H), 3.67-3.78 (m, 1H), 3.39 (br d, J=11.84 Hz, 1H), 2.95 (t, J=1.18 Hz, 1H), 2.60-2.74 (m, 1H), 2.44 (t, J=7.02 Hz, 2H), 2.28 (br d, J=9.21 Hz, 1H), 2.10 (s, 3H), 2.02 (quin, J=7.02 Hz, 2H), 1.81-1.95 (m, 3H).
Example 94 and 95: (S or R)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol and (R or S)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol
To a stirred mixture of (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one (Example 93) (15.0 mg, 0.0320 mmol) in THF (2 mL) was added NaBH4 (2.4 mg, 0.064 mmol). The mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched with 1 M aqueous HCl (2 mL). The mixture was extracted with EtOAc (2×30 mL), and the organic layer was dried over sodium sulfate, filtered and then the solvents of the filtrate were evaporated. The residue was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/ 0.1% TFA as modifier) as eluent), to afford (S or R)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol and (R or S)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol, corresponding to Example 94 and Example 95, respectively.
For Example 94: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J=10.83 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.25 (d, J=7.63 Hz, 1H), 4.19 (br t, J=7.10 Hz, 2H), 4.08-4.00 (m, 4H), 3.78-3.66 (m, 2H), 3.57 (br s, 2H), 3.36 (t, J=1.68 Hz, 1H), 2.40 (br s, 1H), 2.16-1.85 (m, 5H), 1.48-1.36 (in, 2H), 1.17 (d, J=6.26 Hz, 3H).
For Example 95: LCMS (C23H29FN8O2) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, CD3OD) δ: 7.95 (d, J=10.68 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.24 (d, J=7.78 Hz, 1H), 4.11 (t, J=6.87 Hz, 3H), 4.03 (s, 4H), 3.84-3.62 (m, 3H), 3.48-3.37 (m, 5H), 3.31 (br s, 1H), 3.19 (s, 1H), 2.33 (s, 1H), 2.02-1.77 (m, 5H), 1.41 (br d, 0.1=5.80 Hz, 2H), 1.16 (d, J=6.10 Hz, 3H).
Example 96 and Example 97: rac-(1r,4s or 1r,4r)-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol and rac-(1r,4r or 1r,4s)-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol
Step 1: 4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole
To a stirred mixture of 1,4-dioxaspiro[4.5]decan-8-ol (5.00 g, 31.6 mmol 3 PPh3 (12.4 g, 47.4 mmol), and 4-nitro-1H-pyrazole (4.29 g, 37.9 mmol) in DCM (80 mL) was added di-tert-butyl diazene-1,2-dicarboxylate (18.2 g. 79.0 mol) under a nitrogen atmosphere, and the mixture was stirred at 25° C. for 10 h. The mixture was concentrated and purified by silica gel chromatography with 10-25% EtOAc in petroleum ether as eluent to afford 4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole. LCMS (C11H15N3O4) (ES, m/z) [M+H]+: 254.
Step 2: 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-amine
To a stirred mixture of 4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole (5.50 g, 21.7 mmol) in MeOH (50 mL) and EtOAc (50 mL) was added 10% Pd/C (0.462 g, 4.34 mmol). The mixture was purged with nitrogen twice and was stirred under an atmosphere of hydrogen for 6 h. The mixture was filtered and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 20-50% EtOAc in petroleum ether as eluent to afford 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-amine. LCMS (C11H17N3O2) (ES, m/z) [M+H]+: 224.
Step 3: methyl 1-(1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate
To a stirred mixture of 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-amine (2.14 g, 9.60 mmol) and lithium tetrafluoroborate (0.600 g, 6.40 mmol) in TFE (15 mL) was added ethyl 2-methylene-5-oxohexanoate (1.00 g, 5.88 mmol). The mixture was stirred and heated at 80° C. for 10 h. The mixture was cooled, diluted with water (15 mL), and extracted with EtOAc (2×30 mL). The organic layer was dried (anhydrous Na2SO4), filtered, and the solvents of the filtrate were evaporated. To the resulting residue was added MeOH (15 mL) and 10% Pd/C (0.068 g, 0.64 mmol). The mixture was degassed and purged with nitrogen twice and was stirred under an atmosphere of hydrogen for 10 h. The mixture was filtered, and then the filtrate was concentrated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford ethyl 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate. LCMS (C20H31N3O4) (ES, m/z) [M+H]+: 378.
Step 4: 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide
To a stirred mixture of 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate (450 mg, 1.192 mmol) in EtOH (10 mL) was added hydrazine hydrate (382 mg, 11.92 mmol). The mixture was stirred and heated at 80° C. for 10 h. The mixture was concentrated to afford 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide, which was used without further purification. LCMS (C18H29N5O3) (ES, m/z) [M+H]+ 364.
Step 5: rac-2-((3R,6S or 3S,6R)-1-(1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
A 40 mL vial was charged with 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (351 mg, 0.967 mmol) and DCM (2 mL). To this mixture was added AcOH (0.025 mL, 0.44 mmol) followed by 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (300 mg, 0.879 mmol). The mixture was stirred and heated at 35° C. for 16 h. The mixture was then concentrated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to afford the cis diastereomer, 2-((3R,6S and 3S,6R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C36H43FN8O5) (ES, m/z) [M+H]+ 687.
Step 6: 4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclohexanone
To a stirred mixture of 2-((3R,6S and 3S,6R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (40.0 mg, 0.0580 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred for 10 h. The mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with EtOAc as eluent to afford rac-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclohexanone. LCMS (C25H29FN8O2) (ES, m/z) [M+H]+ 493.
Step 7: (1r,4s or 1r,4r)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol and (1r,4r or 1r,4s)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-)-1-methylcyclohexan-1-ol
To a stirred mixture of rac-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclohexanone (18 mg, 0.037 mmol) in THF (5 mL) was added methylmagnesium bromide (0.122 mL, 0.365 mmol). The mixture was stirred at 0° C. for 12 h. The reaction mixture was quenched with aqueous NH4Cl (5 mL) and extracted with EtOAc (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water (w/ 0.1% TFA modifier) as eluent) to afford (1r,4s or 1r,4r)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol and (1r,4r or 1r,4s)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol, corresponding to Example 96 and Example 97.
For Example 96: 1H NMR (400 MHz, MeOD) δ 7.98 (s, 1H), 7.92 (d, J=11.2 Hz, 1H), 7.68 (s, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.18-4.29 (m, 1H), 4.01 (s, 4H), 3.85-3.97 (m, 2H), 3.63-3.65 (m, 1H), 2.46-2.48 (m, 1H), 2.15-2.30 (m, 2H), 1.90-2.13 (m, 5H), 1.73-1.84 (m, 2H), 1.60-1.72 (m, 2H), 1.31 (s, 3H), 1.20 (d, J=6.8 Hz, 3H). LCMS (C26H33FN8O2) (ES, m/z) [M+H]+509.
For Example 97: 1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.91 (d, J=11.2 Hz, 1H), 7.70 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.06-4.25 (m, 2H), 4.00 (s, 3H), 3.84-3.98 (m, 2H), 3.65-3.68 (m, 1H), 2.48-2.50 (m, 1H), 2.10-2.32 (m, 3H), 2.02-2.08 (m, 2H), 1.87-1.96 (m, 2H), 1.80-1.82 (m, 2H), 1.56-1.67 (m, 2H), 1.25 (s, 3H), 1.21 (d, J=6.8 Hz, 3H). LCMS (C26H33FN8O2) (ES, m/z) [M+H]+ 509.
Example 98 and 99: (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol and (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol
A mixture of methylmagnesium bromide (0.318 ml. 0.955 mmol, 3 M in diethyl ether) in THF (1.00 ml) was cooled at 0° C. To the mixture was added 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutanone (Intermediate 125) (86.0 mg, 0.191 mmol) in THF (1.0 mL) The mixture was stirred at 0° C. for 5 h. To the mixture was added water (3 mL), and then the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative silica gel TLC with 10% MeOH in DCM as eluent. The isomeric mixture was purified by SFC (OJ-3 100×4.6 mm column with 5-40% (MeOH w/ 0.05% DEA) as co-solvent) to afford (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol (first eluting peak) and (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol (second eluting peak) corresponding to Example 98 and Example 99, respectively.
For Example 98: LCMS (C23H27FN8O2) (ES, m/z) [M+H]+: 467. 1H NMR (400 MHz, CD3OD) 5=7.98 (d, J=10.68 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.48 Hz, 1H), 7.09 (s, 1H), 5.78 (br s, 2H), 4.48-4.34 (m, 1H), 4.05-3.96 (m, 3H), 3.81-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.42-3.31 (m, 2H), 2.98 (t, J=11.06 Hz, 1H), 2.76-2.59 (m, 1H), 2.52-2.38 (m, 1H), 2.33-2.15 (m, 3H), 2.06-1.77 (m, 5H), 1.42 (s, 3H).
For Example 99: LCMS (C23H27FN8O2) (ES, m/z) [M+H]+: 467. 1H NMR (400 MHz, CD3OD) δ=7.98 (d, J=10.68 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.48 Hz, 1H), 7.09 (s, 1H), 5.78 (br s, 2H), 4.48-4.34 (m, 1H), 4.05-3.96 (m, 3H), 3.81-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.42-3.31 (m, 2H), 2.98 (t, J=11.06 Hz, 1H), 2.76-2.59 (m, 1H), 2.52-2.38 (m, 1H), 2.33-2.15 (m, 3H), 2.06-1.77 (m, 5H), 1.42 (s, 3H).
Example 100: (R)-9-fluoro-7-methoxy-2-(1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
BSA (2 mL, 8.18 mmol) was added to N-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carbohydrazide (Intermediate 104) (25.0 mg, 0.0600 mmol), and the mixture was stirred at 120° C. for 2 h. The solvents were then evaporated. The resulting residue was diluted with chloroform/isopropanol-3:1 (5 mL), washed with aqueous sodium bicarbonate (saturated, 5 mL), and the organic layer collected using a phase separator column (25 mL) and concentrated. The residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/water (with 0.1% TFA modifier) as eluent). The racemic mixture was resolved by chiral SFC separation (OJ-H column 21×250 mm column with 20% (MeOH w/ 0.25% DMEA modifier) as co-solvent) to afford (R or S)-9-fluoro-7-methoxy-2-(1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Example 100, first eluting peak). LCMS (C19H21FN8O) (ES, m/z): 397 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.42 (dd, J=8.4, 2.7 Hz, 1H), 7.30 (s, 1H), 7.21-7.16 (m, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 3.60 (dd, J=11.5, 3.7 Hz, 1H), 3.32-3.30 (m, 1H), 3.29-3.23 (m, 1H), 2.83 (t, J=11.1 Hz, 1H), 2.58-2.52 (m, 2H), 2.20-2.12 (m, 1H), 1.88-1.81 (m, 1H), 1.80-1.74 (m, 2H).
The example compounds of the invention in following Table 24 were prepared from the appropriate intermediates in a manner similar to Example 100, with the exception that the starting materials were enantiopure, thus no SFC separation was conducted for these examples.
TABLE 24
Structure
Observed m/z
Example
Name
[M + H]+
101
(R or S)-8,9-difluoro-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
385
102
(R or S)-9-fluoro-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
367
103
(R or S)-7,9-difluoro-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
385
104
(R or S)-9-chloro-7-methoxy-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
413
105
(R or S)-9-chloro-7-methyl-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
397
106
(R or S)-9-chloro-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
383
107
(R or S)-9,10-difluoro-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
385
108
(R or S)-9-methoxy-2-(1-(1-methyl-1H-pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
379
Example 109: 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: 1-(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 100 mL round bottom flask was added (3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (Intermediate 61) (1.00 g, 3.39 mmol), 2-((((2,4-dimethoxybenzyl)imino)-methylene)amino)-5-fluoro-4-methoxybenzonitrile (Intermediate 37) (1.21 g, 3.55 mmol) and DCM (10 mL). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexane as eluent, yielding 1-(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C32H39FN8O4) (ES, m/z): 619 [M+H]+. The absolute configuration of the product of Step 1 was assigned to be (2S,5R) using Vibrational Circular Dichroism (VCD) spectroscopy with confidence. Analysis was done comparing experimental data to the calculated VCD and IR spectra of the product possessing the (2S,5R) configuration. The experimental VCD spectrum of the product matched well with the calculated (2S,5R) spectrum over the region from 1000-1500 cm-1, resulting in an assignment of (2S,5R).
Step 2: 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 20 mL vial was added 1-(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (962 mg, 1.56 mmol) and TFA (7 mL). The mixture was stirred and heated at 50° C. for 1 h. The mixture was then concentrated. To the resulting residue was added 1 M aqueous HCl (50 mL) and DCM (50 mL). The aqueous layer was washed with DCM (2×50 mL), then filtered. The pH of the aqueous layer was then adjusted to ˜pH 10 with 10 M aqueous NaOH. The aqueous layer was extracted with 10% MeOH in DCM (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM, yielding 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 109). LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=11.0 Hz, 1H), 7.72 (s, 2H), 7.20 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 3.69 (d, J=6.7 Hz, 1H), 3.35 (d, J=3.9 Hz, 1H), 3.20 (dt, J=11.1, 5.8 Hz, 1H), 3.10 (t, J=11.5 Hz, 1H), 2.00 (d, J=6.1 Hz, 3H), 1.70 (d, J=9.3 Hz, 1H), 1.03 (d, J=4.4 Hz, 9H).
The example compounds of the invention in the following Table 25 were prepared in a manner similar to that described for the preparation of Example 109 from the appropriate hydrazide and carbodiimide intermediates.
TABLE 25
Structure
Observed m/z
Example
Name
[M + H]+
110
1-(4-((2S,5R)-5-(5-amino-8-chloro-9-fluoro-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol
473
111
1-(4-((2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol
457
112
1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methyl-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol
453
113
(R)-7,9-dichloro-2-(1-(1-methyl-1H-pyrazol-4-yl)piperidin- 3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
417
Examples 114-117: 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1l-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2R or 2S, 5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: 1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) 2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 2 dram vial was added 1-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (Intermediate 63) (133 mg, 0.431 mmol) and 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (Intermediate 38) (140 mg, 0.410 mmol). To the mixture was added dioxane (1.6 mL) and acetic acid (24 μL, 0.41 mmol), and then the mixture was stirred and then heated at 60° C. for 2 h. The mixture was then allowed to slowly cool to room temperature. The mixture was diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate (2×10 mL) and brine. The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-100% EtOAc in hexanes to afford 1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a mixture of racemic diastereomers. LCMS (C33H42FN8O4) (ES, In/z): 633 [M+H]+
Step 2: 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 20 mL vial was added 1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (80 mg, 0.126 mmol) followed by TFA (0.13 mL). The mixture was stirred and heated at 50° C. for 2 h. The mixture was then concentrated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/water w/ 0.1% TFA as eluent) to afford the product as a mixture of diastereomers. The four isomers were resolved by chiral SFC separation (IC, 21×250 mm column with 35% (2-Propanol w/ 0.1% NH4OH modifier) as cosolvent) to afford 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 114, first eluting peak) and 1-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 115, second eluting peak) and 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 116, third eluting peak) and 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 117, fourth eluting peak).
For Example 114: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.70 (br s, 2H), 7.42 (dd, J=8.4, 2.7 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=11.1, 2.7 Hz, 1H), 4.75 (br s, 1H), 3.93 (s, 3H), 3.80 (s, 2H), 3.37-3.31 (m, 1H), 3.23-3.16 (m, 1H), 2.18-2.15 (m, 1H), 2.01 (s, 3H), 2.09-1.94 (m, 2H), 1.70-1.59 (m, 1H), 1.25-1.10 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H), 0.95 (d, J=12.0 Hz, 3H).
For Example 115: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.61 (br s, 2H), 7.40 (dd, J=8.2, 2.4 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=11.0, 2.1 Hz, 1H), 4.75 (br s, 1H), 3.93 (s, 3H), 3.80 (s, 2H), 3.38-3.30 (m, 1H), 3.19-3.12 (m, 1H), 2.15-2.10 (m, 1H), 2.07 (s, 3H), 2.09-1.94 (m, 2H), 1.72-1.65 (m, 1H), 1.25-1.10 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.93 (d, J=11.8 Hz, 3H).
For Example 116: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.52 (br s, 2H), 7.41 (dd, J=8.4, 2.7 Hz, 1H), 7.39 (s, 1H), 7.15-7.11 (m, 1H), 4.41 (br s. 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.30-3.20 (m, 1H), 3.13-3.09 (m, 1H), 2.18-2.11 (m, 1H), 2.00 (s, 3H), 2.00-1.84 (m, 2H), 1.75-1.66 (m, 1H), 1.24-1.10 (m, 2H), 1.04 (m, 6H), 0.91 (d, J=6.5 Hz. 3H).
For Example 117: LCMS (C24H32FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.77 (br s, 2H), 7.43 (dd, J=8.4, 2.7 Hz. 1H), 7.33 (s, 1H), 7.18 (dd, J=11.1, 2.7 Hz, 1H), 4.60 (br s, 1H), 3.94 (s. 3H), 3.83 (s, 2H), 3.26-3.22 (m, 1H), 3.10-3.06 (m, 1H), 2.18-2.16 (m, 1H), 2.04 (s, 3H), 2.01-1.87 (m, 2H), 1.75-1.69 (m, 1H), 1.24-1.10 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H), 0.93 (d, J=6.5 Hz, 3H).
The example compounds of the invention in the following Table 26 were prepared in a manner similar to that described for the preparation of Examples 114-117 from the appropriate hydrazide and carbodiimide intermediates. The resulting isomeric mixtures were resolved by SFC separation.
TABLE 26
Structure
SFC
Observed m/z
Example
Name
Conditions
[M + H]+
118
1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
469
119
1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
469
120
1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 3; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
469
121
1-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 4; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
469
122
2-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05 % DEA modifier) as cosolvent
469
123
2-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05 % DEA modifier) as cosolvent
469
124
2-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 3; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05 % DEA modifier) as cosolvent
469
125
2-(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 4; IC-3 4.6 × 100 mm column with 40% (IPA w/ 0.05 % DEA modifier) as cosolvent
469
126
rac-2-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1 and 2 overlapping; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (MeOH w/ 0.05 % DEA modifier) as cosolvent
469
127
2-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 3: Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (MeOH w/ 0.05 % DEA modifier) as cosolvent
469
128
1-(4-((2S or 2R,5R or 5S)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-methylpiperidin-1- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 4: Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (MeOH w/ 0.05 % DEA modifier) as cosolvent
469
Example 129 and Example 130: (R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Step 1: mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
A 1-dram vial was charged with the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 117) (391 mg, 0.715 mmol) and (chloromethyl)(methyl)sulfane (359 μL, 4.29 mmol) in dioxane (7.0 mL). To the mixture was added cesium carbonate (466 mg, 1.43 mmol), and then the mixture was stirred and heated at 75° C. for 60 h. The mixture was cooled to room temperature. The mixture was diluted with water and DCM. The mixture was poured into a phase separator. The DCM layer was collected and concentrated. The resulting residue was purified by silica gel column chromatography with 0-10% MeOH in DCM as eluent to afford the mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C30H35FN8O3S) (ES, m/z): 607 [M+H]+.
Step 2: (R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
The mixture of (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (328 mg, 0.541 mmol) was dissolved in acetone (4 mL) and water (1.35 mL). To the mixture was added Oxone® (potassium peroxymonosulfate, 665 mg, 1.08 mmol). The mixture was stirred for 10 min at room temperature. The mixture was concentrated to remove the acetone, diluted with water and DCM, and the organic layer was collected via a phase separator. The organic layer was concentrated. To the resulting residue was added and TFA (2.08 mL, 27.0 mmol), and the mixture was stirred and heated at 50° C. for 16 h. The mixture was then diluted with water and DCM, and the DCM layer was collected via a phase separator and concentrated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm, MeCN/water (w/ 0.1% TFA modifier) as eluent) to afford (R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, TFA (Example 129, first eluting peak) and (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, TFA, (Example 130, second eluting peak).
For Example 129: LCMS (C21H25FN8O3S) (ES, m/z): 489 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J=10.9 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.19 (d, J=7.9 Hz. 1H), 5.67 (s, 2H), 3.97 (s. 3H), 3.44 (m, 1H), 3.17 (s, 1H), 2.99 (s, 3H), 2.31 (s, 3H), 2.20 (m, 1H), 1.87 (m, 3H).
For Example 130: LCMS (C21H25FN8O3S) (ES, m/z): 489 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J=10.9, 3.6 Hz, 1H), 7.78 (s, 2H), 7.58 (s. 1H), 7.19 (d, J=7.8 Hz, 1H), 5.52 (s, 2H), 3.97 (s, 3H), 3.48 (d, J=9.4 Hz, 1H), 3.32 (d, J=10.1 Hz, 1H), 3.21 (d, J=11.2 Hz, 1H), 2.98 (s, 3H), 2.65 (m, 1H), 2.18 (s, 3H), 1.97-1.71 (m, 3H).
The example compounds of the invention in the following Table 27 were prepared in a manner similar to that described for the preparation of Example 129 and Example 130 from the appropriate intermediates and commercially available starting materials.
TABLE 27
Structure
Observed
Example
Name
m/z [M + H]+
131
(R)-9-fluoro-8-methoxy-2-(1-(1-((methylsulfonyl)methyl)-1H- pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
475
132
(R)-2-(1-(3-(difluoromethyl)-1-((methylsulfonyl)methyl)- pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine
525
Example 133: (S or R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: (S or R)-1-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a reaction vial was added (S or R)—N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 90) (78 mg, 0.161 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (52.9 mg, 0.241 mmol), tBuXPhos-Pd G3 (38.4 mg, 0.048 mmol), and sodium tert-butoxide (93 mg, 0.97 mmol) in THF (3 mL). The mixture was flushed with nitrogen for 10 min. The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4OH) as eluent to afford (S or R)-1-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
Step 2: (S or R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1l-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
An 8 mL scintillation vial was charged with (S or R)-1-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (70.0 mg, 0.112 mmol) and TFA (750 μL, 9.73 mmol). The mixture was stirred and heated at 40° C. for 2 h. The mixture was then cooled, and the solvents were evaporated. The resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.05% TFA as eluent) to afford (S or R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2 methylpropan-2-ol 2,2,2-trifluoroacetate. LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 2H), 7.48 (dd, J=8.3, 2.7 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=0.7 Hz, 1H), 7.21 (dd, J=11.1, 2.8 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 2H), 3.68-3.47 (m, 1H), 3.45-3.42 (m, 1H), 3.22-3.08 (m, 1H), 2.84-2.65 (m, 1H), 2.45-2.18 (m, 2H), 1.99 (d, J=9.7 Hz, 1H), 1.80 (dd, J=9.0, 4.0 Hz, 1H), 1.03 (d, J=2.7 Hz, 6H).
Example 134 in the following Table 28 was prepared from Intermediate 91 and the appropriate starting materials in a manner similar to that described for the preparation of Example 133.
TABLE 28
Structure
Observed m/z
Example
Name
[M + H]+
134
(R or S)-1-(4-(3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol
473
Example 135: 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
A mixture of 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 113) (28.0 mg, 0.0440 mmol) in TFA (50.5 mg, 0.443 mmol) was heated at 2-ol (Intermediate 113) (28.0 mg, 0.0440 mmol) in TFA (50.5 mg, 0.443 mmol) was heated at 60° C. for 1 h. The solvents were evaporated, and the resulting residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm MeCN/H2O with 0.1% TFA as eluent) to afford 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol.: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.97-7.89 (m, 2H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 4.12 (s, 2H), 4.08-3.92 (m, 5H), 3.72-3.57 (m, 2H), 2.52-2.38 (m, 1H), 2.31-2.14 (m, 2H), 2.09-1.98 (m, 1H), 1.75-1.56 (m, 211), 1.18 (s, 6H), 0.94 (t, J=7.4 Hz, 3H).
Example 136: 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Example 136 was prepared from Intermediate 114 in a manner similar to that described for the preparation of Example 135. LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 7.93 (d, J=11.9 Hz, 2H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 4.12 (s, 2H), 4.07-3.93 (m, 5H), 3.69-3.58 (m, 2H), 2.51-2.37 (m, 1H), 2.32-2.15 (m, 2H), 2.10-1.99 (m, 1H), 1.74-1.58 (m, 2H), 1.17 (s, 6H), 0.94 (t, J=7.3 Hz, 3H).
Example 137: 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Example 137 was prepared from Intermediate 115 in a manner similar to that described for the preparation of Example 135. LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.90-7.81 (m, 2H), 7.21 (d, J=7.5 Hz, 1H), 4.14 (d, J=20.7 Hz, 3H), 3.98 (d, J=12.7 Hz, 4H), 3.72-3.54 (m, 2H), 2.56 (d, J=16.8 Hz, 1H), 2.45 (d, J=20.5 Hz, 1H), 2.21-2.07 (m, 1H), 1.98-1.82 (m, 1H), 1.81-1.69 (m, 1H), 1.56-1.43 (m, 1H), 1.19 (s, 6H), 0.97 (t, J=7.3 Hz, 3H).
Example 138: 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Example 138 was prepared from Intermediate 116 in a manner similar to that described for the preparation of Example 135. LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.13 (s, 111), 7.86 (d, J=13.4 Hz, 2H), 7.21 (d, J=7.6 Hz, 1H), 4.15 (d, J=13.4 Hz, 3H), 3.99 (d, J=8.8 Hz, 4H), 3.74-3.54 (m, 2H), 2.57 (d, J=11.0 Hz, 1H), 2.50-2.39 (m, 1H), 2.24-2.05 (m, 1H), 1.96-1.83 (m, 1H), 1.82-1.67 (m, 1H), 1.59-1.42 (m, 1H), 1.18 (s, 6H), 0.97 (t, J=7.5 Hz, 3H).
Example 139: rac-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one
Step 1: rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one
To a 20 mL vial was added rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-2-one (Intermediate 89) (0.102 g, 0.212 mmol), 1-(4-iodo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (0.172 g, 0.646 mmol), copper(I) iodide (42.7 mg, 0.224 mmol), potassium phosphate (267 mg, 1.26 mmol), and anhydrous DMF (2.1 mL). The mixture was sparged with nitrogen for 5 min. To the mixture was added N1,N2-dimethylethane-1,2-diamine (0.046 mL, 0.43 mmol). The mixture was stirred and heated at 100° C. for 2 h. The mixture was purified by reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/H2O (with 0.1% TFA) as eluent), to afford rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C31H35FN8O5) (ES, m/z): 619 [M+H]+.
Step 2: rac-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one
To a 20 mL vial was added rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one (11.9 mg, 0.0192 mmol) and TFA (0.26 mL). The mixture was stirred and heated at 50° C. for 1 h. The mixture was concentrated. The residue was purified by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/H2O (with 0.1% TFA) as eluent) to afford rac-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C22H25FN8O3) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.88 (d, J=11.0 Hz, 1H), 7.79 (br s, 2H), 7.66 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.18 (t, J=7.8 Hz, 1H), 3.99-3.93 (m, 5H), 3.86-3.76 (m, 2H), 2.28-2.16 (m, 3H), 2.10-2.00 (m, 1H), 1.03 (s, 3H), 1.03 (s, 3H).
Example 140 and Example 141: (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Step 1: Mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[0.2.4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 20 mL vial was added (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(morpholin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 87) (49.4 mg, 0.105 mmol), a mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) (31.0 mg, 0.133 mmol), tBuXPhos-Pd G3 (33.5 mg, 0.0422 mmol), sodium tert-butoxide (60.8 mg, 0.633 mmol), and anhydrous THF (1.5 mL). The mixture was sparged with nitrogen. The mixture was then stirred and heated at 100° C. for several minutes, then cooled to 23° C., and additional THF (1 mL) was added. The mixture was stirred and heated at 80° C. for 14 h. Additional amounts of the mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) (42.5 mg, 0.182 mmol) and tBuXPhos-Pd G3 (33.5 mg, 0.0422 mmol) were added. The mixture was stirred and heated at 80° C. for 8 h. The mixture was diluted with DCM and MeOH and filtered through Celite® (diatomaceous earth). The filtrate was concentrated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford a mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C31H37FN8O5) (ES, m/z): 621 [M+H]+.
Step 2: (R)-1-(4-(2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
To a 4 mL vial was added the mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (4.6 mg, 0.0074 mmol) and TFA (0.10 mL). The mixture was stirred at 23° C. for 2 h. The mixture was then stirred and heated at 50° C. for 50 min. To a separate vial was added the mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (35.6 mg, 0.0574 mmol) and TFA (0.78 mL), and this mixture was stirred and heated at 50° C. for 50 min. The contents of the two reaction vials were combined and concentrated to a residue. The residue was suspended in MeOH and filtered. The filtrate was concentrated to a residue. The resulting residue was subjected to chiral SFC separation (Chiral Technologies OJ-H 21×250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co-solvent), to afford (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 140) as peak 1, and a second peak. The second peak contained an impurity, and therefore was purified by SFC (Chiral Technologies AS-H 21×250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent), yielding (R)-1-(4-(2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 141).
For Example 140: LCMS (C22H27FN8O3) (ES, m/z): 471 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=10.9 Hz, 1H), 7.80 (br s, 2H), 7.37 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 4.95 (dd, J=10.0, 2.5 Hz, 1H), 4.62 (s, 1H), 4.07-4.00 (m, 1H), 3.97 (s, 3H), 3.88 (td, J=11.1, 2.3 Hz, 1H), 3.83 (s, 2H), 3.07-2.97 (m, 2H), 2.72 (td. J=11.5, 3.1 Hz, 1H), 2.12 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H).
For Example 141: LCMS (C22H27FN8O3) (ES, m/z): 471 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.79 (br s, 2H), 7.34 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 4.95 (dd, J=9.7, 2.6 Hz, 1H), 4.63 (s, 1H), 4.08-4.00 (m, 1H), 3.96 (s, 3H), 3.92-3.82 (nm, 3H), 3.25-3.20 (m, 1H), 3.11 (dd, J=11.5, 10.0 Hz, 1H), 2.96-2.90 (m, 1H), 2.87 (td, J=11.3, 3.1 Hz, 1H), 2.22 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H).
Examples 142-145: (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide
Step 1: mixture of 2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and 2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide
To a 20 mL vial was added rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)thiomorpholine 1,1-dioxide (Intermediate 88) (100 mg, 0.194 mmol), tBuXPhos-Pd G3 (154 mg, 0.194 mmol), a mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 7) (140 mg, 0.598 mmol), and dry THF (3 mL). The mixture was sparged with nitrogen for 4 min. To the mixture was added sodium tert-butoxide (112 mg, 1.16 mmol). The mixture was stirred and heated at 80° C. for 18 h. The mixture was concentrated. The resulting residue was suspended in DCM, mixed with Celite® (diatomaceous earth), and filtered. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc:EtOH (3:1) in hexanes as eluent, yielding a mixture of rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide. LCMS (C31H37FN8O6S) (ES, m/z): 669 [M+H]+.
Step 2: (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (R or S)-2-(5-amino-9-fluoro-8-methoxy-[24]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methoxypropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide
To a 20 mL vial was added the mixture of rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide (48.1 mg, 0.0719 mmol) and TFA (0.96 mL). The mixture was stirred and heated at 50° C. for 1 h. The mixture was concentrated to a residue. The resulting residue was suspended in MeOH and filtered. The filtrate was concentrated to a residue that was purified by SFC (Chiral Technologies AS-H 21×250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent) to afford four peaks that were concentrated. Each peak was subsequently purified individually by preparative reversed-phase HPLC (Waters SunFire C18 OBD Prep Column, 19 mm×100 mm with MeCN/H2O (with 0.1% TFA) as eluent) to afford the final compounds, (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, and (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, corresponding to Example 142 (SFC peak 1), Example 143 (SFC peak 2), Example 144 (SFC peak 3), and Example 145 (SFC peak 4), respectively.
For Example 142: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.91 (d, J=10.9 Hz, 1H), 7.88 (br s, 2H), 7.55 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.3, 3.5 Hz, 1H), 3.99 (s, 3H), 3.87-3.76 (m, 3H), 3.72-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53-3.45 (m, 1H), 3.44-3.34 (m, 1H), 2.06 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
For Example 143: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.91 (d, J=10.9 Hz, 1H), 7.88 (br s, 2H), 7.55 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.3, 3.5 Hz, 1H), 3.99 (s, 3H), 3.87-3.76 (m, 3H), 3.72-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53-3.45 (m, 1H), 3.44-3.34 (m, 1H), 2.06 (s. 3H), 1.05 (s, 3H), 1.04 (s. 3H).
For Example 144: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.86 (br s, 2H), 7.48 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.1, 3.4 Hz, 1H), 3.98 (s, 3H), 3.87-3.78 (m, 3H), 3.64-3.54 (m, 3H), 3.51-3.35 (m, 2H), 2.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
For Example 145: LCMS (C22H27FN8O4S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.86 (br s, 2H), 7.48 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.1, 3.4 Hz, 1H), 3.98 (s, 3H), 3.87-3.78 (m, 3H), 3.64-3.54 (m, 3H), 3.51-3.35 (m, 2H), 2.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).
Example 146 and Example 147: (1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and (1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol
Intermediate 124 (70.0 mg, 0.170 mmol) was resolved by chiral SFC (AD 250×30 mm column with MeOH (0.1% NH4OH modifier) as cosolvent) to afford (1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 146, first eluting peak) and (1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 147, second eluting peak).
For Example 146: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.81 (s, 1H), 7.59-7.70 (m, 2H), 6.91 (br d, J=7.9 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.88-3.99 (m, 3H), 2.89-3.01 (m, 1H), 2.75 (br d, J=13.2 Hz, 1H), 2.39 (br d, J=12.3 Hz, 1H), 1.97-2.13 (m, 2H), 1.88 (br dd, J=9.9, 3.3 Hz, 1H), 1.58-1.77 (m, 2H), 1.50-1.55 (m, 1H), 1.42-1.49 (m, 3H).
For Example 147: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) (ppm) 7.71-7.87 (m, 2H), 7.64 (d, J=2.6 Hz, 1H), 6.96-7.18 (m, 11), 4.20 (q, J=7.3 Hz, 2H), 3.97 (br d, J=13.2 Hz, 3H), 2.89-3.05 (m, 1H), 2.73 (br d, J=12.7 Hz, 1H), 2.40 (br d, J=12.7 Hz, 1H), 1.99-2.13 (m, 2H), 1.91 (br d, J=13.2 Hz, 1H), 1.62-1.79 (m, 2H), 1.52-1.59 (m, 1H), 1.47 (t. J=7.5 Hz, 3H).
Example 148 and Example 149: (1S or 1R,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and (1S or 1R,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol
Intermediate 125 (50.0 mg, 0.120 mmol) was resolved by chiral SFC (AD 250×30 mm column with IPA (0.1% NH4OH modifier) as cosolvent) to afford (1S or 1R,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 148, first eluting peak) and (1S or 1R,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 149, second eluting peak).
For Example 148: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) S (ppm) 7.78-7.94 (m, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.01-7.23 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.99 (br s, 3H), 3.46-3.56 (m, 1H), 2.38 (br d, J=14.0 Hz, 1H), 1.92-2.25 (m, 4H), 1.63-1.85 (m, 3H), 1.42 (t, J=7.2 Hz, 3H).
For Example 149: LCMS (C21H24FN7O2) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.81 (br s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.11 (br s, 1H), 4.09-4.20 (m, 2H), 3.96 (br s, 3H), 3.51 (br s, 1H), 2.38 (br d, J=13.6 Hz, 1H), 1.96-2.24 (m, 4H), 1.59-1.85 (m, 3H), 1.42 (t, J=7.2 Hz, 3H).
Example 150: (1R,3R or 1S,3S)-3-(5-amino-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol
Step 1: ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate
To a 100 mL round bottom flask was added 2,6-di-tert-butylpyridine (11.1 ml, 49.4 mmol), ethyl 3-oxocyclohexane-1-carboxylate (6.32 ml, 35.3 mmol), and DCE (70.5 mL). The mixture was stirred and cooled at 0° C. To the mixture was added a 1 M solution in THF of Tf2O (45.8 mL, 45.8 mmol), dropwise over 5 min. The mixture was stirred for 30 min. The mixture was warmed to room temperature. After 2 h, the mixture was concentrated. To the resulting residue was added 1:1 DCM:hexanes (20 mL) and solids precipitated. The solids were removed by filtration. The filter cake was washed with 1:1 DCM:hexanes. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent, yielding ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.
Step 2: ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate
To a 100 mL round bottom flask was added potassium acetate (3.96 g, 40.4 mmol), Pd(dppf)Cl2 (0.660 g, 0.808 mmol), bis(pinacolato)diboron (8.21 g, 32.3 mmol), and ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (7.08 mL, 26.9 mmol). The flask was evacuated and refilled with nitrogen three times. To the flask was added DMA (40 mL). The mixture was stirred and heated at 90° C. for 16 h. The mixture was cooled to room temperature. The mixture was poured into a flask containing diethyl ether (150 mL). The mixture was stirred for 15 min. The solids were removed by filtration. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in hexanes as eluent to afford ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate. LCMS (C15H25BO4) (ES, m/z) [M+H]+: 281.
Step 3: ethyl (R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate
To a 100 mL flask was added Pd(dppf)Cl2 (0.708 g, 0.968 mmol), K3PO4 (15.4 g, 72.6 mmol), ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (7.12 g, 25.4 mmol), and 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) (5.30 g, 24.2 mmol). To the flask was added dioxane (60 mL) and water (12 mL). The mixture was sparged with nitrogen for 5 min. The mixture was stirred and heated at 90° C. for 2 h. The mixture was diluted in EtOAc (10 mL) and filtered through Celite® (diatomaceous earth) topped with anhydrous sodium sulfate. The solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent, to afford the racemate. The racemate was resolved by chiral SFC (ES Industries CCA 21×250 mm column, 15% (MeOH w/NH4OH modifier) as cosolvent) to afford ethyl (R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (first eluting peak). LCMS (C16H24N2O3) (ES, m/z) [M+H]+: 293.
Step 4: ethyl (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carboxylate
To a 250 mL round bottom flask was added (R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (933 mg, 3.19 mmol), cobalt(II) acetylacetonate hydrate (220 mg, 0.798 mmol), and THF (50 mL). To the mixture was added phenylsilane (1.18 mL, 9.57 mmol), and the mixture was stirred, open to air, at room temperature for 5 days. To the mixture was added a 1 M solution of TBAF (6.38 mL, 6.38 mmol) in THF. The mixture was stirred for 15 min. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM as eluent, to afford the trans-diastereomer ethyl (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carboxylate. LCMS (C6H26N2O4) (ES, m/z) [M+H]+: 311.
Step 5: (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carbohydrazide
To a 20 mL vial was added ethyl (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (190 mg, 0.612 mmol), EtOH (1.5 mL), and hydrazine hydrate (0.210 ml, 3.67 mmol). The mixture was heated at 90° C. for 24 h. The solvents were evaporated to afford (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carbohydrazide. LCMS (C14H24N2O4) (ES, m/z) [M+H]+: 297.
Step 6: (1R,3R or 1S,3S)-3-(5-((2,4-dimethoxybenzyl)amino)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol
The asterisks (*) in the above scheme indicate chiral centers. To a 20 mL vial was added (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carbohydrazide (70.0 mg, 0.236 mmol), 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (105 mg, 0.307 mmol), dioxane (0.5 mL), and AcOH (7 μl, 0.12 mmol). The mixture was stirred and heated at 65° C. for 2 h. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to afford (1R,3R or 1S,3S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol. LCMS (C32H39N7O5) (ES, m/z) [M+H]+: 602.
Step 7: (1R,3R or 1S,3S)-3-(5-amino-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol
To a 20 mL vial was added DDQ (30.3 mg, 0.133 mmol) and DCM (1.0 mL). The mixture was cooled at 0° C. To the mixture was added water (0.05 mL). To the mixture was added (1R,3R or 1S,3S)-3-(5-((2,4-dimethoxybenzyl)amino)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol (53.5 mg, 0.089 mmol) as a solution in DCM (1 mL). The mixture was stirred for 4 h. To the mixture was added 1 M aqueous KOH (20 mL), and then the mixture was extracted with DCM (2×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexane as eluent. The product was further purified by chiral SFC (Chiral Technologies OJ-H 21×250 mm column, with 20% (MeOH with NH4OH modifier) as cosolvent) to afford (1R,3R or 1S,3S)-3-(5-amino-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol (Example 150). LCMS (C23H29N7O3) (ES, m/z) [M+H]+: 452. 1H NMR (499 MHz, DMSO-d6) δ 7.73 (dd, J=8.0, 1.2 Hz, 3H), 7.56 (s, 1H), 7.39 (s, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.24-7.10 (m, 1H), 4.81 (s, 1H), 4.65 (s, 1H), 3.95 (s, 2H), 3.90 (s, 3H), 3.48-3.40 (m, 1H), 2.22 (d, J=13.4 Hz, 1H), 2.09 (d, J=11.9 Hz, 1H), 1.98-1.84 (m, 3H), 1.73-1.58 (m, 3H), 1.16-0.89 (m, 9H).
Example 151: (R)-2-(1-(3-(5-amino-9-fluoro-8-methoxy-[1.24]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
To a 20 mL vial was added (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (400 mg, 0.857 mmol), sodium tert-butoxide (330 mg, 3.43 mmol), 4-bromo-1-(2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-1H-pyrazole (Intermediate 151) (520 mg, 1.72 mmol), tBuXPhos-Pd G3 (272 mg, 0.343 mmol), and THF (5.7 mL). The mixture was purged with nitrogen for 5 min, sealed, and heated at 105° C. for 16 h. The reaction mixture was cooled to room temperature. To the mixture was added water (10 mL) and DCM (10 mL). The mixture was stirred for 10 min and filtered. The organic layer was collected with a phase separator. The solvents were evaporated. To the resulting residue was added TFA (3.8 mL, 49 mmol), and the mixture was heated at 50° C. for 3 h. The solvents were evaporated, and to the resulting residue was added DCM (10 mL), and a 7 M solution of ammonia in MeOH (1.07 mL, 7.52 mmol). The mixture was stirred for 1 h. The mixture was washed with water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography column with 0-40% of MeOH in DCM as eluent to afford (R)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (Example 151). LCMS (C22H27FN8O2) (ES, m/z): 455 [M+H]+. 11H NMR (600 MHz, Methanol-d4) δ 8.18 (s, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.82 (s, 1H), 7.25 (d, J=7.6 Hz, 11), 4.14 (dd, J=12.0, 3.5 Hz, 1H), 3.84 (dd, J=26.2, 11.7 Hz, 2H), 3.76 (s, 2H), 3.66 (dt, J=9.9, 5.9 Hz, 1H), 3.57-3.46 (m, 1H), 2.51-2.39 (m, 1H), 2.30-2.02 (m, 3H), 1.59 (s, 6H).
The example compounds of the invention in the following Table 29 were prepared from the appropriate starting aryl halide and amine intermediates in a manner similar to that described for the preparation of Example 151.
TABLE 29
Structure
Observed
Example
Name
m/z [M + H]+
152
(R)-4-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol
469
153
(R)-1-(4-(3-(5-amino-8-(difluoromethoxy)-9-fluoro-[1,2,4]triazolo[l,5-c] quinazolin-2-yl)piperidin-l-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
491
154
(R)-1-(4-(3-(5-amino-8-(difluoromethoxy)-9-fluoro-[1,2,4]triazolo[l,5-c] quinazolin-2-yl)piperidin-l-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
505
155
racemic, trans-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)- 3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
483
156
racemic, trans-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
469
Example 157 and Example 158: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
A 20 mL microwave vial equipped with a stirbar was charged with rac, cis-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 83) (400 mg, 0.832 mmol) and THF (5.20 mL). To the mixture was added 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 24) (388 mg, 1.67 mmol), followed by tBuXPhos-Pd G3 (264 mg, 0.333 mmol) and sodium tert-butoxide (320 mg, 3.33 mmol). Nitrogen was bubbled through the mixture for 10 min. The vial was then sealed with a fresh cap and heated at 90° C. for 16 h. The reaction was cooled, quenched with saturated ammonium chloride (1 mL), and Celite was added. The biphasic mixture was filtered over Celite topped with anhydrous MgSO4, and the solvents of the filtrate were concentrated. The resulting residue was dissolved in TFA (3.2 mL. 42 mmol) and heated at 50° C. for 3 h. The reaction mixture was cooled, diluted with DCM, and quenched with saturated aqueous NaHCO3. The biphasic mixture was separated and the aqueous phase was further extracted with DCM. The organic layers were combined, dried over anhydrous MgSO4, filtered, and the solvents of the filtrate were concentrated. The resulting residue was purified by silica gel chromatography with 0-20% MeOH in DCM as eluent. The purified product was then subjected to chiral SFC separation (Chiral Technologies AD-H 21×250 mm column with 30% (IPA w/0.1% NH4OH modifier) as co-solvent), to afford 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 157, first eluting peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Example 158, second eluting peak).
For Example 157: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.87 (d, J=11.0 Hz, 1H), 7.69 (s, 2H), 7.34 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 4.61 (s, 11), 3.97 (s, 3H), 3.83 (s, 2H), 3.46 (d, J=10.9 Hz, 1H), 3.28 (d, J=11.8 Hz, 1H), 3.13 (d, J=8.6 Hz, 1H), 2.64 (t, J=11.3 Hz, 1H), 2.22 (d, J=13.4 Hz, 1H), 2.16 (t, J=11.1 Hz, 1H), 2.11 (s, 3H), 1.94 (s, 1H), 1.38 (q, J=12.3 Hz, 1H), 1.03 (d, J=3.1 Hz, 6H), 0.97 (d, J=6.6 Hz, 3H).
For Example 158: LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.87 (d, J=11.0 Hz, 1H), 7.69 (s, 2H), 7.34 (s. 1H), 7.18 (d, J=7.8 Hz. 1H), 4.61 (s, 1H), 3.97 (s, 3H), 3.83 (s, 2H), 3.47 (d, J=8.4 Hz, 1H), 3.29 (s, 1H), 3.13 (d, J=8.0 Hz, 1H), 2.64 (t, J=11.3 Hz, 1H), 2.22 (d, J=12.5 Hz, 1H), 2.16 (t, J=11.0 Hz, 1H), 2.11 (s, 3H), 1.96 (s, 1H), 1.38 (q, J=12.4 Hz, 1H), 1.03 (d, J=3.1 Hz, 6H), 0.97 (d, J=6.6 Hz, 3H).
The example compounds of the invention in the following Table 30 were prepared from the appropriate starting amine and aryl halide in a manner similar to that described for the preparation of Example 157 and Example 158, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 30
Structure
SFC
Observed
Example
Name
Conditions
m/z[M + H]+
159
1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Cellulose-2 30 × 250 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co- solvent
469
160
1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Cellulose-2 30 × 250 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co- solvent
469
161
1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Cellulose-3 4.6 × 150 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co- solvent
483
162
1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Cellulose-3 4.6 × 150 mm column with 5-15% (MeOH w/0.05% DEA modifier) as co- solvent
483
163
1-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
164
1-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
165
2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; Lux-4 21 × 250 mm column with 40% (MeOH w/0.1 % NH4OH modifier) as co-solvent
469
166
2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; Lux-4 21 × 250 mm column with 40% (MeOH w/0.1 % NH4OH modifier) as co-solvent
469
167
1-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Lux-4 21 × 250 mm column with 30% (MeOH w/0.1 % NH4OH modifier) as co-solvent
471
168
1-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Lux-4 21 × 250 mm column with 30% (MeOH w/0.1 % NH4OH modifier) as co-solvent
471
169
2-(4-((3S,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 0-40% (IPA w/0.05% DEA modifier) as co- solvent
483
170
2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 0-40% (IPA w/0.05% DEA modifier) as co- solvent
483
171
2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent
469
172
2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent
469
173
1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent
483
174
1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co-solvent
483
175
2-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent
483
176
2-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent
483
177
2-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
471
178
2-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
471
179
2-(4-((3S,5S or 3R,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
180
2-(4-((3R,5R or 3S,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol
Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
181
1-(4-((3S,5S or 3R,5R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
182
1-(4-((3R,5R or 3S,5S)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
183
(R or S)-1-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-2-methylbutan-2-ol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
469
184
(S or R)-1-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-2-methylbutan-2-ol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
469
185
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; ES Industries CCA 21 × 250 mm column with 30% (MeOH w/0.1% NH4OH modifier) as co-solvent
455
186
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; ES Industries CCA 21 × 250 mm column with 30% (MeOH w/0.1% NH4OH modifier) as co-solvent
455
187
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
455
188
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
455
189
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent
469
190
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/0.1% NH4OH modifier) as co-solvent
469
191
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
192
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
457
193
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
469
194
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
469
195
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies IG 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
469
196
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies IG 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
469
197
(2S,3S or 2R,3R)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
443
198
(2R,3R or 2S,3S)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
443
199
(2R,3S or 2S,3R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies OJ-H 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
455
200
(2S,3R or 2R,3S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
455
201
(2R,3S or 2S,3R)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
455
202
(2S,3R or 2R,3S)-3-(4-((R)-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 35% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
455
203
(2R,3S or 2S,3R)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiralpak AS-3 4.6 × 100 mm column with 0-40% (IPA w/ 0.05% DEA modifier) as co- solvent
443
204
(2S,3R or 2R,3S)-3-(4-((R)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiralpak AS-3 4.6 × 100 mm column with 0-40% (IPA w/ 0.05% DEA modifier) as co- solvent
443
205
(R or S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-3- methylbutan-2-ol
Peak 1; Chiralpak AD-3 4.6 × 100 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent. Then Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 20% (IPA w/0.1% NH4OH modifier) as co- solvent
497
206
(S or R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-3- methylbutan-2-ol
Peak 1; Chiralpak AD-3 4.6 × 100 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent. Then Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 20% (IPA w/0.1% NH4OH modifier) as co- solvent
497
207
(R or S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro- 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-3- methylbutan-2-ol
Peak 2; Chiralpak AD-3 4.6 × 100 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co- solvent
497
208
(2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 1; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
483
209
(2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 2; ES Industries CCA 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co- solvent
483
210
(2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
483
211
(2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 3; ES Industries CC4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
483
212
(2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
471
213
(2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
471
214
(2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 3; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
471
215
(2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 4; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent
471
216
(2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; IG 50 × 250 mm with 5-40% (EtOH w/0.05% DEA modifier)as co- solvent
471
217
(2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; IG 50 × 250 mm with 5-40% (EtOH w/0.05% DEA modifier)as co- solvent
471
218
(2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 3; IG 50 × 250 mm with 5-40% (EtOH w/0.05% DEA modifier)as co- solvent
471
219
(2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-7,9- difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 4; IG 50 × 250 mm with 5-40% (EtOH w/0.05% DEA modifier)as co- solvent
471
220
(2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co- solven
483
221
(2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co- solven
483
222
(2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 3; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co- solven
483
223
(2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-5-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 4; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co- solven
483
224
(2S,3S or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent.
483
225
(2R,3R or 2S,3S)-3-(4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 2; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (IPA w/ 0.05% DEA modifier) as co-solvent.
483
226
(2R,3R or 2S,3S)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent.
483
227
(2S,3S or 2R,3R)-3-(4-((3S,5R or 3R,5S)-3-(5-amino-9- fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5- methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)butan-2-ol
Peak 3; Chiral Technologies AD-H 30 × 250 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent.
483
Example 228-231: (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2S,3S or 2R,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S, 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Step 1: Mixture of diastereomers of (2S,3S and 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
To solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S and 3S,6R)-6-methyl-1-(1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 177) (530 mg, 0.970 mmol) in DMF (10 mL) was added cis-2,3-dimethyloxirane (846 μl, 9.70 mmol) and cesium carbonate (1.26 g, 3.88 mmol). The mixture was stirred and heated at 125° C. for 5 h. The mixture was cooled to room temperature, and the mixture was diluted with water (20 mL) and ethyl acetate (20 mL). The biphasic mixture was separated and the aqueous phase was further extracted with ethyl acetate (20 mL). The combined organic layers were then washed with water (2×20 mL) and brine (1×20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-20% MeOH in DCM as eluent to afford the intermediate mixture of diastereomers of (2S,3S and 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol.
Step 2: (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2S,3S or 2R,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S, 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
To a 20 mL vial was added 3-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (475 mg, 0.768 mmol) and TFA (1.77 mL 23.0 mmol). The mixture was stirred and heated at 50° C. for 3 h. The mixture was cooled at room temperature, and the solvents were evaporated. The residue was dissolved in MeOH (10 mL) and quenched with a 7 M solution of ammonia in MeOH (1.10 mL, 7.68 mmol). The mixture was stirred for 20 minutes. The mixture was filtered, rinsing the solids with MeOH, and the filtrate was concentrated. The residue was suspended in DCM and filtered to remove remaining ammonium salts. The filtrate was loaded directly onto a silica gel column, eluting with 0-15% MeOH in DCM to afford a mixture of isomers. The mixture was submitted for chiral SFC separation (Phenomenex Lux-2 21×250 mm column with 45% (MeOH w/ 0.1% NH4OH modifier) as co-solvent), to afford a mixture of Example 228 and Example 229 (peak 1), (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 230, peak 2) and (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 231, peak 3). The mixture obtained in peak 1 was further purified by SFC separation (Chiral Technologies AS-H 21×250 mm column with 20% (MeOH w/ 0.1% NH4OH modifier) as co-solvent), to afford (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1L2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 228, peak 1) and (2S,3S or 2R,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (Example 229, peak 2).
For Example 228: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=10.6 Hz, 1H), 7.73 (s, 2H), 7.22 (s, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.12 (s, 1H), 4.73 (d, J=5.0 Hz, 1H), 4.13-4.05 (m, 1H), 3.98 (s, 3H), 3.88-3.78 (m, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=11.5 Hz, 1H), 2.01 (d, J=21.4 Hz. 3H), 1.70 (d, J=9.1 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H).
For Example 229: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=8.2 Hz, 1H), 7.73 (s, 2H), 7.25-7.21 (m, 1H), 7.19 (d, J=4.8 Hz, 1H), 7.12 (d, J=2.9 Hz, 1H), 4.72 (s, 1H), 4.09 (s, 1H), 3.98 (d, J=2.7 Hz, 3H), 3.83 (s, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=10.5 Hz, 1H), 1.99 (s, 3H), 1.72 (s, 1H), 1.43-1.30 (m, 3H), 1.03 (d, J=3.4 Hz, 3H), 0.92 (d, J=3.0 Hz. 3H).
For Example 230: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=11.0 Hz, 1H), 7.72 (s, 2H), 7.22 (s. 1H), 7.18 (d, J=7.8 Hz, 1H), 7.11 (s, 1H), 4.77-4.64 (m, 1H), 4.14-4.04 (m, 1H), 4.02-3.94 (m, 3H), 3.88-3.78 (m, 1H), 3.71 (d, J=9.9 Hz, 1H), 3.18 (dd, J=6.4, 4.4 Hz, 1H), 3.09 (t, J=11.4 Hz, 1H), 2.01 (d, J=22.2 Hz, 3H), 1.70 (d, J=10.4 Hz, 1H), 1.38-1.31 (m, 31H), 1.03 (d, J=6.4 Hz, 3H), 0.95-0.89 (m, 3H).
For Example 231: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=9.6 Hz, 1H), 7.73 (s, 2H), 7.22 (s, 1H), 7.19 (d, J=6.7 Hz. 1H), 7.12 (s, 1H), 4.73 (d, J=3.3 Hz, 1H), 4.15-4.03 (m, 1H), 3.98 (s, 3H), 3.83 (d, J=5.2 Hz, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=11.0 Hz, 1H), 2.01 (d, J=21.8 Hz, 3H), 1.70 (d, J=9.6 Hz, 1H), 1.33 (d, J=5.7 Hz, 31), 1.03 (d, J=5.4 Hz, 3H), 0.92 (d, J=5.0 Hz, 3H).
The example compounds of the invention in the following Table 31 were prepared in a manner similar to that described for the preparation of Example 228-231 from the appropriate starting materials and intermediates, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 31
Structure
SFC
Observed
Example
Name
Conditions
m/z [M + H]+
232
(2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1 (mixture of Example 232 and Example 233); Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/ 0.1% NH4OH modifier) as co- solvent. Then Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent.
457
233
(2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1 (mixture of Example 232 and Example 233); Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/ 0.1% NH4OH modifier) as co- solvent. Then Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 20% (MeOH w/0.1% NH4OH modifier) as co-solvent.
457
234
(2R,3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
457
235
(2S,3S or 2R,3R)-3-(4-((2R,5S or 2S,5R)-5-(5- amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 3; Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
457
236
(2S,3R or 2R,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Chiral Technologies AD-H 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co- soivent.
469
237
(2R,3S or 2S,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co- soivent.
469
238
(2S,3R or 2R,3S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 1; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
469
239
(2R,3S or 2S,3R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino- 9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol
Peak 2; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
240
(R or S)-1-(4-((2S,5R or 2R5S)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)propan-2-ol
Peak 1; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
469
241
(S or R)-1-(4-((2S,5R or 2R5S)-5-(5-amino-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1-yl)-1H-pyrazol-1-yl)propan-2-ol
Peak 2; Chiral Technologies AS-H 21 × 250 mm column with 25% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
469
Example 242 and Example 243: (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl))-3-methylbutan-2-ol and (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol
Step 1: (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-one
A 5 mL microwave vial equipped with a stirbar was charged with (R)—N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (Intermediate 82) (100 mg, 0.214 mmol) and THF (1.3 mL). To the mixture was added 3-(4-bromo-1H-pyrazol-1-yl)-3-methylbutan-2-one (Intermediate 137) (99.0 mg, 0.429 mmol), followed by tBuXPhos-Pd G3 (85.0 mg, 0.107 mmol) and sodium tert-butoxide (82.0 mg, 0.857 mmol). Nitrogen was bubbled through the mixture for 10 min. The vial was then sealed with a fresh cap and heated at 105° C. for 16 h. The reaction mixture was cooled to room temperature, and to the mixture was added water (10 mL) and DCM (10 mL). The mixture was stirred for 10 min and filtered. The organic layer was collected and concentrated. To the resulting residue was added TFA (826 μL, 10.7 mmol), and the mixture was heated at 50° C. for 3 h. The solvents were evaporated. The resulting residue was dissolved in MeOH (5 mL), and to the mixture was added a 7 M solution of ammonia in MeOH (1.53 mL, 10.7 mmol). The mixture was stirred for 30 min and filtered. The solids were washed with methanol. The filtrate was concentrated. The residue was dissolved in DCM, and the resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 5-30% MeOH in DCM as eluent to afford (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-one LCMS (C23H27FN8O2) (ES, m/z): 467 [M+H]+.
Step 2: (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol and (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol
To a solution of (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-one (49.0 mg, 0.105 mmol) in EtOH (1 mL) was added NaBH4 (11.9 mg, 0.315 mmol), and the mixture was stirred at room temperature for 1 h. The solvents were evaporated. To the resulting residue was added DCM, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated to afford a mixture of isomers. The mixture was submitted for SFC chiral separation (Chiral Technologies IA 21×250 mm column with 45% (MeOH w/ 0.1% NH4OH modifier) as co-solvent), to afford (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol (Example 242, peak 1) and (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol (Example 243, peak 2).
For Example 242: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.88 (dd, J=10.9, 2.3 Hz, 1H), 7.71 (s, 2H), 7.42-7.34 (m, 1H), 7.24-7.07 (m, 2H), 4.80 (s, 1H), 3.97 (d, J=2.2 Hz, 3H), 3.82 (s, 1H), 3.62 (d, J=11.3 Hz, 1H), 3.36 (s, 1H), 3.24 (s, 1H), 2.82 (t, J=10.2 Hz, 1H), 2.15 (s, 1H), 1.80 (d, J=40.9 Hz, 3H), 1.48-1.42 (m, 3H), 1.42-1.34 (m, 3H), 0.73 (dd. J=6.1, 2.3 Hz, 3H).
For Example 243: LCMS (C23H29FN8O2) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.93-7.83 (m, 1H), 7.71 (s, 2H), 7.38 (s, 1H), 7.22-7.10 (m, 2H), 4.81 (s, 1H), 4.01-3.95 (m, 3H), 3.82 (s, 1H), 3.62 (d, J=10.8 Hz. 1H), 3.37 (s, 1H), 3.24 (s, 1H), 2.82 (t, J=11.3 Hz, 1H), 2.55 (d, J=9.7 Hz, 1H), 2.15 (s, 1H), 1.90-1.67 (m, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.76-0.67 (m, 3H).
The example compounds of the invention in the following Table 32 were prepared in a manner similar to that described for the preparation of Example 242 and Example 243 from the appropriate starting amine and aryl halide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 32
Structure
SFC
Observed
Example
Name
Conditions
m/z [M + H]+
244
(R or S)-3-(4-((R)-3-(5-amino-9-fluoro-7 methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 1; Chiral Technologies IA 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
469
245
(S or R)-3-(4-((R)-3-(5-amino-9-fluoro-7 methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 2; Chiral Technologies IA 21 × 250 mm column with 40% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
469
246
(R or S)-3-(4-((R)-3-(5-amino-7,9-difluoro-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-3-methylbutan-2-ol
Peak 1; ES Industries CCA 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
457
247
(S or R)-3-(4-((R)-3-(5-amino-7,9-difluoro-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H- pyrazol-1-yl)-3-methylbutan-2-ol
Peak 2; ES Industries CCA 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent
457
Example 248 and Example 249: 2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol and 2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol
Step 1: 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol
To a solution of 1-(1-(1,3-dihydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)-6-methylpiperidine-3-carbohydrazide (105 mg, 0.336 mmol) (Intermediate 166) in DMF (1 mL) was added AcOH (9.63 μl, 0.168 mmol), 2-((((3,4-dimethylbenzyl)imino)methylene)amino)-3,5-difluorobenzonitrile (Intermediate 37) (100 mg, 0.336 mmol) at 50° C. under an atmosphere of nitrogen. The mixture was stirred and heated at 50° C. for 16 h. The mixture was cooled, diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvents were evaporated. The resulting residue was purified by preparative silica gel TLC with 10% MeOH in DCM as eluent to afford 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.
Step 2: 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate
To a solution of 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol (60 mg, 0.096 mmol) in DCM (2 mL) was added TFA (2.0 mL, 26 mmol) at 10° C. under a nitrogen atmosphere. The mixture was stirred at 10° C. for 16 h. The solvents were evaporated to afford the crude product of 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate, which was used in the next step without any further purification. LCMS (C24H25F5N8O3) (ES, m/z): 569 [M+H]+.
Step 3: 2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol and 2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol
To a solution of 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate (40 mg, 0.070 mmol) in MeOH (2 mL) was added Na2CO3 (7.5 mg, 0.070 mmol) at 10° C. under a nitrogen atmosphere. The mixture was stirred at 10° C. for 1h. The solvents were evaporated to afford a mixture of isomers. The mixture was submitted for SFC chiral separation (Chiralpak AD-3 4.6×150 mm column with 5-40% (MeOH w/ 0.05% DEA modifier) as co-solvent), to afford 2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol (Example 248, peak 1) and 2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropane-1,3-diol (Example 249, peak 2).
For Example 248: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]f. 1H NMR (500 MHz, methanol-d4) δ=7.71 (br dd, J=1.3, 6.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.22 (s, 1H), 3.78-3.68 (m, 4H), 3.64 (br dd, J=3.8, 6.1 Hz, 1H), 3.41 (br d, J=8.2 Hz, 1H), 2.96 (s, 1H), 2.82 (s, 1H), 2.06-1.99 (m, 2H), 1.98 (s, 1H), 1.73 (br dd. J=3.1, 12.7 Hz, 1H), 1.42 (s, 3H), 1.03 (d, J=6.7 Hz, 3H).
For Example 249: LCMS (C22H26F2N8O2) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, methanol-d4) δ=7.84 (br s, 1H), 7.53-7.41 (m, 2H), 7.36 (br s, 1H), 3.93-3.79 (m, 4H), 3.78 (br s, 1H), 3.55 (br s, 1H), 2.22 (br s. 1H), 2.18-2.09 (m, 2H), 1.87 (br d, J=10.1 Hz, 1H), 1.54 (s, 3H), 1.31 (s, 2H), 1.16 (d, J=6.6 Hz, 3H).
The example compounds of the invention in the following Table 33 were prepared in a manner similar to that described for the preparation of Example 248 and Example 249 from the appropriate starting hydrazide, where the resulting isomeric mixture of the corresponding final compounds were separated by SFC.
TABLE 33
Structure
SFC
Observed
Example
Name
Conditions
m/z [M + H]+
250
2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H- pyrazol-1-yl)-2-methylpropane-1,3-diol
Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent
485
251
2-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H- pyrazol-1-yl)-2-methylpropane-1,3-diol
Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent
485
252
(R or S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 2; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 1; Chiralpak AD-3 4.6 × 150 mm column with 40% (MeOH w/0.05% DEA modifier) as co- solvent.
485
253
(S or R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 2; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 2; Chiralpak AD-3 4.6 × 150 mm column with 40% (MeOH w/0.05% DEA modifier) as co- solvent.
485
254
(R or S)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 3; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent
485
255
(S or R)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 4; Chiralcel OJ-3 4.6 × 100 mm column with 5-40% (EtOH w/ 0.05% DEA modifier) as co-solvent
485
256
(R or S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 3; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 1; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent.
473
257
(S or R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 3; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent. Then Peak 2; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (IPA w/0.05% DEA modifier) as co- solvent.
473
258
(R or S)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 4; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent.
473
259
(S or R)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 5; Cellulose 2 4.6 × 100 mm column with 40% (MeOH w/ 0.05% DEA modifier) as co-solvent.
473
260
(R or S)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 1; Chiralpak AS-3 4.6 × 100 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent
487
261
(S or R)-2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropane-1,2-diol
Peak 2; Chiralpak AS-3 4.6 × 100 mm column with 5-40% (MeOH w/0.05% DEA modifier) as co- solvent
487
262
2-((3R,6S or 3S,6R)-1-(1-(2-amino-2-methylpropyl)-1H- pyrazol-4-yl)-6-methylpiperidin-3-yl)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Peak 1; ES Industries CCA 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co-solvent.
468
263
2-((3S,6R or 3R,6S)-1-(1-(2-amino-2-methylpropyl)-1H- pyrazol-4-yl)-6-methylpiperidin-3-yl)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine
Peak 2; ES Industries CCA 21 × 250 mm column with 40% (MeOH w/0.1% NH4OH modifier) as co-solvent.
468
264
(R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 1; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent.
483
265
(S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 2 (mixture of Example 265 and Example 266); ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 1; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier)
483
266
(R or S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 2 (mixture of Example 265 and Example 266); ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then Peak 2; Lux-4 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier)
483
267
(S or R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 3; ES Industries CCA 21 × 250 mm column with 25% (MeOH w/0.1% NH4OH modifier) as co-solvent.
483
268
(R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 1 (mixture of Example 268 and Example 269); Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then peak 1; ID 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent.
483
269
(S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 1 (mixture of Example 268 and Example 269); Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co-solvent. Then peak 2; ID 21 × 250 mm column with 35% (MeOH w/0.1% NH4OH modifier) as co-solvent.
483
270
(R or S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 2; Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co-solvent.
483
271
(S or R)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-3-methylbutan-2-ol
Peak 3; Chiral Technologies OJ-H 21 × 250 mm column with 10% (MeOH w/0.1% NH4OH modifier) as co-solvent.
483
272
1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)methyl)cyclopropan-1-ol
Peak 1; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent.
467
273
1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1-yl)-1H-pyrazol-1-yl)methyl)cyclopropan-1-ol
Peak 2; Chiralpak AS-3 4.6 × 150 mm column with 5-40% (EtOH w/0.05% DEA modifier) as co- solvent.
467
274
1-((4-((3R,5S or 3S,5R)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 2; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
483
275
1-((4-((3S,5R or 3R,5S)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin- 1-yl)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
Peak 3; Chiral Technologies AD-H 21 × 250 mm column with 30% (MeOH w/ 0.1% NH4OH modifier) as co- solvent.
483
Biological Assays
The IC50 values reported for each of the compounds of the invention shown in the table below were measured in accordance with the methods described below.
The A2a receptor affinity binding assay measured the amount of binding of a tritiated ligand with high affinity for the A2a adenosine receptor to membranes made from HEK293 or CHO cells recombinantly expressing the human A2a adenosine receptor, in the presence of varying concentrations of a compound of the invention. In each assay, the tested compounds of the invention were solubilized in 100% DMSO and further diluted in 100% DMSO to generate, typically, a 10-point titration at half-log intervals such that the final assay concentrations did not exceed 10 μM of compound or 1% DMSO.
Measurement of A2a Binding Affinity Using Radioligand Binding
148 μL (5 μg/mL) membranes (Perkin Elmer, Cat. No. RBHA2aM400UA) and 2 μL compounds of the invention to be tested (test compound) were transferred to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 minutes at room temperature. [3H] SCH58261 ((7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine)) was diluted in assay buffer (50 mM Tris pH 7.4, 10 mM MgCl2, 0.005% Tween20) to a concentration of 4 nM and 50 μL transferred to each well of the assay plate. To define total and non-specific binding, wells containing 1% DMSO and 1 μM ZM241385 (Tocris Bioscience, Cat. No. 1036) respectively, were also included. The assay plate was incubated at room temperature for 60 minutes with agitation. Using a FilterMate Harvester® (Perkin Elmer), the contents of the assay plate were filtered through a UniFilter-96® PEI coated plate (Perkin Elmer Cat. No. 6005274 or 6005277). Filtering was achieved by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cooled wash buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl) and allowing the vacuum manifold to dry the plate for 30 seconds. The filter plate was incubated for at least 1 hour at 55° C., and allowed to dry. The bottom of the filter plate was sealed with backing tape. 40 μL Ultima Gold™ (Perkin Elmer, Cat. No. 6013329) was added to each well of the filter plate and the top of the plate was sealed with TopSeal-A PLUS® clear plate seal (Perkin Elmer, Cat. No. 6050185). The plate was incubated for at least 20 minutes, and then the amount of radioactivity remaining in each well was determined using a TopCount® (Perkin Elmer) scintillation counter. After normalization to total and non-specific binding, the percent effect at each compound concentration was calculated. The plot of percent effect versus the log of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to generate IC50 values.
Measurement of A2b Binding Affinity
The reported affinity of the compounds of the invention for the human A2b adenosine receptor was determined experimentally using a radioligand filtration binding assay. This assay measures the amount of binding of a tritiated proprietary A2b receptor antagonist, in the presence and absence of a compound of the invention, to membranes made from HEK293 cells recombinantly expressing the human A2b adenosine receptor (Perkin Elmer, Cat. No. ES-013-C).
To perform the assay, compounds of the invention to be tested were first solubilized in 100% DMSO and further diluted in 100% DMSO to generate, typically, a 10-point titration at half-log intervals such that the final assay concentrations did not exceed 10 μM of compound or 1% DMSO. 148 μL (135 μg/mL) membranes and 2 μL test compounds were transferred to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 minutes at room temperature with agitation. Tritiated radioligand was diluted to a concentration of 14 nM in assay buffer (phosphate buffered saline without Magnesium and Calcium, pH 7.4; GE Healthcare Life Sciences, Cat. No. SH30256.01) and then 50 μL of the solution were transferred to each well of the assay plate. To define total and non-specific binding, wells containing 1% DMSO and 20 μM N-ethylcarboxamidoadenosine (Tocris Bioscience, Cat. No. 1691) respectively, were also included. The wells of the assay plate were incubated at room temperature for 60 minutes with agitation, then filtered using a FilterMate Harvester® (Perkin Elmer) or similar equipment through a UniFilter-96® PEI coated plate (Perkin Elmer Cat. No. 6005274 or 6005277). Filtering was achieved by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cooled wash buffer (assay buffer supplemented with 0.0025% Brij58) and allowing the vacuum manifold to dry the plate for 30 seconds. The filter plate was incubated for at least 1 hour at 55° C. and allowed to dry. The bottom of the filter plate was then sealed with backing tape. 40 μL Ultima Gold™ (Perkin Elmer, Cat. No. 6013329) was added to each well of the filter plate and the top of the plate was sealed with TopSeal-A PLUS® clear plate seal (Perkin Elmer, Cat. No. 6050185). The plates were then incubated for at least 20 minutes, and then the amount of radioactivity remaining in each well was determined using a TopCount® (Perkin Elmer) scintillation counter. After normalization to total and non-specific binding, the percent effect at each compound concentration was calculated. The plot of percent effect versus the log of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to generate IC50 values.
Example
A2A IC50 binding (nM)
A2B IC50 binding (nM)
1
7.5
554.2
2
3.7
9.4
3
1.5
180.4
4
4.6
2.6
5
3.3
1.6
6
2.0
85.9
7
3.7
104.1
8
4.5
149.3
9
0.5
136.0
10
3.5
63.4
11
0.5
56.0
12
1.7
75.0
13
0.7
72.6
14
3.0
224.9
15
38.4
905.2
16
0.8
426.0
17
1.7
433.9
18
0.7
13.5
19
0.7
87.3
20
5.8
163
21
0.3
514.6
22
8.6
27.6
23
2.0
15.9
24
13.8
480.5
25
0.6
61.7
26
3.9
48.7
27
1.8
860.8
28
2.8
76.3
29
1.5
301.1
30
0.4
97.9
31
1.7
94.8
32
0.5
6.9
33
3.6
17.5
34
1.4
29.7
35
0.6
12.2
36
1.6
93.0
37
1.1
468.1
38
16.9
182.4
39
1.1
43.3
40
1.2
9.2
41
1.2
42.8
42
4.3
475.7
43
0.7
3.4
44
1.3
20.4
45
1.8
150.4
46
0.6
86.4
47
8.2
284.2
48
0.6
17.6
49
0.3
2.7
50
18.3
1889
51
21.0
2079
52
18.3
3006
53
44.1
4239
54
3.3
194.6
55
10.6
500.2
56
1.8
846.5
57
48.3
85.6
58
13.6
136.2
59
67.0
4744
60
31.4
5862
61
5.0
99.0
62
146.1
382.8
63
242.2
2431
64
1.0
555.3
65
1.2
227.9
66
0.6
957.1
67
44% Inh.
31% Inh.
@ 1000 nM
@ 10000 nM
68
181.4
31% Inh.
@ 10000 nM
69
2.6
561.4
70
0.6
786.5
71
35.6
43% Inh.
10000 nM
72
2.0
484
73
436.0
5124
74
0.9
153.3
75
56.9
54% Inh.
@ 10000 nM
76
256.4
34% Inh.
@ 10000 nM
77
0.4
107.9
78
0.9
233.7
79
16.0
3141
80
11.6
404.5
81
121.1
6582
82
4.9
63.0
83
2.7
113.0
84
2.3
116.6
85
5.2
192.1
86
0.3
164.7
87
0.4
133.8
88
0.1
1.8
89
0.2
3.4
90
1.2
29.0
91
44.7
4624
92
10.9
602.3
93
5.8
314.6
94
7.8
752.0
95
205
5041
96
0.7
24.6
97
0.6
33.3
98
0.9
116.4
99
4.4
230.9
100
1.4
4.8
101
32.7
390.0
102
103.5
538.7
103
0.5
136.7
104
17.7
766.1
105
328.6
743.0
106
316.4
429.6
107
126.9
1522
108
36% Inh.
8474
@1000 nM
109
0.7
7.8
110
0.2
1.8
111
0.7
16.5
112
0.4
7.9
113
58.1
470.5
114
50.6
2905
115
2.9
895.1
116
207.4
35% Inh.
@10000 nM
117
0.2
13.0
118
1.9
386.7
119
51.6
1302
120
0.6
7.8
121
55.4
5344
122
368.7
2058
123
0.3
422.2
124
0.3
1.7
125
86.4
2501
126
2.6
2158
127
120.5
1158
128
0.3
2.4
129
4.1
469.9
130
1.2
78.7
131
11.8
66.0
132
6.7
242.6
133
4.3
558.5
134
123.6
4288
135
14.1
583.3
136
1.0
7.9
137
79.3
924.5
138
13.2
2257
139
16.8
2824
140
0.8
2723
141
24.1
1756
142
32% Inh. @
7937
1000 nM
143
984.1
7557
144
30% Inh. @
7143
1000 nM
145
32% Inh. @
8046
1000 nM
146
2.1
137.1
147
870.2
6333
148
385.1
4429
149
1.8
96.6
150
1.4
180.6
Measurement of A2A and A2B Antagonism in cAMP Cell-Based Assay
The ability of compounds to antagonize human A2A and A2B adenosine receptors was determined using a kit to measure changes in intracellular cyclic AMP levels (LANCE cAMP 384 Kit, Perkin Elmer, Cat. No. AD0264). HEK293 cells recombinantly expressing either human A2A or A2B receptors, previously frozen in Recovery Medium (Life Technologies, Cat. No. 12648-010) were thawed and diluted into stimulation buffer (HBSS (Hyclone SH 30268.01), 5 mM HEPES (Gibco 15630-106), 200 nM rolipram (Tocris, Cat. No. 0905), and 1.5% (V/v) BSA stabilizer (kit component). The cell suspension was centrifuged at 200×g for 10 min and then resuspended in stimulation buffer, supplemented with a 1:10 000 dilution of Alexa Fluor 647 anti-cAMP antibody, to a density of 6.0×105 cells/mL. A Labcyte Echo 550 acoustic dispenser was used to transfer up to 25 nL of test compound dissolved in DMSO into the wells of a dry Optiplate-384 plate (Perkin Elmer, Cat. No. 6008289). All subsequent liquid additions were performed using a multichannel pipettor. Next, 5 μL of the cell suspension was added to the wells of the Optiplate-384 and incubated for 30 min. at 37° C. and 5% CO2 in a humidified environment. After this time 5 μL of either 300 nM or 600 nM adenosine (Sigma Cat. No. A9251) for A2A and A2B respectively was added and incubated for 30 minutes at 37° C. and 5% CO2 in a humidified environment. At this time detection mix was prepared by combining the LANCE Eu-W8044 labeled streptavidin and Biotin-cAMP in detection buffer according to the manufacturers protocol. 10 μL of the detection mix was added to each well of the Optiplate-384 which was covered with a plate seal and incubated under ambient conditions for 2 hours prior to reading the plate using an Envision (Perkin Elmer, Waltham, Mass.) multimode plate reader. Data was normalized by defining minimal effect as stimulation in the presence of 0.25% (v/v) DMSO and maximal effect as stimulation in the presence of 1 μM ZM241385 (Cayman, Cat. No. 1036). Curve fitting of the percent effect data versus the log of compound concentration used a 4-parameter concentration response curve fitting algorithm to calculate IC50 values. Compound concentrations tested were 10,000, 3,333, 1,111, 370.4, 123.4, 41.2, 13.7, 4.6, 1.5 and 0.5 nM with 0.25% residual DMSO.
Example
A2A IC50 cAMP (nM)
A2B IC50 cAMP (nM)
151
3.8
56.9
152
5.9
371
153
7.4
719.8
154
1.2
974.1
155
23.9
1436
156
9.5
358.1
157
33.4
4481
158
1.1
32.9
159
1.0
29.3
160
8.7
647.8
161
38.9
3268
162
0.7
20.7
163
36.0
5306
164
1.9
47.7
165
0.8
6.4
166
20.0
2769
167
0.6
46.0
168
23.9
4723
169
96.5
3382
170
0.8
14.1
171
1.2
11.3
172
60.5
14% Inh.
@10000 nM
173
20.7
2022
174
0.6
30.7
175
30.2
2004
176
0.9
10.2
177
154
3957
178
0.6
11.5
179
4.0
335.5
180
54.0
5342
181
16.0
5099
182
361.9
>10000
183
2.0
90.6
184
4.9
345.5
185
1.1
49.8
186
1.0
25.8
187
2.6
95.8
188
1.5
53.1
189
0.5
53.4
190
0.8
55.9
191
0.9
92.4
192
0.8
72.4
193
1.3
250.7
194
1.7
318.4
195
3.4
389.5
196
3.7
474.9
197
6.4
93.0
198
4.3
52.4
199
2.5
97.5
200
2.5
102.5
201
1.9
38.4
202
1.4
62.4
203
7.7
53.2
204
7.8
87.7
205
7.0
1146
206
13.0
4314
207
0.9
10.37
208
0.7
2799
209
0.7
634.9
210
16.2
35% Inh.
@10000 nM
211
89.3
>10000
212
121.7
27% Inh.
@10000 nM
213
330.8
>10000
214
0.5
34.09
215
0.4
27.5
216
1.0
159.7
217
1.1
161.3
218
235.8
5775
219
246.7
27% Inh.
(5)10000 nM
220
20.4
30% Inh.
@10000 nM
221
0.5
63
222
34.6
3277
223
0.7
46
224
0.4
13.1
225
0.4
12.1
226
17.6
1611
227
40.2
5071
228
0.8
16.1
229
1.0
6.6
230
32.9
723.7
231
121.5
3845
232
1.3
12.7
233
0.7
5.6
234
46.8
1195
235
438.8
4450
236
1.0
5.1
237
0.8
8.7
238
21.8
2438
239
75.1
10% Inh.
@10000 nM
240
1.2
22.6
241
1.3
21.7
242
2.0
34.9
243
2.6
50.7
244
0.9
18.8
245
2.0
25.8
246
3.2
21.3
247
4.5
21.8
248
1.4
8.4
249
26.9
197.1
250
0.7
4.9
251
39.5
387.1
252
95.0
8157
253
123.1
>10000
254
1.5
10.
255
2.6
28.8
256
240.7
3892
257
540.6
25% Inh.
@10000 nM
258
2.3
8.1
259
2.3
11.8
260
1.7
10.0
261
86.6
1473
262
2.2
23.9
263
26.0
510.8
264
3.0
14.3
265
1.3
4.5
266
64.2
579.6
267
175.1
1215
268
0.7
4.7
269
1.2
6.4
270
5.2
30.3
271
21.4
241.8
272
43.6
5800
273
1.2
26.7
274
0.7
70.5
275
15.6
2468
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16695367
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merck sharp & dohme corp.
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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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Apr 27th, 2022 09:12AM
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Apr 27th, 2022 09:12AM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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Mar 15th, 2019 12:00AM
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https://www.uspto.gov?id=US11311528-20220426
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Oxo-tetrahydro-isoquinoline carboxylic acids as STING inhibitors
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The instant invention provides compounds of formula I which are STING inhibitors, and as such are useful for the treatment of STING-mediated diseases such as inflammation, asthma, COPD and cancer.
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11311528
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1. A compound of formula I or a pharmaceutically acceptable salt thereof:
wherein: A is a 5- to 7-membered unsaturated non-aromatic ring having 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur;
R1 is selected from —OH amino, —NHOH, —N(C1-6alky)2, and —N(C1-6 alkyl);
n is 0, 1, 2, or 3;
z is 0, 1, 2, or 3;
y is 0, 1, 2, or 3;
each R3 is independently selected from C1-10 alkyl, C1-10 haloalkyl, C3-7cycloalkylC0-6alkyl, and C3-7 heterocycloalkylC0-6alkyl,
R2 is phenyl or pyridyl, wherein R2 is substituted by 0, 1, 2, or 3 R5 substituents and wherein two R5 may join together with the ring atoms to which they are attached to form a 3- to 6-membered ring;
each R4 is independently selected from halogen, —(C1-6alkyl)OH, hydroxy, C1-10 haloalkyl, C2-10 alkenyl, C1-6 alkyl, and aryl(C0-10 alkyl)oxy(C0-10 alkyl);
each R5 is independently selected from:
halogen,
C1-10 alkyl(oxy)0-1C0-10 alkyl,
C1-10 heteroalkyl(oxy)0-1C0-10 alkyl,
C2-10 alkenyl(oxy)0-1C0-10 alkyl,
aryl C0-10 alkyl(oxy)0-1C0-10 alkyl,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1C0-10 alkyl,
heteroaryl C0-10 alkyl(oxy)0-1C0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1C0-10 alkyl,
amino,
C1-10 alkylaminoC0-10 alkyl,
(C1-10)heteroalkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
aryl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
C0-10 alkylamino (carbonyl)0-1C0-10 alkyl,
(C1-10)heteroalkylamino (carbonyl)0-1C0-10 alkyl,
C3-12 cycloalkylamino (carbonyl)0-1C0-10 alkyl,
aryl C0-10 alkylamino (carbonyl)C0-10 alkyl,
heteroaryl C0-10 alkylamino(carbonyl)0-1C0-10 alkyl,
(C3-12)heterocycloalkylamino(carbonyl)0-1C0-10 alkyl,
C1-10 alkylsulfonylC0-10 alkyl,
C1-10 heteroalkylsulfonylC1-10 alkyl,
(C3-12)cycloalkylC0-10alkylsulfonylC0-10 alkyl,
(C3-12)cycloheteroalkylC0-10alkylsulfonylC0-10 alkyl,
heteroarylC0-10 alkylsulfonylC0-10 alkyl,
arylC0-10 alkylsulfonylC0-10 alkyl,
C1-10 alkylsulfonylaminoC0-10 alkyl,
(C1-10 alkyl)1-2 amino,
—SO2NH2,
SO2NH(C1-10 alkyl),
—SO2N(C1-10 alkyl)2,
—SO2CF3,
—SO2CF2H,
—SH,
—S(C1-10 alkyl),
—NH═CH2,
hydroxy,
—(C1-10 alkyl)OH,
—C0-10 alkylalkoxy,
cyano,
—(C1-6alkyl)cyano, and
C1-6haloalkyl(oxy)0-1; wherein each R5 is substituted with 0, 1, 2 or 3 R6 substituents each independently selected by halogen, cyano, oxo, C1-10 alkylcarbonylC0-10 alkyl, C1-10 alkyl, C1-10 alkylcarbonylaminoC0-10 alkyl, and —(C1-10 alkyl)OH.
2. The compound according to claim 1, wherein R1 is selected from —OH, amino, —NHOH, —N(C1-3alkyl)2, and —N(C1-3alkyl) or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein R1 is selected from —OH, amino, —NHOH, dimethylamino, and methylamino or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein each R3 is independently selected from C1-6 alkyl, C1-6haloalkyl, C3-7 cycloalkylC0-6alkyl, and C3-7heterocycloalkylC0-6alkyl or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4, wherein each R3 is independently selected from methyl, isopropyl, and cyclopropyl or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, wherein each R4 is independently selected from halogen, hydroxy, C2-10 alkenyl, and aryl(C0-10alkyl)oxy(C0-10 alkyl) or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6, wherein each R4 is independently selected from halogen, hydroxy, ethenyl, and phenylmethoxy or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, wherein each R5 is independently selected from: halogen, C1-6 alkyl(oxy)0-1C0-10 alkyl, C2-10 alkenyl, aryl C0-10 alkyl(oxy)0-1C0-10 alkyl, C3-12 cycloalkyl C0-10 alkyl, heteroaryl C0-10 alkyl, (C3-12)heterocycloalkyl C0-10 alkyl, C1-10 alkylaminoC0-10 alkyl, aryl C0-10 alkylamino (carbonyl)C0-10 alkyl, C1-10 alkylsulfonylC0-10 alkyl, C1-10 alkylsulfonylaminoC0-10 alkyl, (C1-10 alkyl)1-2 amino, —SO2NH(C1-10 alkyl), —SO2N(C1-10 alkyl)2, —SH, —NH═CH2, —(C1-10 alkyl)OH, —C0-10 alkylalkoxy, cyano, —(C1-6alkyl)cyano, and C1-6haloalkyl(oxy)0-1; wherein each R5 is substituted with 0, 1, 2, or 3 R6 substituents or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8, wherein each R5 is independently selected from: F, Cl, tert-butyl, isopropyl, methyl, ethyl, morpholinyl, methylsufonyl, dimethysulfamoyl, 1-cyano-1-methylethyl, cyclopropyl, piperazinyl, pyrazolyl, methoxy, —SH, —N═CH2, methylamino, cyano, hydroxyethyl, 2,2,2-trifluoroethyloxy, phenylaminocarbonyl, cyclohexyl, propyl, ((methylsulfonyl)amino)methyl, morpholinylmethyl, phenylmethyloxy, Br, prop-2-enyl, hydroxymethyl, phenyl, and piperidinyl, wherein each R5 is substituted with 0, 1, 2 or 3 R6 substituents or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9, wherein each R6 is independently selected from halogen, cyano, oxo, C1-6 alkylcarbonyl, C1-6 alkyl, C1-6 alkylcarbonylamino, and (C1-10 alkyl)OH or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 10, wherein each R6 is independently selected from halogen, methylcarbonyl, hydroxyethyl, oxo, cyano, hydroxymethyl, methylcarbonyl amino, and methyl or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, wherein R5 is selected from hydrogen, methyl, methylcarbonyl, ethyl, isopropyl, morpholinoethyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethyl, 1-phenylethyl, benzyl, tetrahydro-2H-pyranylmethyl, 1-cyclopropylethyl, and tetrahydro-2H-pyranyl or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 11, wherein R6 is hydrogen or oxo or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1, wherein
is selected from:
or a pharmaceutically acceptable salt thereof.
15. The compound or a pharmaceutically acceptable salt, thereof, wherein the compound is selected from:
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(1-methylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(1-methylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-11H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-morpholin-4-ylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-morpholin-4-ylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(methylsulfonyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(methylsulfonyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(dimethylsulfamoyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(dimethylsulfamoyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)(-2-[4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S) (-2-[4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(2-chloropyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(2-chloropyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R))-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(1,3-benzothiazol-5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(1,3-benzothiazol-5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,3-diethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(1H-pyrazol-5-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(1H-pyrazol-5-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-chloro-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-chloro-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-chloro-3-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-chloro-3-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-cyano-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-cyano-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-chloro-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-chloro-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-{4-[(4-chlorophenyl)carbamoyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-{4-[(4-chlorophenyl)carbamoyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4R)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoropyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoropyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(2-chloro-6-methylpyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(2-chloro-6-methylpyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-chloro-3-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-chloro-3-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,6-dimethylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-,4-benzodioxin-6-yl)-2-(2,6-dimethylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dimethylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dimethylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3,4-dichlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3,4-dichlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(benzyloxy)-3-chlorophenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(benzyloxy)-3-chlorophenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-bromophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-bromophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-cyclopropyl-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(3,4-dihydro-2H-1-,5-benzodioxepin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-6-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-6-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalen-2-yl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalen-2-yl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(3,4,5-trichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(3,4,5-trichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-6-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-6-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-7-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-7-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dihydro-1H-isochromen-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dihydro-1H-isochromen-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-chloro-4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-chloro-4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(3,4-dihydro-2H-chromen-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(3,4-dihydro-2H-chromen-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-7-bromo-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-7-bromo-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-7-(benzyloxy)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-7-(benzyloxy)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(l-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4′-acetamido-[1,1-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4′-acetamido-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(ter-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6 yl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxyl-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-((3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid;
2-((3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid;
(3R,4R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((R)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; and
(3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((R)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid.
16. The pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition according to claim 16, further comprising one or more other therapeutic agents.
18. A method for the treatment of a STING-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
19. A method of treating a condition in a mammal that can be ameliorated by the selective inhibition of STING which condition is selected from: arthritis, asthma and obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
20. The method according to claim 19, wherein said condition is arthritis.
21. The method according to claim 20, wherein said condition is selected from rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
22. The method according to claim 19, wherein said condition is asthma or obstructive airways diseases.
23. The method according to claim 22, wherein said condition is selected from: chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease (COPD), and emphysema.
24. The method according to claim 19, wherein said condition is asthma.
25. The method according to claim 19, wherein said condition is cancer.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a U.S. National Phase application under 35 U.S.C. § 371 of PCT Application No. PCT/US2019/022440, filed Mar. 15, 2019 which claims priority under 35 U.S.C. § 119(e) from U.S. Provisional Application Ser. No. 62/645,309, filed on Mar. 20, 2018 and U.S. Provisional Application Ser. No. 62/730,588, filed on Sep. 13, 2018.
BACKGROUND OF INVENTION
The principal role of the human immune system is to maintain the body's equilibrium in the face of external and internal threats. The durable response to foreign insults (e.g., bacterial or viral infection) comes from the adaptive immune system. This response lasts the life of the host, and is characterized by the generation of antigen-specific T cells that are capable of recognizing re-challenge by the same pathogen, and shortening the timeframe to which deep immune protection can occur. Since generation of these durable responses takes weeks to develop, additional aspects of immunity compensate for the time gap.
The immediate response to a foreign insult comes from the innate arm of the immune system. This response launches within moments to hours, and is spurred by the receptor-mediated recognition of common features of that pathogen—for example, components of bacterial cell walls or viral nucleic acid motifs—and not in a sequence-specific manner like the adaptive response. These motifs are pathogen-associated molecular patterns (PAMPs), and favor speed over specificity. The innate immune system also responds to other “danger signals” that come from the host itself—signs of tissue damage or wounding that signify potential danger despite the absence of a PAMP. These “damage associated molecular patterns” (DAMPs) can stimulate similar cellular responses as an infectious agent, thus providing broad protection against a range of threats to the host.
DNA in the cytoplasm is one such DAMP/PAMP. cGAS (cyclic GMP-AMP synthase) has been described as the crucial receptor that recognizes DNA in the cytoplasm. Cytoplasmic DNA can function as either a DAMP (e.g., mitochondrial disruption could allow DNA to access the cytoplasm) or a PAMP (e.g., a DNA virus infecting a cell). Upon recognition of cytosolic DNA, cGAS catalyzes the generation of the cyclic-dinucleotide 2′-3′ cGAMP, an atypical second messenger that strongly binds to the ER-transmembrane adaptor protein STING (Stimulator of Interferon Genes). When 2′3′ cGAM P binds to STING, the protein undergoes a conformnational change, and translocates within the cell to a perinuclear compartment. This translocation induces the activation of critical transcription factors IRF-3 and NF-κB. Transcription factor activation leads to induction of type I interferons (IFNs) and production of pro-inflammatory cytokines such as IL-6, TNF-α and IFN-γ.
The function of these cytokines on immune cells is well established. Specifically. T cell activation is stimulated, as these cytokines enhance the antigen presentation capacity of macrophages and dendritic cells. Type I IFNs are best characterized for their “anti-viral” activity—notably, they stimulate dozens of cellular processes that drive toward clearing a viral insult. These include inhibition of viral replication, affecting the cell cycle so that infected cells are less able to divide, inhibiting budding of viral particles, affecting expression of antigen presentation machinery, and more.
These anti-viral processes driven by STING activation can become dysregulated, and their dysregulation could cause or exacerbate inflammatory, autoimmune, or other disorders where DNA gains access to the cytoplasm of cells. These disorders are characterized by abnormal cytokine responses, and interfering with STING signaling in these disorders could reduce or prevent this cytokine production. Mouse models of DNA-driven inflammation have observed abrogation of symptoms when STING is genetically deleted. (See Lood, Christian, et al., Nature Medicine, Vol. 22, No. 2, 146-153 (February 2016); and Gehrke, Nadine, et al., Immunity 39, 482-495, Sep. 19, 2013). Additionally, in a deeper study involving human patients with Systemic lupus erythematous (SLE) it was observed that oxidized DNA is associated with SLE pathology. (Caielli, Simone, et al., J of Experimental Med., Vol. 213, No. 5, 697-713, (2016). SLE is a prototypical example of a disorder where cytokine response is abnormal. SLE is characterized by chronic, high levels of type I IFNs, as well as circulating immune complexes (formed of antibody-antigen aggregates that are not successfully cleared). Most patients with SLE have high levels of circulating DNA, and have generated inappropriately aggressive innate and adaptive responses to that DNA. This prominent role for both DNA and type I IFNs suggests that inhibitors of the cGAS/STING pathway could have therapeutic benefit in such a disorder.
SUMMARY OF THE INVENTION
The present invention provides novel compounds which are inhibitors of STING activity. The invention also provides a method for the treatment and prevention of STING-mediated diseases and disorders using the novel compounds, as well as pharmaceutical compositions containing the compounds.
The invention is also directed to methods of inhibiting STING activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which suppression of STING plays a role as immunosuppressants. Methods of using STING inhibitory compounds to inhibit cancer cell growth or proliferation are also provided.
DETAILED DESCRIPTION OF THE INVENTION
Compounds are provided that inhibit type I interferon (type 1 IFN) production, specifically compounds that inhibit stimulator of interferon genes (STING) pathway. The invention provides methods of using STING antagonistic compounds to inhibit STING mediated processes in vitro and in vivo.
The present invention provides compounds of formula I or pharmaceutically acceptable salts thereof:
wherein: A is a 5- to 7-membered unsaturated non-aromatic ring having 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur;
R1 is selected from —OH, amino, —NHOH, —N(C1-6 alkyl)2, and —N(C1-6 alkyl);
n is 0, 1, 2, or 3;
z is 0, 1, 2, or 3;
y is 0, 1, 2, or 3;
each R3 is independently selected from C1-10 alkyl, C1-10 haloalkyl, C3-7cycloalkylC0-6alkyl, and C3-7heterocycloalkylC0-6alkyl,
R2 is phenyl or pyridyl, wherein R2 is substituted by 0, 1, 2, or 3 R5 substituents and wherein two R5 may join together with the ring atoms to which they are attached to form a 3- to 6-membered ring;
each R4 is independently selected from halogen, —(C1-6 alkyl)OH, hydroxy, C1-10 haloalkyl, C2-10 alkenyl, C1-6 alkyl, and aryl(C0-10 alkyl)oxy(C0-10 alkyl;
each R5 is independently selected from:
halogen,
C1-10 alkyl(oxy)0-1C1-10 alkyl,
C1-10 heteroalkyl(oxy)0-1C1-10 alkyl,
C2-10 alkenyl(oxy)0-1C1-10 alkyl,
aryl C1-10 alkyl(oxy)0-1C1-10 alkyl,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1C1-10 alkyl,
heteroaryl C1-10 alkyl(oxy)0-1C1-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1C1-10 alkyl,
amino,
C1-10 alkylaminoC1-10 alkyl,
(C1-10)heteroalkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-1 alkyl,
aryl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
C0-10 alkylamino (carbonyl)0-1C0-10 alkyl,
(C1-10)heteroalkylamino (carbonyl)0-1C0-10 alkyl,
C3-12 cycloalkylamino (carbonyl)0-1C0-10 alkyl,
aryl C0-10 alkylamino (carbonyl)C0-10 alkyl,
heteroaryl C0-10 alkylamino(carbonyl)0-1C0-10 alkyl,
(C3-12)heterocycloalkylamino(carbonyl)0-1C0-10 alkyl,
C1-10 alkylsulfonylC0-10 alkyl,
C1-10 heteroalkylsulfonylC0-10 alkyl,
(C3-12)cycloalkylC0-10alkylsulfonylC0-10 alkyl,
(C3-12)cycloheteroalkylC0-10alkylsulfonylC0-10 alkyl,
heteroarylC0-10 alkylsulfonylC0-10 alkyl,
arylC0-10 alkylsulfonylC0-10 alkyl,
C1-10 alkylsulfonylaminoC0-10 alkyl,
(C1-10 alkyl)1-2 amino,
—SO2NH2,
—SO2NH(C1-10 alkyl),
—SO2N(C1-10 alkyl)2,
—SO2CF3,
—SO2CF2H,
—SH,
—S(C1-10 alkyl),
—NH═CH2,
hydroxy,
—(C1-10 alkyl)OH,
—C0-10 alkylalkoxy,
cyano,
—(C1-6alkyl)cyano, and
C1-6haloalkyl(oxy); wherein each R5 is substituted with 0, 1, 2 or 3 R6 substituents each independently selected by halogen, cyano, oxo, C1-10 alkylcarbonylC0-10 alkyl, C1-10 alkyl, C1-10 alkylcarbonylaminoC0-10 alkyl, and —(C1-10 alkyl)OH.
Representative compounds of the instant invention include, but are not limited to, the following compounds and their pharmaceutically acceptable salts thereof.
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(1-methylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-morpholin-4-ylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(methylsulfonyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(dimethylsulfamoyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(-2-[4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(2-chloropyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(1,3-benzothiazol-5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(1H-pyrazol-5-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-chloro-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-chloro-3-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(3-cyano-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[3-chloro-4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(3-chloro-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-{4-[(4-chlorophenyl)carbamoyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoropyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(2-chloro-6-methylpyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-chloro-3-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,6-dimethylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(I-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dimethylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(3,4-dichlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(benzyloxy)-3-chlorophenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(3-bromophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-cyclopropyl-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(1-cyanocyclohexyl)phenyl]-3-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
6-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalen-2-yl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(3,4,5-trichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
6-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
7-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dihydro-1H-isochromen-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(3-chloro-4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-3-(3,4-dihydro-2H-chromen-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
7-bromo-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
7-(benzyloxy)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4′-acetamido-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(I-acetylpiperidin-4-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-[4-(1-acetylpiperidin-4-yl)-3-methylphenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-{4-[cis-4-(acetylamino)cyclohexyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-{4-[trans-4-(acetylamino)cyclohexyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-(4-ter-t-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid; and
3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid.
In a variant of the above-embodiment, compounds of the instant invention include the following compounds and their pharmaceutically acceptable salts thereof:
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(1-methylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(1-methylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1-H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-morpholin-4-ylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-morpholin-4-ylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(methylsulfonyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(methylsulfonyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(dimethylsulfamoyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(dimethylsulfamoyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)(-2-[4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S) (-2-[4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(2-chloropyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(2-chloropyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R))-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(4-acetylpiperazin-1-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(1,3-benzothiazol-5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(1,3-benzothiazol-5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(1H-pyrazol-5-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(H-pyrazol-5-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-chloro-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-chloro-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-chloro-3-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-chloro-3-cyclopropylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-cyano-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-cyano-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(difluoromethoxy)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-chloro-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-chloro-4-morpholin-4-ylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-{4-[(4-chlorophenyl)carbamoyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-{4-[(4-chlorophenyl)carbamoyl]phenyl}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4R)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoropyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoropyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(2-chloro-6-methylpyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(2-chloro-6-methylpyridin-4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-chloro-3-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-chloro-3-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,6-dimethylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,6-dimethylpyridin-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dimethylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dimethylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3,4-dichlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3,4-dichlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(benzyloxy)-3-chlorophenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(benzyloxy)-3-chlorophenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-bromophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-bromophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-cyclopropyl-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-cyclopropyl-3-fluorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(l-cyanocyclohexyl)phenyl]-3-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-6-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-6-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2,3-dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalen-2-yl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-naphthalen-2-yl-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(3,4,5-trichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-(3,4,5-trichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-6-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-6-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-7-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-7-bromo-2-(3-chloro-4-methylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dihydro-1H-isochromen-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,4-dihydro-1H-isochromen-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(3-chloro-4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(3-chloro-4-cyclohexylphenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(3,4-dihydro-2H-chromen-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(3,4-dihydro-2H-chromen-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-7-bromo-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-7-bromo-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-7-(benzyloxy)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-7-(benzyloxy)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-7-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[3-chloro-4-(1-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[3-chloro-4-(I-cyanocyclopropyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4′-acetamido-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4′-acetamido-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-[4-(1-acetylpiperidin-4-yl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-N,N-di methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3R,4R)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6 yl)-N hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
2-((3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid;
2-((3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid;
(3R,4R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3R,4R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((R)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;
(3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid; and
(3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((R)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid.
The invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of STING mediated diseases using compounds of formula I.
One aspect of the present invention is to provide compounds that can inhibit the biological activity of STING. Another aspect of the invention is to provide methods of selectively modulating human STING activity and thereby promoting medical treatment of diseases mediated by STING dysfunction.
In one embodiment of the invention, the compounds of formula I inhibit STING activity in biochemical and cell-based assays and exhibit therapeutic activity in medical conditions in which STING activity is excessive or undesirable.
The invention is described using the following definitions unless otherwise indicated.
When any variable (e.g. aryl, heteroaryl, R1, R5, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
The wavy line , as used herein, indicates a point of attachment to the rest of the compound.
Lines drawn into the ring systems, such as, for example:
indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms. The term “alkyl,” as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 10 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-6 alkyl) or from about 1 to about 3 carbon atoms (C1-3 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.
The term “alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
“Alkenyl” refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-1-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
“Alkoxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by alkoxy groups. Examples include CH2OCH3, CH2CH2OCH3 and CH(OCH)CH3.
“Aminoalkyl” refers to an alkyl group as described above in which one hydrogen atom has been replaced by an amino (—NH2), monoalkylamino or dialkylamino group. Examples include CH2NH2, CH2CH2NHCH3 and CH(N(CH3)2)CH3.
The term “C0” as employed in expressions such as “C0-6alkyl” means a direct covalent bond; or when the term appears at the terminus of a substituent, C0-6 alkyl means hydrogen or C1-6alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond. For example, in the structure
wherein s is an integer equal to zero, 1 or 2, the structure is
when s is zero.
The term “halogen” or “halo”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).
Except where noted, the term “aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl and indanyl. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl. Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.
“Carboxy” refers to the functional group —C(O)OR, for example: ethylcarboxy is
phenylcarboxy is
and cyclopropycarboxy is
The term “carbocycle” (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C3 to C8 monocyclic, saturated or unsaturated ring or (ii) a C7 to C12 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
“Cycloalkyl” or “C12 cycloalkyl” means any univalent radical derived from a monocyclic or bicyclic ring system having 3 to 12 ring carbons atoms; said ring system may be (a) a C3 to a C8 monocyclic, saturated ring, or (b) a bicyclic saturated ring. Here, the point of attachment for a “cycloalkyl” to the rest of the molecule is on the saturated ring. For a bicyclic system, with (b), the rings are fused across two adjacent ring carbon atoms (e.g., decalin), or are bridged groups (e.g., norbornane). Additional examples within the above meaning include, but are not limited to univalent radicals of cyclopropane, cyclobutane, cyclopentane, cyclohexane, decalin, bicyclo[2.2.2]octane and 3a,5,6,7-tetrahydro-4H-indene.
The term “C3-8 cycloalkyl” (or “C3-C8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C3-7 cycloalkyl” “C3-6 cycloalkyl”, “C5-7 cycloalkyl” and the like have analogous meanings.
The term “heteroaryl,” as used herein, refers to an aromatic monocyclic ring comprising about 5 to about 7 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, N or S and the remaining ring atoms are carbon atoms. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, and the like, and all isomeric forms thereof. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6-membered monocyclic heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
The term “heterocycloalkyl,” as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, or N, and the remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon or ring nitrogen atom. Said ring system may be (a) a saturated monocyclic ring or a partially unsaturated ring, or (b) a bicyclic saturated carbocycle. For a bicyclic system, within either (a) or (b), the rings are fused across two adjacent ring carbon atoms (e.g., decahydroisoquinoline), at one ring carbon atom (e.g., spiro[2.4]heptyl, spiro[2.2]pentane), or are bridged groups (e.g., 2,5-diazabicyclo[2.2.1]heptyl).
In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 8 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone and the like, and all isomers thereof.
“Haloalkyl” refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. Cr haloalkyl, for example, includes —CF3, —CF2CF3, —CHFCH3, and the like.
“Hydroxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Examples include CH2OH, CH2CHOH and CHOHCH3.
The term “sulfamoyl” is a suffix to denote radicals derived from sulfamide such as
—SO2NH2, —SO2NHR and —SO2N(RR1).
“Sulfanyl” refers to mercapto radical, —SH. For example, methylsulfanyl is —SCH3.
“Sulfonyl” refers to —S(═O)2R. For example, —S(═O)2H, methylsulfonyl (—S(═O)2CH3), or cyclopropylsulfonyl
Unless expressly stated to the contrary, an “unsaturated” ring is a partially or fully unsaturated ring. For example, an “unsaturated monocyclic C1-6 carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.
Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
The term “substituted” (e.g., as in “aryl which is optionally substituted with one or more substituents . . . ”) includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur (S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”
Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “CH3”, e.g. “—CH3” or using a straight line representing the presence of the methyl group, e.g. “”, i.e.
and
have equivalent meanings.
For variable definitions containing terms having repeated terms, e.g., (CRiRj)r, where r is the integer 2, Ri is a defined variable, and Rj is a defined variable, the value of Ri may differ in each instance in which it occurs, and the value of R may differ in each instance in which it occurs. For example, if Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CRiRj)2 can be
In one embodiment of the invention, R1 is selected from —OH, amino, —NHOH, —N(C1-3 alkyl)2, and —N(C1-3alkyl) and the other groups are provided in the general formula I.
In a second embodiment of the invention, R1 is selected from −OH, amino, —NHOH, dimethylamino, diethylamino, dipropylamino, methylamino, ethylamino, and propylamino and the other groups are provided in the general formula I above.
In a third embodiment of the invention, R1 is selected from —OH, amino, —NHOH, dimethylamino, and methylamino, and the other groups are provided in the general formula I above.
In a fourth embodiment, n is 0, 1, or 2, and the other groups are provided in general formula I above or or as in the first through third embodiments.
In a fifth embodiment, n is 0, or 1, and the other groups are provided in general formula I above or or as in the first through third embodiments.
In a sixth embodiment of the disclosure, z is 0, 1, or 2, and the other groups are provided in general formula I above or or as in the first through fifth embodiments.
In a seventh embodiment, z is 0, or 1, and the other groups are provided in general formula I above or or as in the first through fifth embodiments.
In a eighth embodiment of the disclosure, z is 0, 1, or 2, and the other groups are provided in general formula I above or as in the first through seventh embodiments.
In a ninth embodiment, z is 0, or 1, and the other groups are provided in general formula I above or or as in the first through seventh embodiments.
In a tenth embodiment of the disclosure, each R3 is independently selected from C1-6 alkyl, C1-6haloalkyl, (C3-7cycloakylC0-6alkyl, and C3-7heterocycloalkylC0-6alkyl and the other groups are provided in general formula I above or as in the first through ninth embodiments.
In an eleventh embodiment of the disclosure, each R3 is independently selected from C1-6 alkyl and C3-7-cycloalkylC0-6alkyl, and the other groups are provided in general formula I above or as in the first through ninth embodiments.
In a twelfth embodiment of the invention, each R3 is independently selected from methyl, isopropyl, and cyclopropyl, and the other groups are provided in general formula I above or as in the first through ninth embodiments.
In a thirteenth embodiment of the disclosure, each R4 is independently selected from halogen, hydroxy, C2-10 alkenyl, and aryl(C0-10 alkyl)oxy(C)0-10 alkyl), and the other groups are provided in general formula I above or as in the first through twelfth embodiments.
In a fourteenth embodiment of the disclosure, each R4 is independently selected from halogen, hydroxy, C2-6 alkenyl, and aryl(C0-10alkyl)oxy, and the other groups are provided in general formula I above or as in the first through twelfth embodiments.
In a fifteenth embodiment, each R4 is independently selected from halogen, hydroxy, ethenyl, and phenylmethoxy, and the other groups are provided in general formula I above or as in the first through twelfth embodiments.
In a sixteenth embodiment of the disclosure, each R5 is independently selected from: halogen, C1-10 alkyl(oxy)0-1C0-10 alkyl, C0-10 heteroalkyl(oxy)0-1C0-10 alkyl, C2-10 alkenyl(oxy)0-1 C0-10 alkyl, aryl C0-10 alkyl(oxy)0-1C0-10 alkyl, C3-12 cycloalkyl C0-10 alkyl(oxy)0-1C0-10 alkyl, heteroaryl C0-10 alkyl(oxy)0-1C0-10 alkyl, (C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1C0-10 alkyl, amino, C1-10 alkylaminoC0-10 alkyl, aryl C0-10 alkylamino (carbonyl)C0-10 alkyl, C1-10 alkylsulfonylC0-10 alkyl, C1-10 alkylsulfonylaminoC0-10 alkyl, (C1-10 alkyl)1-2 amino, —SO2NH2, —SO2NH(C1-10 alkyl), —SO2N(C1-10 alkyl)2, —SH, —S(C1-10 alkyl), —NH═CH2, hydroxy, —(C1-10 alkyl)OR, —C0-10 alkylalkoxy,
cyano, —(C1-6alkyl)cyano, and C1-6haloalkyl(oxy)0-1; wherein each R5 is substituted with 0, 1, 2, or 3 R6 substituents, and the other groups are provided in general formula I above or as in the first through fifteenth embodiments.
In a seventeenth embodiment, each R5 is independently selected from: halogen, C1-6 alkyl(oxy)0-1C0-10 alkyl, C2-10 alkenyl, aryl C0-10 alkyl(oxy)0-1C0-10 alkyl, C3-2 cycloalkyl C0-10 alkyl, heteroaryl C0-10 alkyl, (C3-12)heterocycloalkyl C0-10 alkyl, C1-10 alkylaminoC0-10 alkyl, aryl C0-10 alkylamino (carbonyl)C0-10 alkyl, C1-10 alkylsulfonylC0-10 alkyl, C1-10 alkylsulfonylamino C0-10 alkyl, (C1-10 alkyl)1-2 amino, —SO2NH(C1-10 alkyl), —SO2N(C1-10 alkyl)2, —SH, —NH═CH2, —(C1-10 alkyl)OH, —C0-10 alkylalkoxy, cyano, —(C1-6alkyl)cyano, and C1-6haloalkyl(oxy)0-1; wherein each R5 is substituted with 0, 1, 2, or 3 R6 substituents, and the other groups are provided in general formula I above or as in the first through fifteenth embodiments.
In an eighteenth embodiment, each R5 is independently selected from: F, Cl, tert-butyl, isopropyl, methyl, ethyl, morpholinyl, methylsufonyl, dimethysulfamoyl, 1-cyano-1-methylethyl, cyclopropyl, piperazinyl, pyrazolyl, methoxy, —SH, —N═CH2, methylamino, cyano, hydroxyethyl, 2,2,2-trifluoroethyloxy, phenylaminocarbonyl, cyclohexyl, propyl, ((methylsulfonyl)amino)methyl, morpholinylmethyl, phenylethyloxy (benzyloxy), Br, prop-2-enyl, hydroxymethyl, phenyl, and piperidinyl, wherein each R5 is substituted with 0, 1, 2 or 3 R6 substituents, and the other groups are provided in general formula I above or as in the first through fifteenth embodiments.
In a nineteenth embodiment of the disclosure, each R6 is independently selected from halogen, cyano, oxo, C1-6 alkylcarbonyl, C1-6 alkyl, C1-6 alkylcarbonylamino, and —(C1-10 alkyl)OH, and the other groups are provided in general formula I above or as in the first through eighteenth embodiments.
In a twentieth embodiment of the invention, each R is independently selected from halogen, methylcarbonyl, hydroxyethyl, oxo, cyano, hydroxymethyl, methylcarbonyl amino, and methyl, and the other groups are provided in general formula I above or as in the first through eighteenth embodiments.
In a twenty-first embodiment of the disclosure,
is selected from:
and the other groups are provided in general formula I above or as in the first through twentieth embodiments.
In a twenty-second embodiment of the invention,
and the other groups are provided in general formula I above or as in the first through twentieth embodiments.
“Patient” for the purposes of the present invention includes humans and other animals, particularly mammals and other organisms. Thus the methods are applicable to both human therapy and veterinary applications.
“Mammal” means humans and other mammalian animals.
“Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
The term “treatment” or “treating” includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.
The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of formula I, and pharmaceutically acceptable excipients.
The term “optionally substituted” means “unsubstituted or substituted,” and therefore, the generic structural formulas described herein encompasses compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.
Each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when there is more than one substituent for aryl/heteroaryl, each substituent is independently selected at each occurrence, and each substituent can be the same or different from the other(s). As another example, for the group —(CR3R3)2—, each occurrence of the two R groups may be the same or different. As used herein, unless explicitly stated to the contrary, each reference to a specific compound of the present invention or a generic formula of compounds of the present invention is intended to include the compound(s) as well as pharmaceutically acceptable salts thereof.
Recitation or depiction of a specific compound in the claims (i.e., a species) without a specific stereoconfiguration designation, or with such a designation for less than all chiral centers, is intended to encompass the racemate, racemic mixtures, each individual enantiomer, a diastereoisomeric mixture and each individual diastereomer of the compound where such forms are possible due to the presence of one or more asymmetric centers.
Optical Isomers-Diastereomers-Geometric Isomers-Tautomers
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
In the present application when a particular stereometric compound is named using an “and” in the stereometric designation, for example, (3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, the “and” indicates a racemic mixture of the enantiomers. That is, the individual enantiomers were not individually isolated.
When the stereometric nomenclature includes “or”, for example, (3S,4S) or (3R,4R)-2-[4-(1-cyanocyclohexyl)phenyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, the “or” indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not determined.
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography (e.g. chiral HPLC column) and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride ((2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
Salts
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, unless otherwise specified, references to the compound of formula I, subsets thereof, embodiments thereof, as well as specific compounds are meant to also include the pharmaceutically acceptable salts.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such all forms are intended to be included in the present invention.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N—(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, —P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C1-C10)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or benzyl, C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or di-N,N—(C1-C6)alkylaminoalkyl, —C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-N,N—(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
Labelled Compounds
In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Additionally, the present invention is meant to include in compounds of generic Formula I, all suitable replacements of sp3 orbital carbons to sp3 Si as can readily be envisioned by one of ordinary skill in the art.
Utilities
Compounds of the Invention have activity for STING. Compounds of this invention have been tested using the assays described in the Biological Examples and have been determined to be inhibitors of STING. Suitable in vitro assays for measuring STING activity and the inhibition thereof by compounds are known in the art. For further details of an in vitro assay for measuring STING activity, see the Biological Examples herein. Cell-based assays for measurement of in vitro efficacy in treatment of cancer are known in the art. In addition, assays are described in the Biological Examples provided herein.
Compounds of Formula I may be useful for treating diseases, including autoimmune disorders, inflammatory diseases, and cancers, which are listed below.
Cancers: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannomas, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplasia syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
Autoimmune diseases: Hashimoto's thyroiditis, systemic lupus erythematosus (SLE), Goodpasture's syndrome, pemphigus, receptor autoimmune diseases, Basedow's disease (Graves' disease), myasthemia gravis, insulin resistant diseases, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, autoimmune encephalomyelitis, rheumatism, rheumatoid arthritis, scleroderma, mixed connective tissue disease, polymyositis, pernicious anemia, idiopathic Addison's disease, some types of infertility, glomerulonephritis, bullous pemphigus, Sjogren's syndrome, some types of diabetes, adrenergic agent resistance, chronic active hepatitis, primary biliary cirrhosis, endocrine failure, vitiligo, angiitis, post-cardiac surgery syndrome, urticaria, atopic dermatiti and multiple sclerosis, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism, and Guillain-Barre syndrome.
Inflammatory Diseases: asthma, allergic rhinitis, psoriasis, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies, scleracierma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ishchemia/reperfusion injury), dermatomyositis, alopecia greata, chronic actinic dermatitis, eczema, Behcet's disease, Pustulosis palmoplanteris, Pyoderma gangrenum, Sezary's syndrome, atopic dermatitis, systemic sclerosis, and morphea.
Central Nervous System Disorders: Multiple sclerosis, schizophrenia and Alzheimer's disease.
Thus, in one embodiment, the invention provides a method of inhibiting STING activation comprising binding to STING with an effective amount of a compound as disclosed herein.
In another embodiment, the invention provides a method of treating a STING modulated disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as disclosed herein.
In another embodiment, the invention provides a method of treating cancer disease mediated by STING comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as disclosed herein.
Compounds of the invention may also useful as inhibitors of STING in vivo for studying the in vivo role of STING in biological processes, including the diseases described herein. Accordingly, the invention also comprises a method of inhibiting STING in vivo comprising administering a compound or composition of the invention to a mammal.
Accordingly, another aspect of the present invention provides a method for the treatment or prevention of a STING mediated disease or disorder comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I. In one embodiment such diseases include asthma and rheumatoid arthritis.
Another aspect of the present invention provides for the use of a compound of formula I in the manufacture of a medicament for the treatment or prevention of a STING mediated diseases or disorders.
Dose Ranges
The magnitude of prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 milligram of active agent per kilogram body weight of a mammal (mg/kg) to about 100 mg/kg, typically, between 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.01 mg to 10 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition. Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, or 500 mg.
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 the disease state. 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.
Pharmaceutical Compositions
Another aspect of the present invention provides pharmaceutical compositions comprising a compound of formula I with a pharmaceutically acceptable carrier. For the treatment of any of the prostanoid mediated diseases compounds of formula I may be administered orally, by inhalation spray, topically, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. 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 selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or tale. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption 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 may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders. For compositions suitable and/or adapted for inhaled administration, it is preferred that the active substance is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronization.
In one embodiment the medicinal preparation is adapted for use with a pressurized metered dose inhaler (pMDI) which releases a metered dose of medicine upon each actuation. The formulation for pMDIs can be in the form of solutions or suspensions in halogenated hydrocarbon propellants. The type of propellant being used in pMDIs is being shifted to hydrofluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs). In particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) are used in several currently marketed pharmaceutical inhalation products. The composition may include other pharmaceutically acceptable excipients for inhalation use such as ethanol, oleic acid, polyvinylpyrrolidone and the like.
Pressurized MDIs typically have two components. Firstly, there is a canister component in which the drug particles are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well. The canister component typically includes a valve outlet from which the contents of the canister can be discharged. Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valve outlet and causing the medication particles to be conveyed from the valve outlet through the receptacle component and discharged from an outlet of the receptacle. Upon discharge from the canister, the medication particles are “atomized”, forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation, so that the medication particles are entrained in the patient's aspiratory flow and conveyed to the lungs. Typically, pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component. In pMDIs, the formulation is provided in a liquid or suspension form, and resides within the container along with the propellant. The propellant can take a variety of forms. For example, the propellant can comprise a compressed gas or liquefied gas.
In another embodiment the medicinal preparation is adapted for use with a dry powder inhaler (DPI). The inhalation composition suitable for use in DPIs typically comprises particles of the active ingredient and particles of a pharmaceutically acceptable carrier. The particle size of the active material may vary from about 0.1 μm to about 10 μm; however, for effective delivery to the distal lung, at least 95 percent of the active agent particles are 5 μm or smaller. Each of the active agent can be present in a concentration of 0.01-99%. Typically however, each of the active agents is present in a concentration of about 0.05 to 50%, more typically about 0.2-20% of the total weight of the composition.
As noted above, in addition to the active ingredients, the inhalable powder preferably includes pharmaceutically acceptable carrier, which may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. Advantageously, the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols. Preferably, the carrier particles are particles of dextrose or lactose, especially lactose. In embodiments of the present invention which utilize conventional dry powder inhalers, such as the Handihaler, Rotohaler, Diskhaler, Twisthaler and Turbohaler, the particle size of the carrier particles may range from about 10 microns to about 1000 microns. In certain of these embodiments, the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other embodiments, the size of at least 90% by weight of the carrier particles is less than 1000 microns and preferably lies between 60 microns and 1000 microns. The relatively large size of these carrier particles gives good flow and entrainment characteristics. Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder. The powder may optionally contain a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
Compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
Combinations with Other Drugs
In certain embodiments, a compound of Formula I is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with one or more other therapeutic agents that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer). The other therapeutic agent of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula I such that they do not adversely affect each other. Such agents are suitably present in combination in amounts that are effective for the purpose intended.
In one embodiment of the invention, the compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, may be co-administered with one or more other therapeutic agents for the treatment and prevention of STING mediated diseases. Thus in another aspect the present invention provides pharmaceutical compositions for treating STING mediated diseases comprising a therapeutically effective amount of a compound of formula I and one or more other therapeutic agents.
In one embodiment for example, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of formula I may be combined with other therapeutic agents such as: (1) TNF-α inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of rheumatoid arthritis including low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-10) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as zileuton; (6) LTD4 receptor antagonist such as zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast; (8) antihistaminic 1-1 receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, astemnizole, azelastine, and chlorpheniramine; (9) α1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride; (10) anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclidinium bromide, glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium cromoglycate; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate, and (14) PI3K-delta inhibitors (Phosphatidylinositol-4,5-bisphosphate 3-kinase-delta inhibitors).
In another embodiment of the invention, the compounds of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, may be employed alone or in combination with other therapeutic agents for the treatment of hyperproliferative disorders (e.g., cancer) including standard chemotherapy regimens, and anti-CD20 monoclonal antibodies, rituximab, bendamustine, ofatumumab, fludarabine, lenalidomide, and/or bortezomib.
The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active therapeutic agents simultaneously exert their biological activities.
SCHEMES AND EXAMPLES
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
ACN
Acetonitrile
AcOH
acetic acid
AQ, aq,
Aqueous
(Boc)2O
di-tert-butyl dicarbonate
Boc
tert-butoxycarbamate
tBu—OH
tert-butyl alcohol
BuLi (n-BuLi)
n-butyllithium
calcd
Calculated
CELITE, Celite ™, Celite
A trademarked version of diatomaceous earth
D, d
Day
DABCO
1,4-diazabicyclo[2.2.2]octane
DCM
Dichloromethane
DMP Dess-Martin
DessMartin Periodinane, 1,1,1-Triacetoxy)-
Periodinane
1,1-dihydro-1,2-benziodoxol-3(1H)-one;.
A reagent used for mild oxidation of
alcohols to aldehydes and ketones.
DiBAl-H, DIBAL-H
diisobutylaluminum hydride
DIAD
Diisopropyl azodicarboxylate
DIPEA
Diisopropylethylamine
DMA
Dimethylacetamide
DMAP
Dimethylaminopyridine
DMEA
Dimethylethylamine
DMF
Dimethylformamide
DMSO
dimethyl sulfoxide
Dppp
1,3-bis(diphenylphosphino)propane
ES
electron spray
MS ESI, ESI MS
Electrospray ionization mass spectrometers
(ESI MS)
EtOAc
ethyl acetate
EtOH
Ethanol
Et3N
Trimethylamine
g, gm
Gram
HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate
Hunig's Base
N,N-diisopropylethylamine
HPLC
high performance liquid chromatography
IC50, IC50
concentration of drug at which 50% of the
target is inhibited
J
NMR Coupling constant
K2CO3
Potassium carbonate
LCMS
liquid chromatography coupled to mass
spectrometer
LiBH4
Lithium borohydride
mg
Milligram
mL
Milliliter
mmol
Millimole
MeCN
Acetonitrile
MHz
Mega Hertz
MeOH
Methanol
MS
mass spectrum (data)
MsCl
methanesulfonyl chloride
N
Normal,
equivalents of solute/liter of solution
Na2SO4
sodium sulfate
NaCl
Sodium chloride
NaHCO3
Sodium bicarbonate
NaOH
Sodium hydroxide
NEt3, Et3N
Triethylamine
NMR
nuclear magnetic resonance (data)
Pd(OAc)2
palladium II acetate
PdCl2(dppf)
1,1′-bis(diphenylphosphino)ferrocene-
palladium(II)dichloride
Pd2(dba)3
tris(dibenzylideneacetone) dipalladium(0)
Pd(PPh3)4,
tetrakis(triphenylphosphine) palladium(0)
Pd(Ph3P)4
PG
Protecting Group
RPM, rpm
Revolutions per minute
RT, rt, rt.
room temperature
Sat., SAT, sat
Saturated
SFC
Supercritical fluid chromatography
tBu, t-BU
Tert-butyl
TBAI
Tetrabutylammonium iodide
TEA
Trimethylamine
TFA
trifluoroacetic acid
THF
Tetrahydrofuran
THP1 cells
A human monocytic cell line derived from
an acute monocytic leukemia patient.
XPhos
2-dicyclohexylphosphino-2′,4′,6′-
triisopropylbiphenyl
μ
Micro
Methods of Synthesis
The compounds of the present invention can be prepared according to the following general schemes using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not to be construed as forming the only genus that is considered as the invention. The illustrative examples below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions of the instant invention herein above.
Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated.
All reactions were stirred (mechanically, stir bar/stir plate, or shaken) and conducted under an inert atmosphere of nitrogen or argon unless specifically stated otherwise. All temperatures are degrees Celsius (° C.) unless otherwise noted. Ambient temperature is 15-25° C.
Most compounds were purified by reverse-phase preparative HPLC, MPLC on silica gel, recrystallization and/or trituration (suspension in a solvent followed by filtration of the solid). The course of the reactions was followed by thin layer chromatography (TLC) and/or LCMS and/or NMR and reaction times are given for illustration only.
All end products were analyzed by NMR and LCMS. Intermediates were analyzed by NMR and/or TLC and/or LCMS.
In cases where mixtures or gradients of solvents or solution reagents are described, the mixtures are on a volume basis unless otherwise indicated.
General Synthetic Schemes
The compounds of the generic formula may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the compounds are set forth in the Examples below and are generalized in Schemes 1 through 2 presented below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis.
Several synthetic routes may be employed in the syntheses of the compounds described herein. One such route is illustrated in Scheme 1. In this approach, structures of Gen-4 can be synthesized in a one pot with commercially available Gen-1 anilines, Gen-2 homophthalic anhydrides, and Gen-3 aldehydes by heating in a microwave reactor with cesium carbonate (Cs2CO3), acid, and indium chloride (InCl3) as a catalyst.
Alternatively, structures of Gen-4, may be synthesized using a modified route illustrated in Scheme 2, where the homophthalic anhydride is replaced with commercially available benzoic acid (Gen-5) to provide Gen-4.
Example 1
(3S,4S or 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-1)
4-(tert-butyl)-3-chloroaniline (1-a) (60 mg, 0.327 mmol), isochromane-1,3-dione (1-b) (53 mg 0.327 mmol), and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (1-c) (59 mg, 0.359 mmol) were added to a microwave vial followed by Indium(III) chloride (InCl3) (4.3 mg, 0.02 mmol). The vial was sparged with nitrogen then MeCN (acetonitrile) (1.1 mL) was added. The vial was sealed and heated in a microwave reactor for 45 minutes at 100° C. The reaction mixture was cooled to ambient temperature and Cs2CO3 (cesium carbonate) (160 mg, 0.490 mmol) was added. The resulting mixture was heated in the microwave reactor for 45 minutes at 100° C. The reaction mixture was diluted with water (1 mL), 2N HCl (0.49 mL) and EtOAc (3 mL). After stirring for 10 minutes the organic phase was separated and concentrated under reduced pressure. The resulting residue was dissolved in DMSO (1 mL), filtered, and purified by mass triggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford a mixture of trans enantiomers. The mixture was further purified by chiral SFC (Chiralpak® AS-H column (Chiral Technologies, Inc., West Chester, Pa., USA), 15%/85% methanol+0.25% Dimethyl Ethyl Amine/CO2 to afford 1-1 (faster eluting). MS ESI calcd. for C28H26ClNO5 [M+H]+ 492, found 492. 1H NMR (499 MHz, DMSO-d6) δ 7.95 (d, J=7.7 Hz, 1H), 7.50-7.43 (m, 3H), 7.41-7.35 (m, 1H), 7.30-7.23 (m, 2H), 6.71 (d, J=8.3 Hz, 1H), 6.65-6.58 (m, 2H), 5.66 (s, 1H), 4.14 (s, 4H), 3.98 (s, 1H), 1.43 (s, 9H).
Example 2
(3S,4S or 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-2)
To a solution of 4-(tert-butyl)-3-chloroaniline (70 mg, 0381 mmol) in toluene (1.9 mL), 2-(carboxymethyl)-5-fluorobenzoic acid (Bioorg. Med Chem. Left., 2012, 22, 7707-7710) (76 mg, 0.381 mmol) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (63 mg, 0.381 mmol) were added at RT. The vial was sparged with nitrogen, sealed and brought to 110° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by mass triggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford a mixture of trans enantiomers. The mixture was further purified by chiral SFC (Chiralpak® AS-H column, 20%/80% methanol 0.25% Dimethyl Ethyl Amine/CO2) to afford 2-1-2 (faster eluting). MS ESI calcd. for C28H25ClFNO5[M+H]+ 510, found 510. 1H NMR (600 MHz, DMSO-d6) δ 7.60 (d, J=9.1 Hz, 1H), 7.46-7.40 (m, 2H), 7.31-7.20 (m, 3H), 6.68 (d, J=8.4 Hz, 1H), 6.61-6.52 (m, 2H), 5.64 (s, 1H), 4.11 (s, 4H), 3.94 (s, 1H), 1.39 (s, 9H).
Intermediate 1 for 1-56
7-(benzyloxy)isochromane-1,3-dione (I-1)
Step 1: Diisopropyl azodicarboxylate (DIAD) (1-1b) (6.9 g, 27 mmol) was added to a solution of methyl 5-hydroxy-2-(2-methoxy-2-oxoethyl)benzoate (1-1a) (3.0 g, 13.4 mmol) and triphenylphosphine (5.3 g, 20 mmol) in DCM (67 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 hours then concentrated under reduced pressure. The resulting residue was directly purified by silica gel chromatography to afford methyl 5-(benzyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (1-1c). MS ESI calcd. for C18H19O5 [M+H]+ 315, found 315.
Step 2: KOH (1.0M, 5.7 mL, 5.7 mmol) was added to a solution of methyl 5-(benzyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (I-1c) (0.3 g, 0.95 mmol) in dioxane (3.2 mL). The reaction mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and remaining aqueous solution was washed with ether. Aqueous solution adjusted to pH 7 with IM HCl (hydrochloric acid) then extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-(benzyloxy)-2-(carboxymethyl)benzoic acid (I-1d). MS ESI calcd. for C16H15O5 [M+H]+ 287, found 287.
Step 3: 5-(benzyloxy)-2-(carboxymethyl)benzoic acid (I-1d) (0.1 g, 0.35 mmol) was refluxed in a mixture of toluene (2.5 mL) and acetic anhydride (2.5 mL, 27 mmol) for 5 hours. The reaction mixture was concentrated under reduced pressure to afford 7-(benzyloxy)isochromane-1,3-dione (I-1). MS ESI calcd. for C16H13O4 [M+H]+ 269, found 269.
Compounds 1-3 through 1-64 disclosed in Table 1 were prepared in a manner analogous to Examples 1 and 2, using the appropriate amines and aldehydes from commercially available vendors.
TABLE 1
Exact Mass
Ex.
Structure
Name
[M + H]+
1-3
(3R,4R) or (3S,4S)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-[4-(1- methylethyl)phenyl]-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 444; found 444
1-4
(3S,4S) or (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(2,3-dihydro-1H- inden-5-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 442; found 442
1-5
(3R,4R) and (3S,4S)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(4-morpholin-4- ylphenyl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 487; found 487
1-6
(3R,4R) and (3S,4S)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-[4- (methylsulfonyl)phenyl]-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 480; found 480
1-7
(3R,4R) and (3S,4S)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-[4- (dimethylsulfamoyl)phenyl]-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 509; found 509
1-8
(3R,4R) and (3S,4S) (-2-[4-(1-cyano-1- methylethyl)phenyl]-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 469; found 469
1-9
(3R,4R) and (3S,4S)-2-(2-chloropyridin- 4-yl)-3-(2,3-dihydro-1,4-benzodioxin-6- yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 4-carboxylic acid
Calcd 437; found 437
1-10
(3R,4R) and (3S,4S)-2-(4- cyclopropylphenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 442; found 442
1-11
(3S,4S and (3R,4R))-2-[4-(4- acetylpiperazin-1-yl)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 528; found 528
1-12
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-{4-[1-(2- hydroxyethyl)-1H-pyrazol-4-yl]phenyl}- 1-oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 512; found 512
1-13
(3S,4S) and (3R,4R)-2-[4- (difluoromethoxy)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 468; found 468
1-14
(3S,4S) and (3R,4R)-2-(1,3-benzothiazol- 5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6- yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 4-carboxylic acid
Calcd 459; found 459
1-15
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(3,3-dimethyl-2- oxo-2,3-dihydro-1H-indol-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 485; found 485
1-16
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-2-[4-(1H- pyrazol-5-yl)phenyl]-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 468; found 468
1-17
(3S,4S) and (3R,4R)-2-(4-chloro-3- fluorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 454; found 454
1-18
(3S,4S) and (3R,4R)-2-(4-chloro-3- cyclopropylphenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 476; found 476
1-19
(3S,4S) and (3R,4R)-2-(3-cyano-4- morpholin-4-ylphenyl)-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 512; found 512
1-20
(3S,4S) and (3R,4R)-2-[3-chloro-4- (difluoromethoxy)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 502; found 502
1-21
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-[4-(2-hydroxy-1,1- dimethylethyl)phenyl]-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 474; found 474
1-22
(3S,4S) and (3R,4R)-2-(3-chlorophenyl)- 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 436; found 436
1-23
(3S,4S) and (3R,4R)-2-(3-chloro-4- morpholin-4-ylphenyl)-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 521; found 521
1-24
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(2-methylpyridin-4- yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 4-carboxylic acid
Calcd 417; found 417
1-25
(3S,4S and (3R,4R))-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-2-[4-(2,2,2- trifluoroethoxy)phenyl]-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 500; found 500
1-26
(3S,4S and (3R,4R))-2-{4-[(4- chlorophenyl)carbamoyl]phenyl}-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 555; found 555
1-27
(3S,4S) and (3R,4R)-2-(4- cyclohexylphenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 484; found 484
1-28
(3S,4S) and (3S,4R)-2-[4-(1- cyanocyclohexyl)phenyl]-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 509; found 509
1-29
(3S,4S) and (3S,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-2-(5,6,7,8- tetrahydronaphthalen-2-yl)-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 456; found 456
1-30
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(2-fluoropyridin-4- yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 4-carboxylic acid
Calcd 421; found 421
1-31
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-[6-(hydroxymethyl)- 5,6,7,8-tetrahydronaphthalen-2-yl]-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 486; found 486
1-32
(3S,4S) and (3R,4R)-2-(2-chloro-6- methylpyridin-4-yl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 451; found 451
1-33
(3S,4S) and (3R,4R)-2-(4-chloro-3- methylphenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 450; found 450
1-34
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(4- {[methylsulfonyl)amino]methyl}phenyl)- 1-oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 509; found 509
1-35
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(2,6- dimethylpyridin-4-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 431; found 431
1-36
(3S,4S) or (3R,4R)-2-[4-(1- cyanocyclohexyl)phenyl]-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 509; found 509
1-37
(3R,4R) or (3S,4S)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-2-(5,6,7,8- tetrahydronaphthalen-2-yl)-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 456; found 456
1-38
(3S,4S) and (3R,4R)-2-[3-chloro-4- (morpholin-4-ylmethyl)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 535; found 535
1-39
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(3,4- dimethylphenyl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 430; found 430
1-40
(3S,4S) or (3R,4R)-2-(3,4- dichlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 470; found 470
1-41
(3S,4S) and (3R,4R)-2-[4-(benzyloxy)-3- chlorophenyl]-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 542; found 542
1-42
(3S,4S) and (3R,4R)-2-(3-bromophenyl)- 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 480; found 480
1-43
(3S,4S) and (3R,4R)-2-(4-cyclopropyl-3- fluorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 460; found 460
1-44
(3S,4S) or (3R,4R)-2-[4-(1- cyanocyclohexyl)phenyl]-3-(3,4-dihydro- 2H-1,5-benzodioxepin-7-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 523; found 523
1-45
(3S,4S) and (3R,4R)-6-bromo-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-2-(2,3- dihydro-1H-inden-5-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 520; found 520
1-46
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-naphthalen-2-yl-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 42; found 452
1-47
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-2-(3,4,5- trichlorophenyl)-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 504; found 504
1-48
(3S,4S) and (3R,4R)-2-[3-chloro-4-(1- cyano-1-methylethyl)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 503; found 503
1-49
(3S,4S) and (3R,4R)-6-bromo-2-(3- chloro-4-methylphenyl)-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 528; found 528
1-50
(3S,4S) and (3R,4R)-7-bromo-2-(3- chloro-4-methylphenyl)-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 528; found 528
1-51
(3S,4S) and (3R,4R)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-(3,4-dihydro-1H- isochromen-7-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 458; found 458
1-52
(3R,4R) or (3S,4S)-2-(3-chloro-4- cyclohexylphenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 518; found 518
1-53
(3R,4R) and (3S,4S)-2-(4-tert-butyl-3- chlorophenyl)-3-(3,4-dihydro-2H- chromen-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 490; found 490
1-54
(3S,4S) and (3R,4R)-7-bromo-2-(4-tert- butyl-3-chlorophenyl)-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 570; found 570
1-55
(3S,4S) and (3R,4R)-2-(4-tert-butyl-3- chlorophenyl)-7-chloro-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 526; found 526
1-56
(3S,4S) and (3R,4R)-7-(benzyloxy)-2-(4- tert-butyl-3-chlorophenyl)-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 598; found 598
1-57
(3R,4R) or (3S,4S)-2-(4-tert-butyl-3- chlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-6-fluoro-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 510; found 510
1-58
(3R,4R) or (3S,4S)-2-(4-tert-butyl-3- chlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-6-fluoro-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 510; found 510
1-59
(3R,4R) or (3S,4S)-2-(4-tert-butyl-3- chlorophenyl)-7-chloro-3-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 526; Found 526
1-60
(3R,4R) or (3S,4S)-2-(4-tert-butyl-3- chlorophenyl)-3-(4-methyl-3,4-dihydro- 2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 505; Found 505
1-61
(3R,4R) or (3S,4S)-2-(4-tert-butyl-3- chlorophenyl)-3-(4-methyl-3,4-dihydro- 2H-1,4-benzoxazin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid
Calcd 505; Found 505
1-62
(3S,4S) or (3R,4R)-2-(4-tert-butyl-3- chlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-7-hydroxy-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 508; found 508
1-63
(3S,4S) or (3R,4R)-2-[3-chloro-4-(1- cyanocyclopropyl)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 501; found 501
1-64
(3R,4R) or (3S,4S)-2-[3-chloro-4-(1- cyanocyclopropyl)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 501; found 501
Example 3
(3R,4R and 3S,4S)-2-(4′-acetamido-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-xo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid (1-65)
Step 1 (3R,4R and 3S,4S)-2-(4′-amino-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-65) was synthesized following an analogous procedure to that reported for Example 1. MS APCI calcd for C30H25N2O5 [M+H]+ 493, found 493.
Step 2: To a solution of (3R,4R and 3S,4S)-2-(4′-amino-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (3-2) (8.0 mg, 0.016 mmol) in dichloromethane (4 mL) was added acetyl chloride (2 μL, 0.03 mmol) and Hunig's base (0.014 mL, 0.081 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Sodium hydroxide (1.0M in water, 0.065 mL, 0.065 mol) was added and the reaction mixture was stirred for an additional 2 hours at room temperature. The reaction mixture was quenched with TFA (0.013 mL, 0.162 mmol), concentrated under reduced pressure, and directly purified by reverse phase chromatography on a C18 column (CH3CN/H2O with 0.1% TFA) to afford (3R,4R and 3S,4S)-2-(4-acetamido-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-65). LCMS (C32H27N2O6) (ES, m/z) 535 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.04 (s, 1H), 8.00 (d, J=6.8 Hz, 1H), 7.68-7.63 (m, 4H), 7.60 (d, J=8.7 Hz, 2H), 7.53-7.49 (m, 1H), 7.47-7.43 (m, 1H), 7.38 (d, J=8.6 Hz, 2H), 733 (d, J=7.3 Hz, 1H), 6.76-6.62 (m, 3H), 5.63 (s, 1H), 4.23 (s, 1H), 4.14 (s, 4H), 2.06 (s, 3H).
Compound 1-66 found in Table 2, was prepared in a manner analogous to Example 3, using the appropriate amines from commercially available vendors.
TABLE 2
Exact Mass
Ex.
Structure
Name
[M + H]+
1-66
(3S,4S) and (3R,4R)-2-[4-(1- acetylpiperidin-4-yl)phenyl]-3-(2,3- dihydro-1,4-benzodioxin-6-yl)-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 527; found 527
Example 4
(3R,4R and 3S,4S)-2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid (1-67)
Step 1: To a solution of (3R,4R and 3S,4S)-2-(4′-amino-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (4-1) (10.0 mg, 0.016 mmol) in dichloromethane (1 mL) was added acetyl chloride (1 μL, 0.02 mmol) and N,N-diisopropylethylamine (Hunig's Base) (0.008 mL, 0.05 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Sodium hydroxide (1.0M in water, 0.094 ml, 0.094 mmol) was added and the reaction mixture was stirred for an additional 2 hours at room temperature. The reaction mixture was quenched with TFA (0.008 mL, 0.1 mmol), concentrated under reduced pressure, and directly purified by reverse phase chromatography on a C18 column. (CH3CN/H2O with 0.1% TFA) to afford (3R,4R and 3S,4S)-2-(4′-acetamido-2-chloro-[1,1′-biphenyl]-4-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-67). LCMS (C32H26ClN2O6) (ES, m/z) 569 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.08 (s, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.57-7.49 (m, 2H), 7.48-7.41 (m, 2H), 7.40-7.32 (m, 4H), 6.77-6.63 (m, 3H), 5.68 (s, 1H), 4.25 (s, 1H), 4.15 (s, 4H), 2.07 (s, 3H).
Example Compounds 1-68 through 1-70, found in Table 3, were prepared in a manner analogous to Example 4, using the appropriate amines from commercially available vendors.
TABLE 3
Exact Mass
Ex.
Structure
Name
[M + H]+
1-68
(3R,4R) and (3S,4S)-2-[4-(1- acetylpiperidin-4-yl)-3-rnethylphenyl]- 3-(2,3-dihydro-1,4-benzodioxin-6-yl)- 1-oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 541; found 541
1-69
(3R,4R) and (3S,4S)-2-{4-[cis-4- (acetylamino)cyclohexyl]phenyl}-3- (2,3-dihydro-1,4-benzodioxin-6-yl)-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 541; found 541
1-70
(3R,4R) and (3S,4S)-2-{4-[trans-4- (acetylamino)cyclohexyl]phenyl}-3- (2,3-dihydro-1,4-benzodioxin-6-yl)-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid
Calcd 541; found 541
Example 5
(3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (1-71)
Step 1: Methylamine HCl (16 mg, 024 mmol), HATU (28 mg, 0.073 mmol) and Hunig's base (32 μl, 0.18 mmol) were added to a racemic mixture of 2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-1) (30 mg, 0.061 mmol) in DMF (0.20 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography [(25% ethanol in ethyl acetate) in hexanes] to afford (3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (1-71). LCMS (C29H30ClN2O4) (ES, m/z) 505 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.05-7.87 (m, 2H), 7.49-7.29 (m, 4H), 7.24 (d, J=7.0 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.71-6.65 (m, 2H), 6.59 (d, J=83 Hz, 1H), 5.34 (s, 1H), 4.11 (s, 4H), 3.96 (s, 1H), 2.59 (d, J=4.0 Hz, 3H), 1.39 (s, 9H).
Example Compounds 1-72 through 1-74 found in Table 4, were prepared in a manner analogous to Example 5, using the appropriate amines from commercially available vendors.
TABLE 4
Exact Mass
Ex.
Structure
Name
[M + H]+
1-72
(3S,4S) or (3R,4R)-2-(4-tert-butyl-3- chlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-4-carboxamide
Calcd 491; found 491
1-73
(3S,4S) and (3R,4R)-2-(4-tert-butyl-3- chlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-N,N-dimethyl-1- oxo-1,2,3,4-tetrahydroisoquinoline-4- carboxamide
Calcd 519; found 519
1-74
(3S,4S) or (3R,4R)-2-(4-tert-butyl-3- chlorophenyl)-3-(2,3-dihydro-1,4- benzodioxin-6-yl)-7-fluoro-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4- carboxamide
Calcd 509; found 509
Example 6
(3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-75)
Step 1: (3S,4S and 3R,4R)-7-bromo-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-54) (40 mg, 0.068 mmol), potassium vinyltrifluoroborate (14 mg, 0.10 mmol) and PdCl2(dppf) (5 mg, 7 μmol) were combined and suspended in ethanol (0.7 mL). Triethylamine (0.024 mL, 0.17 mmol) was added to the mixture. The reaction mixture was heated to 90° C. for 1.5 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The product residue was purified by reverse phase chromatography on a C18 column (CH3CN/H2O with 0.1/TFA) to afford (3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][,4]dioxin-6-yl)-1-oxo-7-vinyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-75). LCMS (C30H29ClNO5) (ES, m/z) 518 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.98 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.38 (s, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 6.78 (dd, J=17.6, 10.9 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 6.60 (d, J=8.3 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.57 (s, 1m), 5.30 (d, J=10.9 Hz, 1H), 4.18 (s, 1H), 4.11 (s, 4H), 1.39 (s, 9H).
Intermediate 2
tert-butyl (4′-amino-2′-chloro-[1,1′-biphenyl]-4-yl)carbamate (1-2)
Step 1: A mixture of 4-bromo-3-chloroaniline (1-2a) (250 mg, 1.2 mmol) (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (1-2b) (287 mg, 1.21 mmol), Pd2(dba)3 (55 mg, 0.061 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos) (58 mg, 0.12 mmol), and cesium carbonate (789 mg, 2.42 mmol) was degassed with argon for 3 minutes. Dioxane (4.0 mL) and water (0.4 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 5 minutes at room temperature while degassing with argon. The reaction mixture was then heated to 95° C. and stirred for 6 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (25 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (eluting ethyl acetate in hexanes) to afford tert-butyl (4′-amino-2′-chloro-[1,1′-biphenyl]-4-yl)carbamate (I-2) LCMS (C17H20ClN2O2) (ES, m/z) 319 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.55 (dd, J=8.3, 2.2 Hz, 1H), 5.43 (s, 2H), 1.48 (s, 9H).
Intermediate 3
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (I-3)
Step 1: DIBAL-H (1-3b) (1.0M in THF, 5.3 mL, 5.3 mmol) was added dropwise to a solution of methyl 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (I-3a) (500 mg, 2.41 mmol) in tetrahydrofuran (5.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C. and additional DIBAL-H (1.0M in THF, 6.0 mL, 6.0 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was then stirred for 1 hour at room temperature. The reaction mixture was cooled to 0° C. under a stream of argon gas. The mixture was quenched with saturated aqueous ammonium chloride solution under a stream of argon gas. Additional water was added (50 mL) and the mixture was diluted with ethyl acetate (50 mL) and methanol (50 mL). The resulting suspension was filtered and the filtrate was concentrated under reduced pressure, azeotroping several times with acetonitrile, to afford the crude product residue. The isolated residue was suspended in methanol and filtered. The filtrate was purified by silica gel chromatography (eluting [5% methanol in ethyl acetate] in dichloromethane) to afford (4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methanol (I-3c). LCMS (C10H14NO2) (ES, m/z) 180 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 6.64 (s, 1H), 6.58 (d, J=8.0 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 4.94 (t, J=5.7 Hz, 1H), 4.34 (d, J=5.7 Hz, 2H), 4.23-4.16 (m, 2H), 3.24-3.16 (m, 2H), 2.81 (s, 3H).
Step 2: Dess-Martin periodinane (1-3d) (1270 mg, 3.00 mmol) was added portion wise to a solution of (4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methanol (I-3c) (430 mg, 2.4 mmol) in dichloromethane (5.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was then stirred for 1 hour at room temperature. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution (25 mL), and the mixture was then diluted with ethyl acetate (250 mL) and water (25 mL). The organic layer was separated, and the aqueous layer was washed with additional ethyl acetate (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (eluting ethyl acetate in hexanes) to afford 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (I-3). LCMS (C10H12NO2) (ES, m/z) 178 [M+]+. 1H NMR (499 MHz, DMSO-d6) δ 9.77 (s, 1H), 7.19 (dd, J=8.1, 1.7 Hz, 1H), 7.14 (d, J=1.4 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.36-4.29 (m, 2H), 3.31-3.25 (m, 2H), 2.89 (s, 3H).
Intermediate 4
tert-butyl 4-(4-amino-2-methylphenyl)piperidine-1-carboxylate (I-4)
Step 1: A mixture of 4-bromo-3-methylaniline (I-4a) (1.23 g, 6.61 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (I-4b) (1.50 g, 6.61 mmol), Pd2(dba)3 (0.30 g, 0.33 mmol), 2-Dicyclohexylphosphino-2′4′6′-triisopropylbiphenyl (X-phos) (0.32 g, 0.66 mmol), and cesium carbonate (431 g, 13.2 mmol) was degassed with argon for 3 minutes. Dioxane (10.0 mL) and water (1.0 mL) were added to the mixture at room temperature. The reaction mixture was stirred for 5 minutes while degassing with argon, and then the mixture was heated to 90° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with brine (50 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (eluting ethyl acetate in hexanes) to tert-butyl 4-(4-amino-2-methylphenyl)-5,6-dihydropyridine-(2H)-carboxylate (I-4c). LCMS (C17H25N2O2) (ES, m/z) 289 [M+H]+. 1H NMR (499 MHz, DMSO-de) 6.73 (d, J=8.1 Hz, 1H), 6.36 (s, 1H), 6.35-6.30 (m, 1H), 5.42 (s, 1H), 4.92 (s, 2H), 3.90 (s, 2H), 3.48 (s, 2H), 2.20 (s, 2H), 2.09 (s, 3H), 1.42 (s, 9H).
Step 2: A flask containing tert-butyl 4-(4-amino-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I-4c) (1.68 g, 5.83 mmol) and palladium on carbon (0.310 g, 0.291 mmol) was degassed with argon for 5 minutes. Ethanol (20 mL) and hydrochloric acid (370 in water, 0.96 mL, 12 mmol) were added under a stream of argon. The headspace above the reaction mixture was evacuated by vacuum and backfilled with hydrogen gas. The reaction mixture was stirred under a hydrogen atmosphere for 18 hours at room temperature. The reaction mixture was filtered through Celite™ and washed with methanol. The filtrate was concentrated under reduced pressure to afford the crude product residue. The crude product residue was suspended in ethyl acetate (250 mL) and diluted with saturated aqueous sodium bicarbonate solution (50 mL). The mixture was stirred until all solids had dissolved. The organic layer was separated and washed with brine (25 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (eluting ethyl acetate in hexanes) to afford the product. A portion of the isolated product was further purified by reverse phase HPLC (eluting acetonitrile in water with 0.1% TFA modifier) to afford tert-butyl 4-(4-amino-2-methylphenyl)piperidine-1-carboxylate (I-4) LCMS (C17H27N2O2—C4H8) (ES, m/z) 235 [M+H-tBu]+. 1H NMR (499 MHz, DMSO-d6) δ 9.06 (s, 2H), 7.21 (d, J=8.1 Hz, 1H), 6.98-6.93 (m, 2H), 4.06 (s, 2H), 2.84 (t, J=11.9 Hz, 2H), 2.30 (s, 3H), 1.64 (d, J=12.8 Hz, 2H), 1.48-1.40 (m, 3H), 1.41 (s, 9H)
Intermediate 5
tert-butyl ((cis)-4-(4-aminophenyl)cyclohexyl)carbamate and tert-butyl ((trans)-4-(4-aminophenyl)cyclohexyl)carbamate (I-5)
Step 1: A mixture of 4-bromoaniline (I-5b) (500 mg, 2.91 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (1-5a) (940 mg, 2.91 mmol), Pd2(dba)3 (133 mg, 0.145 mmol), X-phos (139 mg, 0.291 mmol), and cesium carbonate (1.9 g, 5.8 mmol) was degassed with argon for 3 minutes. Dioxane (8.0 mL) and water (0.8 mL) were added to the mixture at room temperature. The reaction mixture was stirred for 5 minutes while degassing with argon, and then the reaction mixture was heated to 90° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (250 ml), and washed with brine (50 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (eluting ethyl acetate in hexanes) to afford tert-butyl (4′-amino-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate (I-5c) LCMS (C17H25N2O2) (ES, m/z) 289 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.07 (d, J=8.5 Hz, 2H), 6.83-6.74 (M, 1H), 6.48 (d, J=8.6 Hz, 2H), 5.79 (s, 1H), 5.04 (s, 2H), 3.50-3.42 (m, 1H), 2.45-2.25 (m, 3H), 2.07-1.94 (m, 1H), 1.92-1.81 (m, 1H), 1.53-1.45 (m, 1H), 1.39 (s, 9H).
Step 2: A flask containing tert-butyl (4′-amino-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate (1-4c) (580 mg, 2.0 mmol) and palladium on carbon (107 mg, 0.101 mmol) was degassed with argon for 5 minutes. Ethanol (20 ml) and hydrochloric acid (37% in water, 0.50 mL, 6.0 mmol) were added under a stream of argon. The headspace above the reaction mixture was evacuated by vacuum and backfilled with hydrogen gas. The reaction mixture was stirred under a hydrogen atmosphere for 6 hours at room temperature. The reaction mixture was filtered through Celite™ and washed with methanol. The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was suspended in ethyl acetate (250 mL) and diluted with saturated aqueous sodium bicarbonate solution (50 mL). The mixture was stirred until all solids had dissolved. The organic layer was separated and washed with brine (25 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (eluting ethyl acetate in hexanes) to afford the product as a mixture of cis/trans isomers. The isolated product was further purified by reverse phase HPLC (eluting acetonitrile in water with 0.1% TFA modifier) to afford tert-butyl (4-(4-aminophenyl)cyclohexyl)carbamate as a mixture of cis/trans isomers. tert-Butyl (4-(4-aminophenyl)cyclohexyl)carbamate 2,2,2-trifluoroacetate (1-5) was separated into pure stereoisomers (Chiralpak® AS-H, 21×250 mm, eluting methanol+0.25% dimethyl ethyl amine in CO2) to afford two peaks eluting at 2.58 minutes and 4.00 minutes.
Peak 1: tert-butyl ((cis)-4-(4-aminophenyl)cyclohexyl)carbamate: LCMS (CH17H26N2O2+Na) (ES, m/z) 313 [M+Na]+. 1H NMR (499 MHz, DMSO-d6) δ 6.96-6.90 (m, 3H), 6.47 (d, J=7.8 Hz, 2H), 4.77 (s, 2H), 3.66 (s, 1H), 2.31-2.25 (m, 1H), 1.75-1.62 (m, 4H), 1.58-1.42 (m, 4H), 1.40 (s, 9H).
Peak 2: tert-butyl ((trans)-4-(4-aminophenyl)cyclohexyl)carbamate: LCMS (C17H27N2O2—C4H8) (ES, m/z) 235 [M+H-tBu]+. 1H NMR (499 MHz, DMSO-d6) δ 6.85 (d, J=8.3 Hz, 2H), 6.73 (d, J=7.9 Hz, 1H), 6.46 (d, J=8.2 Hz, 2H), 4.79 (s, 2H), 3.27-3.19 (m, 1H), 2.26-2.18 (m, 1H), 1.82 (d, J=11.0 Hz, 2H), 1.70 (d, J=12.0 Hz, 2H), 1.42-1.31 (m, 2H), 1.38 (s, 9H), 1.29-1.19 (M, 2H)
Example 7
(3R,4R or 3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-76)
Step 1: To a stirred solution of methyl 3,4-dihydroxybenzoate (7-a) (7.0 g, 41.6 mmol) in DMF (70 mL) was added dimethylcarbamothioic chloride (20.58 g, 166.5 mmol) followed by 1,4-diazabicyclo[2.2.2]octane (DABCO)(1868 g, 166.5 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (3×50 mL), washed with water (3×50 mL) and brine solution. The mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure. To the crude compound was added ethanol (100 mL) and kept at room temperature for 16 h. The resulting solid was filtered and dried to afford methyl 3,4-bis((dimethylcarbamothioyl)oxy)benzoate (7-b). MS ESI calcd for C14H19N2O4S2 [M+H]+ 343 found 343. 1H NMR (400 MHz, CDCl3) δ57.99 (dd, J=8.4 Hz, 2.0 Hz, 1H) 7.85 (d, J=2.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.43 (d, J=1.7 Hz, 6H), 3.30 (d, J=2.6 Hz, 6H)
Step 2: To the compound methyl 3,4-bis ((dimethylcarbamothioyl)oxy)benzoate (7-b) (4.5 g, 13.1 mmol) was added diphenyl ether (145 mL). The reaction mixture was stirred at 290° C. for 1.5 h with vigorous stirring. The reaction mixture was cooled to room temperature, and then purified by column chromatography on silica by using 6% ethylacetate/hexanes as eluent to afford methyl 2-oxobenzo[d][1,3]dithiole-5-carboxylate (7-c). MS ESI calcd for C9H7O3S2 [M+H]+ 226 found 226.
Step 3: To the compound methyl 2-oxobenzo[d][1,3]dithiole-5-carboxylate (7-c) (1.2 g, 5.30 mmol) was added IM NaOH aqueous solution (50 mL) The reaction mixture was stirred at 75° C. for 4 h. The reaction mixture was cooled to 0° C., acidified by using 1N HCl (100 mL). The resulting solid was filtered and dried to afford 3,4-dimercaptobenzoic acid (7-d). MS ESI calcd for C7H7O2S2 [M+H]+ 186 found 186.
Step 4: To a stirred solution of 3,4-dimercaptobenzoic acid (7-d) (780 mg, 4.2 mmol) in methanol (15 mL) was added 2 drops of sulfuric acid. The solution was allowed to stir at 75° C. for 16 h. The reaction mixture then was concentrated. The resulting residue was basified by using saturated NaHCO3 solution, extracted with ethyl acetate (30 mL), washed with water (10 mL) and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 3,4-dimercaptobenzoate (7-e). MS ESI calcd for C8H9O2S2 [M+H]+ 201 found 201.
Step 5: To a stirred solution of methyl 3,4-dimercaptobenzoate (7-e) (750 mg, 3.75 mmol) in acetone (20 mL) was added potassium carbonate (1.55 g, 11.25 mmol) followed by 1,2-dibromoethane (1.76 g, 9.37 mmol). The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite™, the filtrate was concentrated. The crude compound was purified by column chromatography on silica by using 10% ethylacetate/hexanes as eluent to afford methyl 2,3-dihydrobenzo[b][1,4]dithiine-6-carboxylate (7-f). MS ESI calcd for C10H11O2S2 [M+H]+ 227 found 227. 1H NMR (400 MHz, CDCl3) 7.81 (s, 11H), 7.61 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 3.88 (s, 3H), 3.37-3.23 (m, 4H).
Step 6: To a stirred solution of methyl 2,3-dihydrobenzo[b][1,4]dithiine-6-carboxylate (7-f) (350 mg, 1.54 mmol) in anhydrous dichloromethane (15 mL) at −78° C., DiBAL-H (3.5 mL, 2.32 mmol) was added. The reaction mixture was stirred at −78° C. for 1.5 h, then slowly warmed to room temperature and stirred for an additional 1 h. The reaction mixture was quenched with ammonium chloride solution, extracted with dichloromethane (30 mL), washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica by using 20% ethylacetate/hexanes as eluent to afford (2,3-dihydrobenzo[b][1,4]dithiin-6-yl)methanol (7-g). MS ESI calcd for C9H11OS2 [M+H]+ 199 found 199. 1H NMR (400 MHz, CDCl3) δ7.17 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 3.26 (s, 4H), 1.60 (s, 1H).
Step 7: To a stirred solution of (2,3-dihydrobenzo[b][1,4]dithiin-6-yl)methanol (7-g) (240 mg, 1.21 mmol) in dichloromethane (10 mL) was added dessmartin periodinane (DMP) (770 mg, 1.81 mmol). The reaction mixture was stirred at room temperature for 3 h. Then the reaction mixture was diluted with DCM (30 mL), washed with aqueous Na2S2O4 solution, aqueous NaHCO3 solution, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica by using 6% ethylacetate/hexanes as eluent to afford 2,3-dihydrobenzo[b][1,4]dithiine-6-carbaldehyde (7-h). MS ESI calcd for C9H9OS2[M+H]+ 197 found 197. 1H NMR (400 MHz CDCl3) δ9.84 (s, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.46 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.27 (s, 1H), 3.39-3.25 (m, 4H).
Step 8: To the compound 2-(carboxymethyl)benzoic acid (60 mg, 0.33 mmol), 4-(tert-butyl)-3-chloroaniline (61 mg, 0.33 mmol), 2,3-dihydrobenzo[b][1,4]dithiine-6-carbaldehyde (7-h) (65 mg, 0.33 mmol) was added toluene (3.0 mL), kept in a dean-stark apparatus, stirred at 140° C. for 24 h. To the reaction mixture was added ethyl acetate (15 mL). The mixture then was washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by reverse phase column chromatography by using 70% acetonitrile/water as eluent to afford 2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dithiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ13.14 (s, 1H), 7.98 (dd, J=7.8 Hz, 1.6 Hz, 1H), 7.54-7.41 (m, 4H), 7.32 (d, J=7.4 Hz, 1H), 7.21 (dd, J=8.6 Hz, 2.2 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 6.79 (dd, J=8.6 Hz, 2.2 Hz, 1H), 5.63 (s, 1H), 3.21 (s, 4H), 1.43 (s, 9H).
Step 9: Isomers were separated by SFC, IA column eluting with 15% MeOH and CO2 to give isomer I 1-76 (fast eluting) 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.2 Hz, 1H), 7.41-7.32 (m, 4H), 7.15-7.10 (m, 2H), 6.99-6.92 (m, 2H), 6.70 (dd, J=8.0, 1.6 Hz, 1H), 5.48 (s, 1H), 3.88 (s, 1H), 3.19 (s, 4H), 1.41 (s, 9H). MS ESI calcd for C28H26ClNO3S2 [M+H]+ 524 found 524.
Example 8
(3R,4R or 3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-77)
Step 1: To a stirred solution of 1,2-dibromoethane (1.51 mL, 17.58 mmol in acetone (90 ml), potassium carbonate (4.86 g, 35.2 mmol) was added at RT. To this reaction mixture, 2-mercaptobenzene-1,4-diol (8-a) (2.50 g, 1.58 mmol) in acetone (30 ml) was added slowly over period of 20 minutes at RT. The reaction mixture was stirred at RT for 16 hours and then filtered through Celite™ bed and the solvent was concentrated under reduced pressure. The residue was diluted with EtOAc (150 mL) and water (50 mL), and the layers were separated. The organic fraction was washed with brine (100 mL), dried (Na2SO4), and filtered. The filtrate then was concentrated under reduced pressure. The residue was purified by column chromatography on silica (0 to 60 EtOAc/Hexanes) to afford 2,3-dihydrobenzo[b][1,4]oxathiin-6-ol (8-b). 1H NMR (400 MHz, CDCl3) δ 669 (d, J=8.8 Hz, 1H), 6.53 (d, J=3.0 Hz, 1H), 6.49-6.45 (m, 1H), 4.70 (S, 1H), 4.36-4.32 (m, 2H), 3.13-3.08 (m, 2H)
Step 2: To a stirred solution of 2,3-dihydrobenzo[b][1,4]oxathiin-6-ol (8-b) (50 mg, 0.297 mmol) in DCM (1 ml), pyridine (0.048 ml, 0.594 mmol) and trifluoromethane sulfonic anhydride (Tf2O) (0.065 ml, 0.386 mmol) were added at −78° C. The reaction mixture was stirred at RT for 16 hours under nitrogen atmosphere. The reaction mixture then was diluted with DCM (10 mL) and water (10 mL), and the layers separated. The organic layer washed with aq solution of 1N HCl (10 mL) and aq sat NaHCO3 solution (10 mL) and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2,3-dihydrobenzo[b][1,4]oxathiin-6-yl trifluoromethanesulfonate (8-c). 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=2.8 Hz, 1H), 6.89-6.81 (m, 2H), 4.45-4.38 (m, 2H), 3.16-3.10 (m, 2H).
Step 3: To a stirred solution of 2,3-dihydrobenzo[b][1,4]oxathiin-6-yl trifluoromethane sulfonate (8-) (100 mg, 0.333 mmol) in DMF (1.2 ml) and MeOH (0.6 ml), Et3N (0.186 ml, 1332 mmol), Pd(OAc)2 (14.95 ng, 0.067 mmol) and 1,3-bis(diphenylphosphino)propane (dppp) (27.5 mg, 0.067 mmol) were added at RT under nitrogen atmosphere. The reaction mixture was purged with carbon monoxide (balloon) for 30 minutes and then the vessel was sealed and the reaction was stirred for 16 hours at 80° C. under carbon monoxide atmosphere. The mixture was cooled, filtered through a Celite™ bed, washed with EtOAc (20 mL) and water (15 mL), and the layers separated. The organic layer washed with brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0 to 60% EtOAc/Hexanes) to afford methyl 2,3-dihydrobenzo[b][1,4]oxathiine-6-carboxylate (8-d). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.1 Hz, 1H), 7.67-7.63 (m, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.49-4.44 (m, 2H) 3.86 (S, 3H), 3.16-3.08 (M, 2H).
Step 4: To a stirred solution of methyl 2,3-dihydrobenzo[b][1,4]oxathiine-6-carboxylate (8-d) (500 mg, 2.378 mmol) in THF (20 mL), DIBAL-H (IM in THF, 7.13 ml, 7.13 mmol) was added at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 36 hours RT under nitrogen atmosphere. The reaction mixture was quenched with sat. NH4Cl (30 mL) and the mixture was extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (30 mL), dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (0 to 60% EtOAc/H exanes) to afford (2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methanol (8-e). 1H NMR (400 MHz, CDCl3) δ 7.03-7.01 (m, 1H), 6.96-6.91 (m, 1H), 6.78 (d, J=8.3 Hz, 1H), 4.50-4 (s, 2H), 4.40-434 (m, 2H), 3.13-3.07 (m, 2H) 2.06 (brs, 1H).
Step 5: To a stirred solution of (2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methanol (8-e) (410 mg, 2.250 mmol) in DCM (12 ml), Dess-Martin periodinane (DMP) (1.431 g, 3.37 mmol) was added under N2 nitrogen atmosphere at 0° C. The reaction mixture was stirred for 3 hours at RT. The reaction mixture was diluted with DCM (20 mL) and water (20 mL), and then the layers were separated. The organic layer washed with aq. solution of sodium thiosulfate (20 mL) and aq. sat aq NaHCO3 solution (20 mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0 to 60% EtOAc/Hexanes) to afford 2,3-dihydrobenzo[b][1,4]oxathiine-6-carbaldehyde (8-f). NMR (400 MHz, CDCl3) 9.80 (s, 1H) 7.59 (d, J=2.0 Hz, 1H), 7.53-7.49 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 4.52-4.47 (m, 2H), 3.17-3.11 (m, 2H).
Step 6: To a stirred solution of 4-(tert-butyl)-3-chloroaniline (1-a) (100 mg, 0.544 mmol) in toluene (5 ml), homophthalic anhydride (1-b) (88 mg, 0.544 mmol) and 2,3-dihydrobenzo[b][1,4]oxathiine-6-carbaldehyde (8-f) (98 mg, 0.544 mmol) were added under N2 nitrogen atmosphere at RT. The reaction mixture was refluxed for 16 hours at 120° C. using a dean-stark apparatus. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica (0 to 60% EtOAc/Hexanes) to afford (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-77 racemic). MS ESI calcd for C28H26ClNO4S [M+H]+ 508, found 508, 510.
Step 7: (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid 130 mg, 0.256 mmol) (Racemic mixture) was separated by chiral SFC (IA column, 25% MeOH in 0.1% TFA/CO2) to afford (3R,4R)-2-(4-(tert-buty)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid. (Enantiomer A, first eluting) 1-77: MS ESI calcd for C28H26ClNO4S [M+H]+ 508, found 508, 510. 1H NMR (400 MHz, CDCl3) δ 8.10-8.05 (m, 1H) 7.54-7.42 (m, 3H), 738 (d, J=2.2 Hz, 1H), 7.32-7.28 (m, 1H), 7.18-7.14 (m, 1H), 6.79-6.77 (m, 1H), 6.74-6.69 (m, 1H), 6.65-661 (m, 1H), 5.51 (s, 1H), 4.32-4.24 (m, 2H), 4.10 (s, 1H), 4.08-4.01 (m, 2H), 1.46 (s, 9H).
Example 9
(3R,4R or 3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-78)
Step 1: To solution of methyl 3-(2-(acetylthio)ethoxy)-4-iodobenzoate (9-a) (1 g, 2.63 mmol) [prepared from methyl 3-hydroxy-4-iodobenzoate as reported in Organic Letters, 15(3), 550-553; 2013] in MeOH (2 ml) was added sodium methoxide (NaOMe) (213 mg, 3.95 mmol). The reaction was stirred for 1 hour at room temperature and then quenched with 1 N aqueous HCl (5.0 mL). The reaction mixture was extracted with EtOAc (3×20 ml) and the organic layer was washed with brine (5.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (4 g, 0 to 10% EtOAc/Hexane) to afford methyl 4-iodo-3-(2mercaptoethoxy)benzoate (9-b). (400 MHz, CDCl3) δ 7.85 (d, J=9.5 Hz, 1H), 7.43-7.37 (m, 2H), 4.26 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.93 (d, J=6.0 Hz, 2H).
Step 2: To a solution of methyl 4-iodo-3-(2-mercaptoethoxy)benzoate (9-b) (450 mg, 1.331 mmol) in THF (1.5 ml) was added trimethylamine (Et3N) (0.371 ml, 2.66 mmol) and Pd(Ph3P)4 (tetrakis(triphenylphosphine)palladium(0)) (77 mg, 0.067 mmol). The reaction mixture was stirred for 6 hours at 65° C., and then quenched with 1N aqueous HCl (5.0 mL) and extracted with EtOAc (3×20 ml). The organic layer was washed with brine (5.0 mL) and dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (24 g, 0 to 50% EtOAc/Hexane) to afford methyl 2,3-dihydrobenzo[b][1,4]oxathiine-6-carboxylate (9-c). (400 MHz, CDCl3) δ 7.48 (m, 2H), 7.02 (d, J=8.0 Hz, 1H), 4.80 (d, J=4.8 Hz, 2H), 3.87 (s, 3H), 3.16 (d, J=4.8 Hz, 2H).
Step 3: To the solution of methyl 2,3-dihydrobenzo[b][1,4]oxathiine-7-carboxylate (9-c) (220 mg, 1.046 mmol) was added DIBAL-H (2.61 mL, 2.62 mmol) at −78° C. The resulting reaction mixture was stirred at −−78° C. for 3 hours. The reaction mixture was quenched with MeOH (2 ml) and extracted with EtOAc (3×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography on silica gel (24 g, 0 to 50% EtOAc/Hexane) to afford (2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)methanol (9-d). (400 MHz, CDCl3) δ 7.01 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 4.58 (bs, 2H), 4.57 (d, J=12 Hz, 2H), 3.14 (d, J=12.0 Hz, 2H).
Step 4: To the solution of (2,3-dihydrobenzo[b][1,4]oxathiin-7-yl)methanol (9-d) (130 mg, 0.713 mmol) in DCM (2 ml) was added dessmartin periodinane (DMP) (454 mg, 1.070 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with 1N aq Na2SO3 (5 ml) and extracted with DCM (3×30 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (4 g, 0 to 10% EtOAc/Hexane) to afford 2,3-dihydrobenzo[b][1,4]oxathiine-7-carbaldehyde (9-e). (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.37-7.29 (m, 2H), 7.18 (d, J=8.0 Hz, 1H), 4.44 (d, J=9.2 Hz, 2H), 3.18 (d, J=9.2 Hz, 2H).
Step 5: To a mixture of 2,3-dihydrobenzo[b][1,4]oxathiine-7-carbaldehyde (9-e) (95 mg, 0.527 mmol) in toluene (4 ml) was added 2-(carboxymethyl)benzoic acid (9-f) (95 ng, 0.527 mmol) and 4-(tert-butyl)-3-chloroaniline (1-a) (97 mg, 0.527 mmol). The resulting reaction mixture was stirred for 5 hours at 130° C. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (4 g, 0 to 10% MeOH/CH2Cl2) to afford (3R,4R or 3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-7 yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4 carboxylic acid. The racemate mixture was separated by SFC, IA column eluting with 15% MeOH and CO2 to afford 1-78 as second eluting isomer. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=2.8 Hz, 1H), 7.50-7.29 (m, 4H), 7.20-7.15 (m, 2H), 688 (d, J=8.8 Hz, 1H), 6.61-6.59 (m, 2H), 5.47 (s, 1H), 4.32 (d, J=3.2 Hz, 2H), 3.97 (s, 1H), 3.04 (d, J=4.0 Hz, 2H), 1.4 (s, 9H). MS ESI calcd for C28H26ClNO4S [M+H]+ 508 found 508.
Example 10
(3R,4R) and (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (1-79)
Step 1: To a solution of (3R,4R) and (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-1) (100 mg, 0.203 mmol) in DMF (1.0 mL) were added O-(tetrahydro-2h-pyran-2-yl)hydroxylamine (119 mg, 1.016 mmol), N,N-diisopropylethylamine (263 mg, 2.033 mmol) and HATU (100 mg, 0.264 mmol) at room temperature. The reaction mixture was continued stirring for 3 hours before 3N aqueous HCl was added and the pH was adjusted to 2. The reaction mixture was stirred for another hour. The reaction mixture was diluted with water (10 mL), extracted using EtOAc (20 ml). The layers were separated and solvent was evaporated. The crude product was purified by column chromatography on C-18 column using 0 to 100% acetonitrile/water to afford (3R,4R) and (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-1-oxa-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (1-79). (400 MHz, CDCl3) δ 8.27 (d, J=8.5 Hz, 1H), 7.54-7.48 (m, 2H), 7.36-7.30 (m, 2H), 7.14-7.12 (m, 2H), 6.70-6.57 (m, 3H), 5.73 (s, 1H), 4.16 (s, 4H), 3.93 (s, 1H), 1.43 (s, 9H). MS ESI calcd for C28H27ClN2O5 [M+H]+ 507 found 507.
Example 11
(3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-80)
(3R,4R and 3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(chroman-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, (1-80) were prepared by following an analogous procedure to that reported for Example 1 using commercially available chromane-6-carbaldehyde. MS ESI calcd for C29H29ClNO4 [M+H]+ 490, found 490. 1H NMR (400 MHz, CDCl3) δ 8.23-8.18 (m, 1H), 7.49-739 (m, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.20-7.18 (m, 1H), 7.15 (dd, J=8.4, 2.4 Hz, 1H), 6.81 (dd, J=8.4, 2.4 Hz, 1H), 6.79-6.73 (m, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.49 (s, 1H), 4.10 (t, J=4.8 Hz, 2H), 3.97 (s, 1H), 2.69-2.50 (m, 2H), 198-185 (m, 2H), 1.43 (s, 9H).
Example 12
(3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-81)
Step 1: To a solution of 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (12-a) (1.00 g, 4.67 mmol) in CH2CH2 (30 mL) was added di-tert-butyl dicarbonate ((Boc)2O) (1.63 mL, 7.01 mmol), DIPEA (1.63 ml, 9.34 mmol) and DMAP (57 mg, 0.47 mmol) at rt. The resulting mixture was stirred at rt for 2 days under a nitrogen atmosphere. To the reaction mixture was added water (20 mL) and the mixture was stirred for 5 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (×2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-100% EtOAc/hexanes to afford tert-butyl 6-bromo-2R-benzo[b][1,4]oxazine-4(3H)-carboxylate. 1H NMR (400 MHz, CDCl3) δ 8.01 (br s, 1H), 7.06 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.24-4.18 (m, 2H), 3.86-3.81 (m, 2H), 1.55 (s, 9H).
Step 2: To a solution of ter-butyl 6-bromo-2H-benzo[b][1,4]oxazine-4(3)-carboxylate (400 ng, 1.27 mmol) in THF (13 mL) was added n-butyllithium (0.83 ml, 1.7 mmol) dropwise at −78° C. After stirring at −78° C. for 30 min, DMF (0.98 ml, 12.7 mmol) was then added to the reaction mixture and stirred at −78° C. for 1 h. The mixture was quenched with water (10 mL) diluted with EtOAc (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). The combined organic extracts were dried anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a RediSep® 12 g silica gel column (Teledyne ISCO, Lincoln, Nebr. USA) using 0-100% EtOAc/hexanes to afford tert-butyl 6-formyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (12-b). 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 8.37 (br s, 1H), 7.54 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.32 (t, J=4.4 Hz, 2H), 3.90 (t, J=4.4 Hz, 2H), 1.57 (s, 9H).
Step 3: To a solution of tert-butyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (12-b) (105 mg, 0.400 mmol) in toluene (10 mL) was added 4-(tert-butyl)-3-chloroaniline (1-a) (70 mg, 0.38 mmol) and homophthalic acid (9-) (72 mg, 0.40 mmol) at rt. The resulting mixture was heated under reflux for 4 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on a silica gel column using 0-30% MeOH/CH2Cl2 followed by reverse phase chromatography on a C18 column using (0-100% ACN/water) and then semi-prep HPLC (ACN/water with 0.05% TFA modifier) to afford (3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-81). MS ESI calcd for C28H28ClN2O4 [M+H]+ 491, found 491. 1H NMR (400 MHz, CD3OD) δ 8.07 (dd, J1=7.6 Hz, J2=1.6 Hz, 1H), 7.55-7.49 (m, 1H), 7.49-7.44 (m, 2H), 7.40 (d, J=2.41 Hz, 1H), 7.33-7.28 (m, 1H), 7.20 (dd, J=8.8 Hz, J2=2.4 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.48-6.39 (m, 2H), 5.49-5.44 (m, 1H), 4.16-4.07 (m, 3H), 3.29-3.26 (m, 2H), 1.47 (s, 9H).
Example 13
(3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-82)
Step 1: To a solution of 6-bromo-3,4-dihydro-2R-benzo[b][1,4]oxazine (12-a) (500 mg, 2.34 mmol) in DMA (5 mL) was added sodium bicarbonate (589 mg, 7.01 mmol) and 2-iodopropane (1.17 mL, 11.7 mmol) at rt. The resulting mixture was heated at 80° C. for 3 d. The mixture was diluted with water and washed with ice water (5 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a RediSep 24 g silica gel column using 0-100% EtOAc/hexanes to afford 6-bromo-4-isopropyl-3,4-dihydro-2-benzo[b][1,4]oxazine (13-a). MS ESI calcd for C11H15BrNO [M+H]+ 256, found 256.
Step 2: To a solution of 6-bromo-4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (13-a) (340 mg, 1.33 mmol) in THF (12 mL) was added n-butyllithium (0.86 mL, 1.73 mmol) dropwise at −78° C. After stirring at −78° C. for 30 min, DMF (1.03 mL, 133 mmol) was then added dropwise to the mixture and stirred at −78° C. for 1 h. The mixture was diluted with EtOAc and quenched with sat. aq. NH4Cl (ammonium chloride) solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (×2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-100% EtOAc/hexanes to afford 4-isopropyl-3,4-dihydro-2-benzo[ ][1,4]oxazine-6-carbaldehyde (13-b). MS ESI calcd for C12H16NO2 [M+H]+ 206, found 206.
Step 3: To a solution of 4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (13-b) (150 mg, 0.73 mmol) in toluene (10 mL) was added 4-(tert-butyl)-3-chloroaniline (1-a) (128 mg, 0.70 mmol) and di-acid (9-f) (132 mg, 0.730 mmol) at rt. The resulting mixture was heated under reflux for 3 d. The solvent was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on a silica gel column using 0-30% MeOH/CH2Cl2 followed by reverse phase chromatography on a C18 column (0-100% ACN/water) and then semi-prep HPLC (ACN/water with 0.05% TFA modifier) to afford (3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-82). MS ESI calcd for C31H34ClN2O4 [M+H]+ 533, found 533. 1H NMR (400 MHz, CD30D) 8.08 (dd, J=7.6 Hz, J=1.6 Hz, H), 7.57-7.51 (m, 1H), 7.50-7.44 (m, 2H), 7.37 (d, J=2.4 Hz, 1H), 7.35-731 (m, 1H), 7.18 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.56 (d, J=8.0 Hz, 1H), 6.47 (s, 1H), 6.38-6.30 (m, 1H), 5.48 (s, 1H), 4.15-4.06 (m, 3H), 3.82-3.69 (m, 1H), 3.22-3.05 (m, 2H), 1.47 (s, 9H), (m, 2H), 1.41 (s, 9H), 1.10 (d, J=6.8 Hz, 3H), 0.88 (d, J=6.4 Hz, 3H).
Example 14
(3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-83)
Step 1: (3S,4S and 3R,4R)-3-(3-bromo-4-hydroxyphenyl)-2-(4-(tert-buty)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (14-b) was synthesized following an analogous procedure to Example 2 using 3-bromo-4-hydroxybenzaldehyde MS APCI calcd for C26H23BrClFNO4 [M+H]+ 546/548, found 546/548.
Step 2: (3S,4S and 3R,4R)-3-(3-bromo-4-hydroxyphenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (14-b) (1.96 g, 3.58 mmol) and H2SO4 (sulfuric acid) (0.038 ml, 0.72 mmol) in MeOH (50 mL) was heated under reflux for 3 h under a nitrogen atmosphere. The reaction mixture was cooled to rt and methanol was removed under reduced pressure. The resulting residue was diluted with water (30 mL) and sat, aq. sodium bicarbonate until pH 9. The mixture was then extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to methyl (3S,4S) and (3R,4R)-3-(3-bromo-4-hydroxyphenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-c). MS APCI calcd for C27H23BrClFNO4 [M−H]− 558/560, found 558/560.
Step 3: To a solution of methyl (3S,4S and 3R,4R)-3-(3-bromo-4-hydroxyphenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-c) (600 mg, 1.07 mmol) in DMF (10 mL) at 0° C. were added K2CO3 (potassium carbonate) (222 mg, 1.61 mmol) followed by 2-chloro-1-cyclopropylethanone (190 mg, 1.61 mmol). The resulting mixture was stirred at rt under nitrogen atmosphere for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash chromatography on a silica gel column (0 to 40% EtOAc/hexanes) to afford methyl (3S,4S and 3R,4R)-3-(3-bromo-4-(2-cyclopropyl-2-oxoethoxy)phenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-d). MS APCI calcd for C32H29BrClFNO5 [M−H]− 640/642, found 640/642.
Step 4: To a clear solution of methyl (3S,4S and 3R,4R)-3-(3-bromo-4-(2-cyclopropyl-2-oxoethoxy)phenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-d) (250 mg, 0.389 mmol) in ethyl acetate (75 mL) at rt was added NaH4 (14.7 mg, 0.389 mmol) and the resulting mixture was stirred at rt for 24 hours (open to air). Water (5 mL) was added to the reaction mixture and the two layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford methyl (3S,4S) and (3R,4R)-3-(3-bromo-4-(2-cyclopropyl-2-hydroxyethoxy)phenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-e). MS APCI calcd for C32H29BrClFNO5 [M−H]− 642/644, found 642/644.
Step 5: An over-dried reaction vial was charged with methyl (3S,4S and 3R,4R)-3-(3-bromo-4-(2-cyclopropyl-2-hydroxyethoxy)phenyl)-2-(4-(tert-butyl)-3-chlorophenyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-e) (230 mg, 0.357 mmol), 2-(di-tert-butylphosphino)biphenyl (JohnPhos) (13 mg, 0.043 mmol), Cs2CO3 (349 mg, 1.07 mmol), and palladium (II) acetate (Pd(OAc)2) (8.0 ng, 0.036 mmol). The reaction mixture was placed under nitrogen by three vacuum/nitrogen cycles. The resulting brown mixture was heated at 90° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was concentrated to dryness and the resulting residue was purified by combiflash chromatography on a silica gel column using 0 to 50% EtOAc/hexanes to afford methyl a mixture of diastereomers of (3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-f). MS APCI calcd for C32H30ClFNO5 [M−H]− 562, found 562.
Step 6: To a solution of diastereomers, methyl (3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (14-f) (65 mg, 0.12 mmol), in MeOH (1 mL) were added LiOH (lithium hydroxide) (8.28 mg, 0.346 mmol) and water (0.5 mL). The resulting colorless mixture was stirred at rt (open to air) for 16 hours. The reaction mixture was concentrated to dryness and suspended in 1 M HCl aq sol (3 mL). It was extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by reverse phase chromatography on a C18 column using 10 to 100% acetonitrile/water to afford a mixture of diastereomers (3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-83 diastereomeric mixture). MS APCI calcd for C31H30ClFNO5 [M+H]+ 550, found 550.
Step 7: The mixture of diastereomers was purified by chiral SFC (Chiralpak® AD-H column, 25% IPA/75% CO2) to afford (diastereomer A, first eluting): 1H NMR (400 MHz, CD3OD) δ 7.74 (dd, J=9.0, 2.4 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.30-7.20 (m, 3H), 6.70 (d, J=8.8 Hz, 1H), 6.63-6.58 (m, 2H), 5.60 (s, 1H), 4.26 (dd, J=11.2, 2.4 Hz, 1H), 3.96 (br s, 1H), 3.90 (dd, J=11.2, 8.0 z, 1H), 3.43-3.31 (m, 1H), 1.46 (s, 9H), 1.09-0.90 (m, 1H), 0.66-0.55 (m, 2H), 0.52-0.43 (m, 1H), 0.41-0.32 (m, 1H) (diastereomer B, second eluting): MS APCI calcd for C31H30ClFNO5 [M+H]+ 550, found 550. 1H NMR (400 MHz, CD3OD) δ 7.56 (dd, J=9.0, 2.6 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 7.36-7.19 (m, 3H), 6.71 (d, J=7.2 Hz, 1H), 6.63-6.58 (m, 2H), 5.57 (s, 1H), 4.28-4.25 (m, 1H), 4.07 (s, 1H), 3.93-3.87 (m, 1H), 3.47-3.31 (m, 1H), 1.33 (s, 9H), 1.01-0.89 (m, 1H), 0.65-0.53 (m, 2H), 0.52-0.44 (m, 1H), 0.42-0.37 (m, 1H).
The racemic mixture of diastereomer A (first eluting isomer) (rac-trans)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid was further purified by chiral SFC (Chiralpak® AD-H column, 15% EtOH/85% CO2CO2, 254 nm, 15 min) to afford (3S,4S) or (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(3-cyclopropyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid Enantiomer B, slower eluting enantiomer, tR=6.54 min), 1-83: MS APCI calcd for C31H30ClFNO5 [M+H]+ 550, found 550. 1H NMR (400 MHz, CD3OD) δ 7.74 (dd, J=9.0, 2.4 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.30-7.20 (m, 3H), 6.70 (d, J=8.8 Hz, 1H), 6.63-6.58 (m, 2H), 5.60 (s, 1H), 4.26 (dd, J=11.2, 2.4 Hz, 1H), 3.96 (br s, 1H), 3.90 (dd, J=11.2, 8.0 Hz, 1H), 3.43-3.31 (m, 1H), 1.46 (s, 9H), 1.09-0.90 (m, 1H), 0.66-0.55 (m, 2H), 0.52-0.43 (m, 1H), 0.41-0.32 (m, 1H).
Example 15
(3S,4S or 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-84)
Racemate compound (1-84) was prepared by following an analogous procedure to that reported in Example 2 using 2,3-dihydrobenzo[b][1,4]oxathiine-6-carbaldehyde. The racemic mixture of compound was purified by chiral SFC (IA column, 25%/75% methanol/CO2, 254 nm, 10 min) to afford (trans)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Enantiomer A, first eluting, tR=4.72 min) 1-84. MS APCI calcd for C28H26ClFNO4 [M+H]+ 526, found 526. 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=8.7, 2.7 Hz, 1H), 7.41-7.35 (m, 2H), 7.24-7.10 (m, 3H), 6.82-6.78 (m, 1H), 6.71-6.67 (m, 2H), 5.49 (s, 1H), 4.39 (dd, J=4.5, 3.0 Hz, 2H), 3.96 (s, 1H), 3.08-3.05 (dd, J=4.5, 3.0 Hz, 2H), 1.44 (s, 9H).
Example 16
2-((3S,4S or 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid (1-85)
Step 1: To a solution of racemic (3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-2) (480 mg, 0.941 mmol) in anhydrous THF (5 mL) was added BH3.THF (1 M in THF, 4.71 mL, 4.71 mmol) dropwise at rt. The resulting mixture was heated under reflux for 2 h under nitrogen atmosphere. The reaction mixture was cooled to rt and quenched with MeOH (0.5 mL). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography on a C18 column (10 to 100 CH3CN/H2O) to afford ((3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-4-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (16-a). MS APCI calcd for C28H28ClFNO4 [M+H]+ 496, found 496.
Step 3: To a solution of ((3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-4-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (16-a) (210 mg, 0.424 mmol) in dichloromethane (10 mL) at 0° C. were added trimethylamine (Et3N) (0.12 mL, 0.85 mmol) and methanesulfonyl chloride (MsCl) (0.050 mL, 0.64 mmol). The resulting mixture was stirred at rt for 3 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and the two layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford ((3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl methanesulfonate (16-b). MS APCI calcd for C29H30ClFNO6S [M+H]+ 574, found 574.
Step 4: To a solution ((3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl methanesulfonate (16-b) (260 mg, 0.464 mmol) in DMSO (3 mL) was added potassium cyanide (KCN) (181 mg, 2.79 mmol) and tetrabutylammonium iodide (TBAI) (343 mg, 0.929 mmol). The resulting mixture was heated at 75° C. for 4 h. The reaction was cooled to rt and diluted with water (50 mL). The mixture was extracted with EtOAc (×3). The combined organic extracts were washed with water (×4), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash chromatography on a silica gel column (0 to 60% f EtOAc/hexanes) to afford 2-((3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetonitrile (16-c). MS APCI calcd for C29H27ClFN2O3 [M+H]+ 505, found 505.
Step 5: To a solution of 2-((3S,4S and 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetonitrile (16-c) (135 mg, 0.267 mmol) in MeOH (10 mL) was added NaOH (5 M in water, 0.5 mL, 2.5 mmol). The resulting mixture was heated under reflux for 48 h. The reaction mixture was cooled to rt and diluted with water (50 mL). The mixture was acidified with aq. 2 N HCl to pH=3 and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (10 to 100% acetonitrile/water) to afford 2-((3S,4S) and (3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid (1-85 racemic mixture). MS APCI calcd for C29H28ClFNO5 [M+H]+ 524, found 524. 1H NMR (400 MHz, CD3OD) δ 7.76 (dd, J=8.6 Hz, 2.4 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.22-7.25 (m, 2H), 7.16 (dd, J=8.6 Hz, 2.4 Hz, 1H), 6.70-6.82 (m, 1H), 6.59-6.61 (m, 2H), 5.12 (s, 1H), 4.16 (s, 4H), 3.61-3.65 (m, 1H), 2.99 (dd, J=16.4, 9.2 Hz, 1H), 2.73 (dd, J=16.4, 6.0 Hz, 1H), 1.47 (s, 9H).
The racemic mixture was resolved by CHIRAL-SFC (Column CCOF4, (250 mm*21 mm), with 30% MeOH (+0.25% DMEA) in CO2) affording two peaks with retention times of 3.9 min and 5.8 minutes. Peak 1 afforded 2-((3S,4S or 3R,4R)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid (1-85).
Peak 1 (1-85): LCMS (C29H28ClFNO5) (ES, m/z) 524 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 7.69 (d, J=7.7 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.39 (s, 1H), 7.35-7.27 (m, 2H), 7.16 (d, J=8.1 Hz, 1H) 675 (d, J=8.2 Hz, 1H), 6.61-6.55 (M, 2H), 4.16 (s, 4H), 3.58-3.54 (m, 1H), 2.97 (dd, J=15.9, 8.1 Hz, 1H), 2.59 (dd, J=16.0, 6.1 Hz, 1H), 2.47-2.40 (m, 1H), 1.41 (s, 9H).
Example 17
(3R,4R and 3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S and R)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-86)
Step 1: (3R,4R and 3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S and R)-6-(ethoxycarbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (17-1) was synthesized following an analogous procedure to that reported as in Example 1-1 using ethyl 6-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate. MS ESI calcd for C31H29NO7 [M+H]+ 528, found 528.
Step 2: To a solution of (3R,4R and 3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S and R)-6-(ethoxycarbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (17-1) (12 mg, 0.023 mmol) in THF (1 mL) was added LiBH4 (2.0 mg, 0.091 mmol). The reaction mixture was brought to 60° C. for 1 hour. The reaction mixture was cooled to room temperature then diluted with MeOH (1 mL). After stirring for 10 minutes reaction mixture was concentrated tinder reduced pressure and directly purified by silica gel chromatography (0-100%, 3:1 (EtOAc:EtOH)/hexanes) to afford (3R,4R and 3S,4S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((S and R)-6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (1-86). MS ESI calcd for C29H27NO6 [M+H]+ 486, found 486. 1H NMR (600 MHz, DMSO-d6) δ 7.91 (d, J=7.5 Hz, 1H), 7.47-7.41 (m, 1H), 7.40-7.34 (m, 1H), 7.28-720 (1H), 7.05-6.94 (m, 3H), 6.66 (d, J=8.4 Hz, 1H), 6.61-6.53 (m, 2H), 5.51 (s, 1m), 4.56-4.46 (m, 1H), 4.10 (s, 4H), 3.37-3.31 (m, 3H), 2.77-2.61 (m, 3H), 2.37-2.26 (m, 1H), 1.90-1.81 (m, 1H), 1.79-1.69 (m, 1H).
Biological Data
Biological Evaluation
The individual compounds described in the Examples above are defined as STING inhibitors by demonstrating binding to the STING protein with an IC50 of less than 20 μM in the STING Biochemical [3H]cGAMP Competition Assay (using either HAQ or wild type (WT) STING) and demonstrating inhibition of interferon production less than 30 μM in the cGAMP stimulated INF-β (interferon-β) THP1 cell assay. The methods below describe each of these assays.
[3H]-cGAMP (Cyclic Guanosine Monophosphate (GMP)-Adenosine Monophosphate (AMP) Synthesis
2.3 mL of buffer solution containing 80 mM tris Cl, 200 mM MgCl2 and 20 mM NaCl followed by 0.32 mL of a 10 mM aqueous solution of guanosine triphosphate (GTP) was added to a plastic 50 mL Amicon® centrifuge tube. A solution of [3H]ATP (adenosine triphosphate) (21 Ci/mmol, 45 mCi) in 0.5 mL H2O was then added followed by 1 mL of a 1 mg/mL solution of DNA and 53 uL of a 47 mM solution of enzyme. Additional 20 was added to bring the total volume to 10 mL.
The reaction was stirred for 2 h at 37° C. and then added directly to an Amicon® Ultra-15 10K centrifuge tube (Millipore Sigma, Burlington, Mass., USA) and spun for 1 h at 4,000 g. The collected solution was then purified on a semi-prep Mono Q® column (Supelco, Bellefonte, Pa., USA) using the following mobile phases:
A: 0.05M TrisCl pH 8.5 adjusted with IM NaOH
B: 0.05M TrisCl, 0.5M NaCl pH 8.5 adjusted with IM NaOH
Gradient: 100% A for 5 min followed by a linear gradient to 50:50 (A:B) over 25 min, 3 ml/min, 254 nm.
The collected product fractions were pooled and adjusted to a total volume of 30 mL with buffer A. A total yield of 15.5 mCi of [3H]cGAMP was isolated at a radiochemical purity of 98.0% at a specific activity of 21.5 Ci/mmol.
cGAS (Cyclic GMP-AMP Synthase) Enzyme
A recombinant DNA vector was chemically synthesized to express the truncated human cGAS enzyme (residues 161-522). To aid in expression and purification, the amino terminus contains a hexahistidine tag, SUMO (small ubiquitin-like modifier) tag and TEV (tobacco etch virus) cleavage site. The recombinant enzyme was overexpressed in Rosetta™ 2(DE3) Singles™ Competent Cells (Novagen). Affinity purification was carried out using HIS-Select HF Nickel Affinity Gel (Sigma-Aldrich®, St. Louis, Mo., USA) followed by size exclusion chromatography using a Hi-Load® 26/60 Superdex® 200 prep grade column (GE Healthcare, Chicago, Ill., USA). Fractions were pooled, concentrated, flash frozen in liquid nitrogen and stored at −80° C. until needed for research applications.
3H-cGAMP Filtration Binding Assay (HAQ STING)
The ability of compounds to bind STING is quantified by their ability to compete with tritiated cGAMP ligand for human STING receptor membrane using a radioactive filter-binding assay. The binding assay employs STING receptor obtained from Trichoplusia ni (T. ni; Expression Systems, cat #94-002F, Expression Systems, Davis, Calif., USA) cell membranes overexpressing full-length HAQ STING prepared in-house and tritiated cGAMP ligand also purified in-house.
The basic HAQ STING filtration assay protocol is as follows:
The compounds were serially titrated by the Hamilton STARplus CORE™ in a 96-well plate (Greiner Bio One, Monroe, N.C., USA, catalog #651201) using a 1:3 ten-point dose response format. After compound preparation, a 2.2 g/ml working concentration of STING membrane (SEQ. ID. No. 1) was prepared by diluting concentrated membrane into assay buffer (1×PBS (Phosphate-Buffered Saline); Invitrogen™, Thermo Fisher Scientific, Waltham, Mass., USA, catalog #SH30028.02) and douncing 7× using a manual tissue homogenizer (Wheaton®, Millville, N.J., USA, catalog #357546), 148 μL of prepared membrane was then manually added to each well of a 96-well deep-well PP plate (Thermo Fisher Scientific, catalog #12-566-121). Following membrane addition, 2 μL of either titrated test compound, DMSO (dimethyl sulfoxide) control (Sigma-Aldrich®, catalog #276855), or cold cGAMP control (prepared in-house) was added to the appropriate wells using a Biomek® FX (Beckman Coulter Life Sciences, Indianapolis, Ind., USA). Compound and membrane then preincubated for 60 min at RT to allow compound binding to equilibrate. Following equilibration, 8 nM of [3H] c-GAM/P ligand was prepared by diluting into assay buffer, and 50 μL of this working stock was then manually added to each well of the assay plate. Plates were then incubated at RT for 60 min, and the contents of each assay plate were then filtered through a 96-well GF/B filter plate (PerkinElmer, Akron, Ohio, USA, catalog #6005250) using a TomTec MachIII Cell Harvester equipped with 20 mM HEPES buffer (Fisher Scientific, catalog #BP299500). The filter plates were then dried at 55° C. for 30 min using a pressurized VWR oven (VWR, Radnor, Pa., USA) before 302 μL of Ultima Gold™ F scintillate (PerkinElmer) was added to each well. Tritium levels for each reaction well were then measured using a TopCount™ plate reader (PerkinEmer).
After normalization to controls, the percent activity for each compound concentration was calculated by measuring the amount of remaining radioactivity. The plot of percent activity versus the log of compound concentration was fit with a 4-parameter dose response equation to calculate EC50 values.
The final reaction conditions were:
Component
Volume (uL)
Final Concentration
STING membrane
148
1.5
ug/ml
3H-cGAMP
50
2.0
nM
Low Control
2
10
uM
(cold cGAMP)
Test compound/DMSO
2
10
uM
Compound concentrations tested were 20.000, 637.00, 2.200, 0.740, 0.247, 0.082, 0.027, 0.009, 0.003, and 0.001 μM with 1.0% residual DMSO.
Full-Length STING (HAQ) Virus Generation
STING virus was generated using an insect cell baculovirus system. Spodoptera frugiperda Sf21 cells (Kempbio, Inc., Gaithersburg, Md., USA) were diluted to 5e5 cells/ml in Sf-900™ II SFM media (LifeTechnologies (Thermo Fisher Scientific), Waltham, Mass., USA, catalog #10902088) without antibiotics. The cell suspension was added to each well of a treated 6-well plate (2 mL per well, 1e6 cells total), and the cells were allowed to adhere for at least 30 min. Meanwhile, a 1 mL co-transfection mix was assembled by combining 500 ng of HAQ STING [STING(1-379)R71H,G230A,H232R,R293Q-GG-AviTag-GS-HRV3C-HIS8/pBAC1]DNA (custom synthesis, Genewiz, Inc., South Plainfield, N.J., USA) with mL Sf-900™ II SFM media containing 10 μL Cellfectin® II Reagent (Invitrogen (Thermo Fisher Scientific), catalog #10362100) and 100 ng viral backbone BestBac™ 2.0, v-cath/chiA Deleted Linearized Baculovins DNA (Expression Systems, catalog #91-002). The transfection mixtures were allowed to incubate for 30 min. After incubation, media was gently removed from the adhered cells in the 6-well plate, the 1 mL transfection mixtures were added (1 mL per well), and the plate was placed in a humidified incubator at 27° C. The following day, mL Sf-900™ II SFM media (no antibiotics) was added to each well of the 6-well plate. After media addition, the cells were allowed to incubate with DNA at 27° C. for 5-7 days to generate the P0 viral stock. To generate P1 viral stocks, 0.5 mL of P0 viral supernatant was added to 50 mL uninfected Sf21 cells (seeded the day prior to infection at a density of 5×105 cells/mL to allow for one overnight doubling) in Sf-900™ II SFM media containing 5 μg/mL gentamicin (Invitrogen (Thermo Fisher Scientific), catalog #15710072). The infected cells were then incubated at 27° C. for 3d while shaking at 110 rpm (ATR Biotech Multitron Infors HT incubator Shaker, catalog #AJ=118, ATR, Inc, Laurel, Md., USA). On day 3, P1 cultures were counted using a Vi-Cell XR (Beckman Coulter Life Sciences, catalog #383556) to confirm infection had occurred (cell size ≥3 μm larger than uninfected cells and viability approximately 85-95%). Cultures were harvested in 50 mL conical tubes and centrifuged at 2000×g for 10 min at 4° C. The P1 viral supernatants were poured off into clean 50 mL centrifuge tubes, and the remaining P1 cell pellets were used to generate Baculovirus Infected Insect Cells (BIICs) according to in-house validated SOP (standard operating procedure). Cryopreservation media containing Sf-900™ II SFM media with 10% heat inactivated fetal bovince serum FBS, 10% DMSO (Sigma #D2650), and 5 μg/ml gentamicin was prepared in-house and sterilized through 0.22 μM filter immediately prior to use. P1 cell pellets were resuspended to a density of 2e7 cells/ml and aliquoted into cryovials (1 mL per vial). Cryovials were placed in Mr. Frosty cell freezers O/N (Nalge Nunc International (Thermo Fisher Scientific)) at −80° C. and transferred to liquid nitrogen for long term storage the following day. To generate P2 viral stock, 0.5 mL of the P1 viral supernatant was added to 50 mL uninfected Sf2l cells (seeded the day prior to infection at a density of 5×105 cells/mL to allow for one overnight doubling) in Sf-900™ II SFM media containing 5 μg/mL gentamicin. These cells were incubated at 27° C. for 3d while shaking at 110 rpm before harvesting P2 stock with centrifugation at 2000×g for 10 min at 4° C. The P2 viral supernatants were poured off and discarded, while the P2 cell pellets were used to generate P2 BIICs following the same protocol described above. The baculovirus generation protocol has been validated to consistently produce P1/P2 BIICs with titers of 2e9 pfu/mL (2e7 cells/mL×100 pfu/cell; pfu=plague forming units).
Full-Length STING (HAQ) Expression
To generate STING membranes, P1/P2 BIICs were amplified overnight by adding thawed BIICs to Sf21 cells seeded at a density of 1.0×106 cells/mL The volume of BIIC used to infect the culture was calculated using an assumed BIIC titer of 2e9 pfu/ml to achieve an MOI (multiplicity of infection) of 10 in the overnight amplification. After culturing overnight, the cells were counted on a Vi-Cell XR to confirm infection had occurred (cell size ≥3 μm larger than uninfected cells and viability approximately 80-90%). The volume of infected Sf21 cells from the overnight amplification used to infect the large-scale expression of Trichoplusia ni (T. ni; Expression Systems, cat #94-002F, www.expressionsystems.com) seeded at a density of 0.0×106 in cell media (ESF921 SFM containing 5 μg/mL gentamicin) at MOI=2.0 was calculated based on (100 pfu/infected Sf21 cell). The cells were allowed to express for 48 h at 27° C. before harvesting the cell pellet, by centrifugation at 3,400×g for 10 min at 4° C. T. ni cells were counted on a Vi-Cell XR to confirm infection had occurred (cell size ≥3 μm larger than uninfected cells and viability approximately 80-90%) prior to harvest.
Full-Length STING (HAQ) Membrane Generation
Buffer stock reagents:
1) 1 M HEPES (hydroxyethyl piperazineethanesulfonic acid) pH 7.5 (Teknova, Hollister, Calif., USA, Catalog #H1035)
2) 5 M NaCl, (Sigma-Aldrich®, St. Louis, Mo., USA, Cat #S5150-IL)
3) KCl, (Sigma-Aldrich®, St. Louis, Mo., USA, Cat #319309-500 ML)
4) Complete EDTA-free protease inhibitor tablets (Roche Diagnostics, Indianapolis, Ind., USA, Cat #11873580001)
5) Benzonase, Pierce™ Universal Nuclease for Cell Lysis, Thermo Scientific (Thermo Fisher Scientific), Cat. #88702)
Lysis buffer [25 mM HEPES pH 7.5, 10 mM MgCl2, 20 mM KCl, (Benzonase 1:5000, Complete Protease Inhibitor tab/50 mL)] was added to the pellet of cells expressing full-length STING (HAQ) prepared above at 5 mL Lysis buffer/g of cell pellet. The pellet was resuspended and dounced twenty times using a Wheaton Dounce Homogenizer (Wheaton®, Millville, N.J., USA) to disrupt the cell membrane. Homogenized lysate was then passed through the EmulsiFlex-C5 microfluidizer (Avestin, Inc., Ottowa, Calif.) at a pressure close to 5000 PSI. The resuspended pellet was centrifuged at 36,000 rpm (00,000×g) in a 45 Ti rotor in the ultra-high speed centrifuge for 45 min, 4° C. The supernatant was removed. The pellet then was resuspended in wash buffer [(25 mM HEPES pH7.5, 1 mM MgCl2, 20 mM KCl, IM NaCl (Complete Protease Inhibitor tab/50 mL)] at a volume of 50 mL pellet/centrifuge tube. The pellet/wash buffer mixture was then homogenized, using a glass homogenizer on ice (20 strokes), followed by centrifugation at 36,000 rpm for 45 min at 4° C. The supernatant was removed. The wash step was repeated once more. The resulting membrane was resuspended in 20 mM HEPES pH 7.5, 500 mM NaCl, 10% glycerol, EDTA-free Protease Inhibitors (1 tablet/50 mL). The protein concentration was measured by Bradford assay (Bio-Rad Protein Assay, Cat #500-0006, Bio-Rad, Hercules, Calif., USA), and protein enrichment was determined by SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and confirmed by Western blot. The resuspended membranes were stored at −80° C.
Full-Length HAG STING [STING(1-379)R71H, G230A,
H232R, R293Q-GG-AviTag-GS-HRV3C-HIS]Amino AGd
Sequence:
(SEQ. ID. No. 1)
MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLNATGLGEPPEHTLRYLVLHLASLQLGLL
LNGVCSLAEELHHIFISRYRGSYWRTVRACLGGPLRRGALLLLSIYFYYSLPNAVGPPETW
MLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIR
TYNQHYNNLLRGAVSQRLY1LLPLDCGVPDNLSMADPNIRFLDKLPQQTADRAGIKDRVYS
NSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLITQTLEDILADA
PESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPEL
LISGMEKPLPLRTDFSGGGLNDIFEAQKIEWHEGSLEVLFQGPHHHHHHHH
Full-length HAQ [STING(1-379)R71H, G230A, H232R,
R293Q-GG-AviTag-GS-HRV3C-HIS8/pBAC1] PlasMid
DNA Sequence:
(SEQ. ID. No. 2)
GGAACGGCTCCGCCCACTATTAATGAAATTAAAAATTCCAATTTTAAAAAACGCAGCAAGA
GAAACATTTGTATGAAAGAATGCGTAGAAGGAAAGAAAAATGTCGTCGACATGCTGAACAA
CAAGATTAATATGCCTCCGTGTATAAAAAAAATATTGAACGATTTGAAAGAAAACAATGTA
CCGCGCGGCGGTATGTACAGGAAGAGGTTTATACTAAACTGTTACATTGCAAACGTGGTTT
CGTGTGCCAAGTGTGAAAACCGATGTTTAATCAAGGCTCTGACGCATTTCAACAACCACGA
CTCCAAGTGTGTGGGTTGAAGTCATGCATCTTTTAATCAAATCCCAAGATGTGTATAAACC
ACCAAACTGCCAAAAAATGAAAACTGTCGACAAGCTCTGTCCGTTTGCTGGCAACTGCAAG
GGTCTCAATCCTATTTGTAATTATTGAATAATAAAACAATTATAAATGCTAAATTTGTTTT
TTATTAACGATACAAACCAAACGCAACAAGAACATTTGTAGTATTATCTATAATTGAAAAC
GCGTAGTTATAATCGCTGAGGTAATATTTAAAATCATTTTCAAATGATTCACAGTTAATTT
GCGACAATATAATTTTATTTTCACATAAACTAGACGCCTTGTCGTCTTCTTCTTCGTATTC
CTTCTCTTTTTCATTTTTCTCTTCATAAAAATTAACATAGTTATTATCGTATCCATATATG
TATCTATCGTATAGAGTAAATTTTTTGTTGTCATAAATATATATGTCTTTTTTAATGGGGT
GTATAGTACCGCTGCGCATAGTTTTTCTGTAATTTACAACAGTGCTATTTTCTGGTAGTTC
TTCGGAGTGTGTTGCTTTAATTATTAAATTTATATAATCAATGAATTTGGGATCGTCGGTT
TTGTACAATATGTTGCCGGCATAGTACGCAGCTTCTTCTAGTTCAATTACACCATTTTTTA
GCAGCACCGGATTAACATAACTTTCCAAAATGTTGTACGAACCGTTAAACAAAAACAGTTC
ACCTCCCTTTTCTATACTATTGTCTGCGAGCAGTTGTTTGTTGTTAAAAATAACAGCCATT
GTAATGAGACGCACAAACTAATATcACAAACTGGAAATGECTATCAATATATAGTTGCTGA
TCAGATCTGATCATGGAGATAATTAAAATGATAACCATCTCGCAAATAAATAAGTATTTTA
CTGTTTTCGTAACAGTTTTGTAATAAAAAAACCTATAAATATAGGATCCATGCCCCACTCC
AGCCTGCATCCATCATCCCGTGTCCCAGGGGTCACGGGGCCCAGAAGGCAGCCTTGGTTCT
GCTGAGTGCCTGCCTGGTGACCCTTTGGGGGCTAGGAGAGCCACCAGAGCACACTCTCCGG
TACCTGGTGCTCCACCTAGCCTCCCTGCAGCTGGGACTGCTTGTTAAACGGGGTCTGCAGC
CTGGCTGAGGAGCTGCACCACATCCACTCCAGGTACCGGGGCAGCTAGGGAGGAGGTGCGG
GCCTGCCTGGGCTGCCCCCTCCGCCGTGGGGCCCTGTTGCTGCTGTCCATCTATTTCTACT
ACTCCCTCCCAAATGCGGTCGGCCCGCCCTTCACTTGGATGCTTGCCCTCCTGGGCCTCTC
GCAGGCACTGAACATCCTCCTGGGCCTCAAGGGCCTGGCCCCAGCTGAGATCTCTGCAGTG
TGTGAAAAAGGGAATTFCAACGTGGCCCATGGGCTGGCATGGTCATATTACATCGGATATC
TGCGGCTGATCCTGCCAGAGCTCCAGGCCCGGATTCGAACTTACAATCAGCATTACAACAA
CCTGCTACGGGGTGCAGTGAGCCAGCGGCTGTATATTCTCCTCCCATTGGACTGTGGGGTG
CCTGATAACCTGAGTATGGCTGACCCCAACATTCGCTTCCTGGATAAACTGCCCCAGCAGA
CCGCTGACCGTGCTGGCATCAAGGATCGGGTTTACAGCAACAGCATCTATGAGCTTCTGGA
GAACGGGCAGCGGGCGGGCACCTGTGTCCTGGAGTACGCCACCCCCTTGCAGACTTTGTTT
GCCATGTCACAATACAGTCAAGCTGGCTTTAGCCGGGAGGATAGGCTTGAGCAGGCCAAAC
TCTTCTGCCAGACACTTGAGGACATCCTGGCAGATGCCCCTGAGTCTCAGAACAACTGCCG
CCTCATTGCCTACCAGGAACCTGCAGATTGACAGCAGCTTCTCGCTGTCCCAGGAGGTTCT
CCGGCACCTGCGGCAGGAGGAAAAGGAAGAGGTTACTGTGGGCAGCTTGAAGACCTCAGCG
GTGCCCAGTACCTCCACGATGTCCCAAGAGCCTGAGCTCCTCATCAGTGGAATGGAAAAGC
CCCTCCGTCTCCGCACGGATTTCTCTGGCGGTGGCCTGAACGACATCTTCGAAGCCCAGAA
AATCGAATGGCATGAAGGCAGCCTGGAAGTGCTGTTCCAGGGCCCACACCACCATCATCAC
CATCACCATTAATGAGCGGCCGCACTCGAGCACCACCACCACCACCACTAACCTAGGTAGC
TGAGCGCATGCAAGCTGATCCGGGTTATTAGTACATTTATTAAGCGCTAGATTCTGTGCGT
TGTTGATTTACAGACAATTGTTGTACGTATTTTAATAATTCATTAAATTTATAATCTTTAG
GGTGGTATGTTAGAGCGAAAATCAAATGATTTTCAGCGTCTTTATATCTGAATTTAAATAT
TAAATCCTCAATAGATTTGTAAAATAGGTTTCGATTAGTTTCAAACAAGGGTTGTTTTTCC
GAACCGATGGCTGGACTATCTAATGGATTTTCGCTCAACGCCACAAAACTTGCCAAATCTT
GTAGCAGCAATCTAGCTTTGTCGATATTCGTTTGTGTTTTGTTTTGTAATAAAGGTTCGAC
GTCGTTCAAAATATTATGCGCTTTTGTATTTCTTTCATCACTGTCGTTAGTGTACAATTGA
CTCGACGTAAACACGTTAAATAGAGCTTGGACATATTTAACATCGGGCGTGTTAGCTTTAT
TAGGCCGATTATCGTCGTCGTCCCAACCCTCGTCGTTAGAAGTTGCTTCCGAAGACGATTT
TGCCATAGCCACACGACGCCTATTAATTGTUTCGGCTAACACGTCCGCGATCAAATTTGTA
GTTGAGCTTTTTGGAATTATTTCTGATTGCGGGCGTTTTTGGGCGGGTTTCAATCTAACTT
GTGCCCGAVTTTAATTCAGACAACACGTTAGAAAGCGATGGTGCAGGCGGTGGTAACATTT
CAGACGGCAAATCTACTAATGGCGGCGGTGGTGGAGCTGATGATAAATCTACCATCGGTGG
AGGCGCAGGCGGGGCTGGCGGCGGAGGCGGAGGCGGAGGTGGTGGCGGTGATGCAGACGGC
GGTTTAGGCTCAAATGTCTCTTTAGGCAACACAGTCGGCACCTCAACTATTGTACTGGTTT
CGGGCGCCGTTTTTGGTTTGACCGGTCTGAGACGAGTGCGATTTTTTTCGTTTCTAATAGC
TTCCAACAATTGTTGTCTGTCGTCTAAAGGTGCAGCGGGTTGAGGTTCCGTCGGCATTGGT
GGAGCGGGCGGCAATTCAGACATCGATGGTGGTGGTGGTGGTGGAGGCGCTGGAATGTTAG
GCACGGGAGAAGGTGGTGGCGGCGGTGCCGCCGGTATAATFTGTTCTGGTTTAGTTTGTTC
GCGCACGATTGTGGGCACCGGCGCAGGCGCCGCTGGCTGCACAACGGAAGGTCGTCTGCTT
CGAGGCAGCGCTTGGGGTGGTGGCAATTCAATATTATAATTGGAATACAAATCGTAAAAAT
CTGCTATAAGCATTGTAATTTCGCTATCGTTTACCGTGCCGATATTTAACAACCGCTCAAT
GTAAGCAATTGTATTGTAAAGAGATTGTCTCAAGCTCGGATCGATCCCGCACGCCGATAAC
AAGCCTTTTCATTTTTACTACAGCATTGTAGTGGCGAGACACTTCGCTGTCGTCGAGGTTT
AAACGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCA
GCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACA
TGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTT
CCATAGGCTCCGCCCCCGGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAA
ACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCC
TGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCG
CTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGG
GCTGTGTGCACGAACCCCCCGfTCAGCCCGACCGCTGCGCCTTATCCGGTAAGATCGTCTT
GAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTA
GCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTA
CACTAGAAGGACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGA
GTTGGTAGGGTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAG
CAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCGTTGATCTTTTCTACGGGGTC
TGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGG
ATGTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGA
GTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGT
CTATTTCGTTCATCCATAGTTGCCTGAGCCCCGTCGTGTAGATAACTACGATACGGGAGGG
CTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGAT
TTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTAT
CCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAA
TAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGT
ATGGCTTCCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTG
TGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAG
TGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAG
ATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGA
CCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAA
AAGTGCTCATGCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGT
TGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTT
CACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGG
GCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATC
AGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGG
GGTTCCGCGCACATTTCCCCGAAAAMGMACCTGACGCGCCCTGTAGCGGCGCATTAAGCGC
GGCGGGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCT
CCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAA
ATCGGGGGCTCCCTTTAGGGTTCCGMTTAGTGCTTTACGGCACCTCGACCCCAAAAAACTT
GATTAGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGA
CGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTTCCAAAGGGAACAACACTCAACCCT
ATCTCGGTCTATTCTTTTGATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAA
ATGAGCTGATTTAACAAAAATTTAACGCGAATTTTAACAAAATATTAACGTTTACAATTTC
CCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTA
TTACGCCA
Certain compounds of the disclosure were evaluated in HAQ STING in vitro binding assay as described above. The following table tabulates the biological data disclosed for the instant invention. The biological data was collected using the methodology described above. For each compound, STING IC50 values are listed
TABLE 5
3H-cGAMP filtration binding assay for HAQ STING
Compound Number
HAQ STING IC50 (nM)
1-1
53
1-2
33
1-3
1159
1-4
732
1-5
11350
1-6
7551
1-7
12250
1-8
2971
1-9
1520
1-10
4225
1-11
10670
1-12
4443
1-13
15690
1-14
10870
1-15
16820
1-16
10210
1-17
3927
1-18
11310
1-19
2284
1-20
1631
1-21
3560
1-22
2243
1-23
858
1-24
9912
1-25
11380
1-26
6643
1-27
2964
1-28
803
1-29
339
1-30
11460
1-31
1216
1-32
952
1-33
4874
1-34
10420
1-35
5288
1-36
669
1-37
339
1-38
3268
1-39
3752
1-40
483
1-41
1574
1-42
1240
1-43
828
1-44
5882
1-45
10880
1-46
1797
1-47
1135
1-48
213
1-49
18030
1-50
1288
1-51
4220
1-52
186
1-53
602
1-54
266
1-55
135
1-56
5696
1-57
9893
1-58
538
1-59
4135
1-60
7502
1-61
106
1-62
95
1-63
16670
1-64
225
1-65
1563
1-66
3439
1-67
122
1-68
1469
1-69
7611
1-70
1928
1-71
4638
1-72
737
1-73
6210
1-74
209
1-75
3208
1-76
357
1-77
41
1-78
670
1-79
482
1-80
602
1-81
441
1-82
329
1-83
10
1-84
55
1-85
68
1-86
1216
cGAMP Stimulated THP1 Cytokine Inhibition-Assay
The ability of compounds to inhibit STING activation is quantified by their ability to inhibit cGAMP mediated cytokine production.
THP1 cells (catalog #TIB-202; American Type Culture collection (ATCC), Manassas, Va. USA) are grown in RPMI640 (catalog #11875-085; Thermo Fisher Scientific) with 10% fetal bovine serum (catalog #F2442, Sigma-Aldrich®, St. Louis, Mo., USA), 1×pen/strep (penicillin streptomycin, catalog #15140-148, Thermo Fisher Scientific) and 1 mM/sodium pyruvate (catalog #11360-070, Thermo Fisher Scientific) at a density between 0.3 and 1.0×10{circumflex over ( )}6 cells/mL. Cells are diluted into RPMI1640+0.5% fetal bovine serum, and preincubated with antagonist compounds (30 μM to 1.75 μM from 10 mM DMSO stock solution) for six hours before stimulating with 2′3′ cGAMP (InvivoGen, San Diego, Calif. USA)/Lipofectamine 2000 (catalog #11668-027, Thermo Fisher Scientific) overnight. IFNb is measured by ELISA (enzyme-linked immunosorbent assay for Interferon Beta; PBL InterferonSource, Piscataway, N.J., USA), and compared to cell viability with CellTiter-Glo® (Promega Life Sciences, Madison, Wis., USA).
Certain compounds of the disclosure were evaluated in in vitro cellular assay as described above. The following table tabulates the biological data disclosed for the instant invention. The biological data was collected using the methodology described above. For each compound, STING IC50 values are listed
Compound Number
THP1 Cell IC50 (nM)
1-1
11500
1-2
10000
I-85
11400
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16980594
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merck sharp & dohme corp.
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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.
|
Open
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|
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Apr 27th, 2022 09:12AM
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Apr 27th, 2022 09:12AM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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|
nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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Jul 30th, 2018 12:00AM
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https://www.uspto.gov?id=US11312772-20220426
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Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment
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Therapeutic combinations that comprise at least one antagonist of the Programmed Death 1 receptor (PD-1) and at least one benzo[b]thiophene compound that activates the Stimulator of Interferon Genes (STING) pathway are disclosed herein. Also disclosed is the use of such therapeutic combinations for the treatment of cancers.
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11312772
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1. A method of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises
a) a PD-1 antagonist; and
b) a benzo[b]thiophene STING agonist; wherein
the PD-1 antagonist is administered once every 21 days; and
the benzo[b]thiophene STING agonist is administered once every 3 to 28 days; and
the benzo[b]thiophene STING agonist is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1, wherein the cancer occurs as one or more solid tumors or lymphomas.
3. The method according to claim 1, wherein the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas.
4. The method according to claim 1, wherein the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphoma.
5. The method according to claim 2, wherein the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma.
6. The method according to claim 1, wherein the cancer has metastasized.
7. The method according to claim 1, wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody.
8. The method according to claim 7, wherein the PD-1 antagonist is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP-224.
9. The method according to claim 8, wherein the PD-1 antagonist is nivolumab.
10. The method according to claim 8, wherein the PD-1 antagonist is pembrolizumab.
11. The method of claim 1, wherein the PD-1 antagonist is administered by intravenous infusion, and the benzo[b]thiophene STING agonist is administered orally, by intravenous infusion, by intertumoral injection or by subcutaneous injection.
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11
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application of International Patent Application No. PCT/US2018/044275, filed Jul. 30, 2018, which claims priority to U.S. Provisional Patent Application No. 62/541,180, filed Aug. 4, 2017.
FIELD OF THE INVENTION
The present disclosure relates to combinations of therapeutic compounds that are useful to treat cancer. In particular, this disclosure relates to combination therapies comprising at least one antagonist of a Programmed Death 1 protein (PD-1) and at least one benzo[b]thiophene compounds that is useful as a STING (Stimulator of Interferon Genes) agonist and activates the STING pathway.
REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY
The sequence listing of the present application is submitted electronically via EFS-Web as an ASCII-formatted sequence listing, with a file name of “24492W0PCT-SEQLIST-29JUNE2018”, a creation date of Jun. 29, 2018, and a size of 21 KB. This sequence listing submitted via EFS-Web is part of the specification and is herein incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
The cytotoxic T-lymphocyte-associated antigen 4 (CLTA-4) and PD-1 pathways are important negative regulators of immune response. Activated T-cells up-regulate CTLA-4, which binds on antigen-presenting cells and inhibits T-cell stimulation, IL-2 gene expression, and T-cell proliferation. These anti-tumor effects have been observed in mouse models of colon carcinoma, metastatic prostate cancer, and metastatic melanoma. PD-1 binds to active T-cells and suppresses T-cell activation. PD-1 antagonists have demonstrated anti-tumor effects as well. PD-1 is moderately expressed on naïve T-, B- and natural killer (NK) T-cells and is upregulated by T/B cell receptor signaling on lymphocytes, monocytes, and myeloid cells.
Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers that arise in various tissues. In large sample sets of, for example, ovarian, renal, colorectal, pancreatic, and liver cancers, and of melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall patient survival irrespective of subsequent treatment. Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T-cells in breast cancer and melanoma and to correlate with poor prognosis in renal cancer patients. Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T-cells to attenuate T-cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.
Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 are in clinical development for treating cancer. It has been proposed that the efficacy of such antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune enhancing agents. See Morrissey et al., Clinical and Translational Science 9(2): 89-104 (2016).
Another potential immune therapy for cancers and for other cell-proliferation disorders is related to the immune system response to certain danger signals associated with cellular or tissue damage. The innate immune system has no antigen specificity but does respond to a variety of effector mechanisms, such as the damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), such as those associated with opsonization, phagocytosis, activation of the complement system, and production of soluble bioactive molecules such as cytokines or chemokines. These are all mechanisms by which the innate immune system mediates its response. In this way, the innate immune system is able to provide broad protection against a wide range of threats to the host.
Free cytosolic DNA and RNA are among these PAMPs and DAMPs. It has recently been demonstrated that the main sensor for cytosolic DNA is cGAS (cyclic GMP-AMP synthase). Upon recognition of cytosolic DNA, cGAS catalyzes the generation of the cyclic-dinucleotide 2′-3′ cGAMP, an atypical second messenger that strongly binds to the ER-transmembrane adaptor protein STING. A conformational change is undergone by cGAMP-bound STING, which translocates to a perinuclear compartment and induces the activation of critical transcription factors IRF-3 and NF-κB. This leads to a strong induction of type I interferons and production of pro-inflammatory cytokines such as IL-6, TNF-α and IFN-γ.
The importance of type I interferons and pro-inflammatory cytokines on various cells of the immune system has been very well established. In particular, these molecules strongly potentiate T-cell activation by enhancing the ability of dendritic cells and macrophages to uptake, process, present and cross-present antigens to T-cells. The T-cell stimulatory capacity of these antigen-presenting cells is augmented by the up-regulation of critical co-stimulatory molecules, such as CD80 or CD86. Finally, type I interferons can rapidly engage their cognate receptors and trigger the activation of interferon-responsive genes that can significantly contribute to adaptive immune cell activation.
From a therapeutic perspective, interferons, and compounds that can induce interferon production, have potential use in the treatment of human cancers. Such molecules are potentially useful as anti-cancer agents with multiple pathways of activity. Interferons can inhibit human tumor cell-proliferation directly and may be synergistic with various approved chemotherapeutic agents. Type I interferons can significantly enhance anti-tumor immune responses by inducing activation of both the adaptive and innate immune cells. Finally, tumor invasiveness may be inhibited by interferons by modulating enzyme expression related to tissue remodeling.
In view of the potential of type I interferons and type I interferon-inducing compounds as anti-viral and anti-cancer agents, there remains a need for new agents that can induce potent type I interferon production. With the growing body of data demonstrating that the cGAS-STING cytosolic DNA sensory pathway has a significant capacity to induce type I interferons, STING activating agents are rapidly taking an important place in today's anti-tumor therapy landscape.
SUMMARY OF THE INVENTION
Embodiments of the disclosure include combination therapies, or therapeutic combinations, comprising at least one PD-1 antagonist and at least one benzo[b]thiophene STING agonist.
Another embodiment includes a method of treating a cell-proliferation disorder in a subject in need thereof, comprising administering a combination therapy comprising at least one PD-1 antagonist and at least one benzo[b]thiophene STING agonist.
Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the amino acid sequences of the light chain and heavy chain variable regions for pembrolizumab that may be used in the combinations disclosed herein.
FIG. 2 shows the amino acid sequence of the light chain for pembrolizumab.
FIG. 3 shows the amino acid sequence of the heavy chain for pembrolizumab.
FIG. 4 shows the amino acid sequences of the CDRs 1, 2, and 3 of the light chain variable region (CDRL1, CDRL2, and CDRL3) and of the CDRs 1, 2, and 3 of the heavy chain variable region (CDRH1, CDRH2, and CDRH3) for pembrolizumab.
FIG. 5 shows the amino acid sequences of the light chain and heavy chain variable regions for nivolumab that may be used in the combinations disclosed herein.
FIG. 6 shows the amino acid sequence of the light chain for nivolumab.
FIG. 7 shows the amino acid sequence of the heavy chain for nivolumab.
FIG. 8 shows the amino acid sequences of the CDRs 1, 2, and 3 of the light chain variable region (CDRL1, CDRL2, and CDRL3) and of the CDRs 1, 2, and 3 of the heavy chain variable region (CDRH1, CDRH2, and CDRH3) nivolumab.
FIG. 9 shows the amino acid sequence for the human PD-L1 molecule (amino acids 19-290).
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations
μg, ug Microgram
Anti-PD-1 Antagonist of a Programmed Death 1 protein
BID One dose twice daily
C57Bl/6 Common inbred strain of laboratory mouse, also “C57 black 6”, “C57”, “black 6”, or “B6”
CDR Complementary determining region
CR Complete regression
Ctrl Control
DFS Disease free survival
DLT Dose limiting toxicity
FFPE Formalin-fixed, paraffin-embedded
FR Framework region
IgG Immunoglobulin G
IgG1 Immunoglobulin G subclass 1
IHC Immunohistochemistry or immunohistochemical
IP Intraperitoneal
IT Intratumoral
kg Kilogram
mAb Monoclonal antibody
MC38 Murine Carcinoma-38 Mouse colon adenocarcinoma cell line
mg Milligram
mIgG1 Murine immunoglobulin G subclass 1, Isotype control mAb for anti-PD-1 antibody muDX400
mL Milliliter
mm Millimeter
mm3 Cubic millimeter, 0.001 mL
MPK Milligram per kilogram
MTD Maximum tolerated dose
n Number of subjects in a treatment group
NCI National Cancer Institute
OR Overall response
OS Overall survival
PBS Phosphate-buffered saline, vehicle control for benzo[b]thiophene STING agonists
PD-1 Programmed cell death protein 1
PFS Progression free survival
PR Partial response
p-values Calculated probability
QD One dose per day
RECIST Response Evaluation Criteria in Solid Tumors
SD Stable disease
SEM Standard error of the mean
TGI Tumor growth inhibition
T/C Median tumor volume of the treated animal/Median tumor volume of the control animal
Additional abbreviations may be defined throughout this disclosure.
Definitions
Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure relates.
“About” when used to modify a numerically defined parameter (e.g., the dose of a PD-1 antagonist or benzo[b]thiophene STING agonist, or the length of treatment time with a combination therapy described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter; where appropriate, the stated parameter may be rounded to the nearest whole number. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg.
As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.
The terms “administration of” and or “administering” a compound should be understood to include providing a compound described herein, or a pharmaceutically acceptable salt thereof, and compositions of the foregoing to a subject.
As used herein, the term “antibody” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies, and camelized single domain antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic. As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.
As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability to bind specifically to the antigen, e.g. fragments that retain one or more CDR regions. An antibody that “specifically binds to” PD-1 or PD-L1 is an antibody that exhibits preferential binding to PD-1 or PD-L1 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g. without producing undesired results such as false positives. Antibodies, or binding fragments thereof, will bind to the target protein with an affinity that is at least two fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.
Antigen binding portions include, for example, Fab, Fab′, F(ab′)2, Fd, Fv, domain antibodies (dAbs, e.g., shark and camelid antibodies), fragments including complementarity determining regions (CDRs), single chain variable fragment antibodies (scFv), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR, and bis-scFv, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the PD-1 or PD-L1. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.
As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.
The term “pharmaceutically acceptable carrier” refers to any inactive substance that is suitable for use in a formulation for the delivery of a therapeutic agent. A carrier may be an antiadherent, binder, coating, disintegrant, filler or diluent, preservative (such as antioxidant, antibacterial, or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifying agent, buffer, and the like. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), dextrose, vegetable oils (such as olive oil), saline, buffer, buffered saline, and isotonic agents such as sugars, polyalcohols, sorbitol, and sodium chloride.
The term “subject” (alternatively “patient”) as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g., pigs), ovine (e.g., sheep), capra (e.g., goats), equine (e.g., horses), canine (e.g., domestic dogs), feline (e.g., house cats), Lagomorpha (rabbits), rodents (e.g., rats or mice), Procyon lotor (e.g., raccoons). In particular embodiments, the subject is human.
The term “subject in need thereof” as used herein refers to a subject diagnosed with, or suspected of having, a cell-proliferation disorder, such as a cancer, as defined herein.
As used herein, the terms “treatment” and “treating” refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.
“Variable regions” or “V region” or “V chain” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.
“Chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain contains sequences derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
“Human antibody” refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.
“Humanized antibody” refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefix “hum”, “hu” or “h” may be added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.
“Biotherapeutic agent” means a biological molecule, such as an antibody or fusion protein, that blocks ligand/receptor signaling in any biological pathway that supports tumor maintenance and/or growth or suppresses the anti-tumor immune response.
“Chemotherapeutic agent” refers to a chemical or biological substance that can cause death of cancer cells, or interfere with growth, division, repair, and/or function of cancer cells. Examples of chemotherapeutic agents include those that are disclosed in WO2006/129163, and US20060153808, the disclosures of which are incorporated herein by reference. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison, plant alkaloids, cytoxic/antitumor antibiotics, topisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of genes implicated in abnormal cell-proliferation or tumor growth. Chemotherapeutic agents useful in the treatment methods of the present disclosure include cytostatic and/or cytotoxic agents.
The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral route or parenteral route of administration. The term “enteral route” of administration refers to the administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route. “Parenteral route” of administration refers to a route of administration other than enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous, or topical administration. The therapeutic agents and compositions of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. The suitable route and method of administration may vary depending on a number of factors such as the specific antibody being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the patient, and can be readily selected by a person skilled in the art.
The term “simultaneous administration” as used herein in relation to the administration of medicaments refers to the administration of medicaments such that the individual medicaments are present within a subject at the same time. In addition to the concomitant administration of medicaments (via the same or alternative routes), simultaneous administration may include the administration of the medicaments (via the same or an alternative route) at different times.
“Chothia” as used herein means an antibody numbering system described in Al-Lazikani et al., JMB 273:927-948 (1997).
“Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and/or specificity. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 1 below.
TABLE 1
Exemplary Conservative Amino Acid Substitutions
Original residue
Conservative substitution
Ala (A)
Gly; Ser
Arg (R)
Lys; His
Asn (N)
Gln; His
Asp (D)
Glu; Asn
Cys (C)
Ser; Ala
Gln (Q)
Asn
Glu (E)
Asp; Gln
Gly (G)
Ala
His (H)
Asn; Gln
Ile (I)
Leu; Val
Leu (L)
Ile; Val
Lys (K)
Arg; His
Met (M)
Leu; Ile; Tyr
Phe (F)
Tyr; Met; Leu
Pro (P)
Ala
Ser (S)
Thr
Thr (T)
Ser
Trp (W)
Tyr; Phe
Tyr (Y)
Trp; Phe
Val (V)
Ile; Leu
“Consists essentially of,” and variations such as “consist essentially of” or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion of other elements, of similar or different nature than the recited elements, that do not materially change the basic or novel properties of the specified dosage regimen, method, or composition.
“Diagnostic anti-PD-L monoclonal antibody” means a mAb that specifically binds to the mature form of the designated PD-L (PD-L1 or PDL2) expressed on the surface of certain mammalian cells. A mature PD-L lacks the presecretory leader sequence, also referred to as leader peptide. The terms “PD-L” and “mature PD-L” are used interchangeably herein, and shall be understood to mean the same molecule unless otherwise indicated or readily apparent from the context.
As used herein, a diagnostic anti-human PD-L1 mAb or an anti-hPD-L1 mAb refers to a monoclonal antibody that specifically binds to mature human PD-L1. A mature human PD-L1 molecule consists of amino acids 19-290 set forth in SEQ ID NO 21.
Specific examples of diagnostic anti-human PD-L1 mAbs useful as diagnostic mAbs for IHC detection of PD-L1 expression in FFPE tumor tissue sections are antibodies 20C3 and 22C3, which are described in PCT International Patent Application Publication No. WO2014/100079. Another anti-human PD-L1 mAb that has been reported to be useful for IHC detection of PD-L1 expression in FFPE tissue sections (Chen, B. J. et al., Clin Cancer Res 19: 3462-3473 (2013)) is a rabbit anti-human PD-L1 mAb publicly available from Sino Biological, Inc. (Beijing, P. R. China; Catalog number 10084-R015).
“Homology” refers to sequence similarity between two polypeptide sequences when they are optimally aligned. When a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, e.g., if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position. The percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared×100. For example, if 8 of 10 of the positions in two sequences are matched when the sequences are optimally aligned then the two sequences are 80% homologous. Generally, the comparison is made when two sequences are aligned to give maximum percent homology. For example, the comparison can be performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.
The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S. F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T. L., et al., (1996) Meth. Enzymol. 266:131-141; Altschul, S. F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J. C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J. M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M. O., et al., “A model of evolutionary change in proteins.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M. O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R. M., et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” M. O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S. F. “Evaluating the statistical significance of multiple distinct local alignments.” in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, N.Y.
The term “isolated” as used in reference to an antibody or fragment thereof refers to the purification status and, in such context, means the named molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.
“Kabat” as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).
“Monoclonal antibody” or “mAb” or “Mab”, as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.
“RECIST 1.1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E. A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.
“Sustained response” means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.
“Tissue Section” refers to a single part or piece of a tissue, e.g., a thin slice of tissue cut from a sample of a normal tissue or of a tumor.
“Treat” or “treating” a cell-proliferation disorder as used herein means to administer a combination therapy of a PD-1 antagonist and a benzo[b]thiophene STING agonist to a subject having a cell-proliferation disorder, such as cancer, or diagnosed with a cell-proliferation disorder, such as cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth. Such “treatment” may result in a slowing, interrupting, arresting, controlling, or stopping of the progression of a cell-proliferation disorder as described herein but does not necessarily indicate a total elimination of the cell-proliferation disorder or the symptoms of the cell-proliferation disorder. Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, a T/C≤42% is the minimum level of anti-tumor activity. A T/C<10% is considered a high anti-tumor activity level, with T/C (%)=Median tumor volume of the treated/Median tumor volume of the control×100. In some embodiments, the treatment achieved by a combination therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a combination therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria. The treatment regimen for a combination therapy of the disclosure that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student's t-test, the chi2-test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.
As used herein, the terms “combination therapy” and “therapeutic combination” refer to treatments in which at least one PD-1 antagonist and at least one benzo[b]thiophene STING agonist, and optionally additional therapeutic agents, each are administered to a patient in a coordinated manner, over an overlapping period of time. The period of treatment with the at least one PD-1 antagonist (the “anti-PD-1 treatment”) is the period of time that a patient undergoes treatment with the PD-1 antagonist; that is, the period of time from the initial dosing with the PD-1 antagonist through the final day of a treatment cycle. Similarly, the period of treatment with the at least one benzo[b]thiophene STING agonist (the “benzo[b]thiophene STING agonist treatment”) is the period of time that a patient undergoes treatment with the CDN STING agonist; that is, the period of time from the initial dosing with the benzo[b]thiophene STING agonist through the final day of a treatment cycle. In the therapeutic combinations described herein, the anti-PD-1 treatment overlaps by at least one day the benzo[b]thiophene STING agonist treatment. In certain embodiments, the anti-PD-1 treatment and the benzo[b]thiophene STING agonist treatment are coextensive. In embodiments, the anti-PD-1 treatment begins prior to the benzo[b]thiophene STING agonist treatment. In embodiments, the benzo[b]thiophene STING agonist treatment begins prior to the anti-PD-1 treatment. In embodiments, the anti-PD-1 treatment is terminated prior to termination of the benzo[b]thiophene STING agonist treatment. In embodiments, the benzo[b]thiophene STING agonist treatment is terminated prior to termination of the anti-PD-1 treatment.
The terms “treatment regimen”, “dosing protocol”, and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.
“Tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).
“Advanced solid tumor malignancy” and “advanced solid tumor” are used interchangeably to refer to a tumor for which curative resection is not possible. Advanced solid tumors include, but are not limited to, metastatic tumors in bone, brain, breast, liver, lungs, lymph node, pancreas, prostate, and soft tissue (sarcoma).
“Tumor burden” also referred to as “tumor load”, refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.
The term “tumor size” refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.
It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of” and/or “consisting essentially of” are also provided.
The term “alkyl” refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, “C1-6 alkyl” (or “C1-C6 alkyl”) refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec-, and tert-butyl, n- and iso-propyl, ethyl, and methyl. As another example, “C1-4 alkyl” refers to n-, iso-, sec-, and tert-butyl, n- and isopropyl, ethyl, and methyl.
As used herein, the term “alkylene” refers to a bivalent straight chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
As used herein, the term “alkenyl” refers to a monovalent straight or branched chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more double bond.
As used herein, the term “alkenylene” refers to a bivalent straight chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more double bond.
As used herein, the term “alkynyl” refers to a monovalent straight or branched chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more triple bond.
As used herein, the term “alkynylene” refers to a bivalent straight chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more triple bond.
The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine, and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo or F, Cl, Br, and I).
The term “haloalkyl” refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen. Thus, for example, “C1-6 haloalkyl” (or “C1-C6 haloalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term “fluoroalkyl” has an analogous meaning except the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).
As used herein, the term “haloalkenyl” refers to an alkenyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen.
As used herein, the term “haloalkynyl” refers to an alkynyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen.
As used herein, the term “alkoxy” as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom. The term “alkoxy” also includes alkyl ether groups, where the term ‘alkyl’ is defined above, and ‘ether’ means two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as ‘dimethyl ether’), and methoxyethane (also referred to as ‘ethyl methyl ether’).
As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclic”, as used herein, represents a stable 3- to 6-membered monocyclic that is either saturated or unsaturated, and that consists of carbon atoms and from one to two heteroatoms selected from the group consisting of N, O, and S. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl and thienyl.
As used herein, the term “fused ring” refers to a cyclic group formed by substituents on separate atoms in a straight or branched alkane, or to a cyclic group formed by substituents on separate atoms in another ring.
As used herein, the term “spirocycle” or “spirocyclic ring” refers to a pendant cyclic group formed by substituents on a single atom.
Unless expressly stated to the contrary, all ranges cited herein are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. As an example, temperature ranges, percentages, ranges of equivalents, and the like described herein include the upper and lower limits of the range and any value in the continuum there between. Numerical values provided herein, and the use of the term “about”, may include variations of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, and ±20% and their numerical equivalents. All ranges also are intended to include all included sub-ranges, although not necessarily explicitly set forth. For example, a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days. In addition, the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or” includes each listed alternative separately as well as their combination.
Where aspects or embodiments of the disclosure are described in terms of a Markush group or other grouping of alternatives, the present disclosure encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present disclosure also envisages the explicit exclusion of one or more of any of the group members in the claims.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.
Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.
The present disclosure relates to methods of treating a cell-proliferation disorder as defined herein, wherein the method comprises administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist.
The present disclosure relates to methods of treating a cell-proliferation disorder, wherein the method comprises administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist; wherein the cell-proliferation disorder is selected from the group consisting of solid tumors and lymphomas.
PD-1 Antagonist
“PD-1 antagonist” or “PD-1 pathway antagonist” means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T-cell, B-cell, or NKT-cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any of the treatment methods, medicaments and uses of the present disclosure in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively, and in SEQ ID NO: 21.
PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present disclosure include a mAb, or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in specific embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′)2, scFv, and Fv fragments.
Examples of mAbs that bind to human PD-1, and that may be useful in the treatment methods, medicaments, and uses of the present disclosure, are described in U.S. Pat. Nos. U.S. Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, and 8,168,757, PCT International Patent Application Publication Nos. WO2004/004771, WO2004/072286, and WO2004/056875, and U.S. Patent Application Publication No. US20110271358.
Examples of mAbs that bind to human PD-L1, and that may be useful in the treatment methods, medicaments and uses of the present disclosure, are described in PCT International Patent Application Nos. WO2013/019906 and WO2010/077634 and in U.S. Pat. No. 8,383,796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment methods, medicaments, and uses of the present disclosure include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C, and an antibody that comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013/019906. In particular embodiments, the PD-1 antagonist is an antigen binding fragment having variable regions comprising the heavy and light chain CDRs of WO2013/019906.
Other PD-1 antagonists useful in any of the treatment methods, medicaments, and uses of the present disclosure include an immune-adhesion molecule that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immune-adhesion molecules that specifically bind to PD-1 are described in PCT International Patent Application Publication Nos. WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment methods, medicaments, and uses of the present disclosure include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.
In embodiments, the PD-1 antagonist can be conjugated, e.g., to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG).
In some embodiments of the treatment methods, medicaments, and uses of the present disclosure, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising CDRH1 of SEQ ID NO 8, CDRH2 of SEQ ID NO 9, and CDRH3 of SEQ ID NO 10, and (b) a light chain variable region comprising CDRL1 of SEQ ID NO 5, CDRL2 of SEQ ID NO 6, and CDRL3 of SEQ ID NO 7. In specific embodiments, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising SEQ ID NO 2, and (b) a light chain variable region comprising SEQ ID NO 1. In specific embodiments, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain comprising SEQ ID NO 4, and (b) a light chain comprising SEQ ID NO 3.
In some embodiments of the treatment methods, medicaments, and uses of the present disclosure, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising CDRH1 of SEQ ID NO 18, CDRH2 of SEQ ID NO 19, and CDRH3 of SEQ ID NO 20, and (b) a light chain variable region comprising CDRL1 of SEQ ID NO 15, CDRL2 of SEQ ID NO 16, and CDRL3 of SEQ ID NO 17. In specific embodiments, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising SEQ ID NO 12, and (b) a light chain variable region comprising SEQ ID NO 11. In specific embodiments, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain comprising SEQ ID NO 14, and (b) a light chain comprising SEQ ID NO 13.
In some embodiments of the treatment methods, medicaments, and uses of the present disclosure, the PD-1 antagonist is an anti-PD-1 monoclonal antibody. In aspects of these embodiments, the PD-1 antagonist is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP-224. In specific aspects, the PD-1 antagonist is selected from nivolumab and pembrolizumab. In a more specific aspect, the PD-1 antagonist is nivolumab. In a further specific aspect, the PD-1 antagonist is pembrolizumab.
The present disclosure relates to PD-1 antagonists that are monoclonal antibodies, or antigen binding fragments thereof, which specifically bind to human PD-1 as described herein. In embodiments, PD-1 antagonists may comprise variant heavy chain variable region sequence and/or variant light chain variable region sequence identical to the reference sequence except having up to 17 conservative amino acid substitutions in the framework region (i.e., outside of the CDRs), and preferably have less than ten, nine, eight, seven, six, or five conservative amino acid substitutions in the framework region.
Table 2 below provides a list of the amino acid sequences of exemplary anti-PD-1 mAbs for use in the treatment methods, medicaments, and uses of the present disclosure, and the sequences are shown in FIGS. 1-9.
TABLE 2
Description of Sequences in Sequence Listing
SEQ ID NO:
Description
1
Pembrolizumab, variable light chain, amino acid
2
Pembrolizumab, variable heavy chain, amino acid
3
Pembrolizumab, light chain, amino acid
4
Pembrolizumab, heavy chain, amino acid
5
Pembrolizumab, CDRL1
6
Pembrolizumab, CDRL2
7
Pembrolizumab, CDRL3
8
Pembrolizumab, CDRH1
9
Pembrolizumab, CDRH2
10
Pembrolizumab, CDRH3
11
Nivolumab, variable light chain, amino acid
12
Nivolumab, variable heavy chain, amino acid
13
Nivolumab, light chain, amino acid
14
Nivolumab, heavy chain, amino acid
15
Nivolumab, CDRL1
16
Nivolumab, CDRL2
17
Nivolumab, CDRL3
18
Nivolumab, CDRH1
19
Nivolumab, CDRH2
20
Nivolumab, CDRH3
21
Human PD-L1
“PD-L1” expression or “PD-L2” expression as used herein means any detectable level of expression of the designated PD-L protein on the cell surface or of the designated PD-L mRNA within a cell or tissue. PD-L protein expression may be detected with a diagnostic PD-L antibody in an IHC assay of a tumor tissue section or by flow cytometry. Alternatively, PD-L protein expression by tumor cells may be detected by PET imaging, using a binding agent (e.g., antibody fragment, affibody, and the like) that specifically binds to the desired PD-L target, e.g., PD-L1 or PD-L2. Techniques for detecting and measuring PD-L mRNA expression include RT-PCR and realtime quantitative RT-PCR.
Several approaches have been described for quantifying PD-L1 protein expression in IHC assays of tumor tissue sections. See, e.g., Thompson, R. H., et al., PNAS 101 (49); 17174-17179 (2004); Thompson, R. H. et al., Cancer Res. 66:3381-3385 (2006); Gadiot, J., et al., Cancer 117:2192-2201 (2011); Taube, J. M. et al., Sci Transl Med 4, 127ra37 (2012); and Toplian, S. L. et al., New Eng. J. Med. 366 (26): 2443-2454 (2012).
One approach employs a simple binary end-point of positive or negative for PD-L1 expression, with a positive result defined in terms of the percentage of tumor cells that exhibit histologic evidence of cell-surface membrane staining. A tumor tissue section is counted as positive for PD-L1 expression is at least 1%, and preferably 5% of total tumor cells.
In another approach, PD-L1 expression in the tumor tissue section is quantified in the tumor cells as well as in infiltrating immune cells, which predominantly comprise lymphocytes. The percentage of tumor cells and infiltrating immune cells that exhibit membrane staining are separately quantified as <5%, 5 to 9%, and then in 10% increments up to 100%. For tumor cells, PD-L1 expression is counted as negative if the score is <5% score and positive if the score is ≥5%. PD-L1 expression in the immune infiltrate is reported as a semi-quantitative measurement called the adjusted inflammation score (AIS), which is determined by multiplying the percent of membrane staining cells by the intensity of the infiltrate, which is graded as none (0), mild (score of 1, rare lymphocytes), moderate (score of 2, focal infiltration of tumor by lymphohistiocytic aggregates), or severe (score of 3, diffuse infiltration). A tumor tissue section is counted as positive for PD-L1 expression by immune infiltrates if the AIS is ≥5.
The level of PD-L1 mRNA expression may be compared to the mRNA expression levels of one or more reference genes that are frequently used in quantitative RT-PCR, such as ubiquitin C.
In some embodiments, a level of PD-L1 expression (protein and/or mRNA) by malignant cells and/or by infiltrating immune cells within a tumor is determined to be “overexpressed” or “elevated” based on comparison with the level of PD-L1 expression (protein and/or mRNA) by an appropriate control. For example, a control PD-L1 protein or mRNA expression level may be the level quantified in nonmalignant cells of the same type or in a section from a matched normal tissue. In some embodiments, PD-L1 expression in a tumor sample is determined to be elevated if PD-L1 protein (and/or PD-L1 mRNA) in the sample is at least 10%, 20%, or 30% greater than in the control.
Benzo[b]Thiophene Sting Agonists
As used herein, “benzo[b]thiophene STING agonist” means any benzo[b]thiophene STING agonist chemical compound that activates the STING pathway, and in particular, the benzo[b]thiophene STING agonist STING agonists as disclosed in U.S. Provisional Patent Application No. 62/404,062, filed Oct. 4, 2016, which is incorporated herein in its entirety. Benzo[b]thiophene STING agonist STING agonists, and particularly the compounds of formulas (I), (Ia), and (Ib), may be used in the therapeutic combinations of this disclosure.
In embodiments, the benzo[b]thiophene STING agonist is selected from benzo[b]thiophene compounds of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R2 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R3 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R4 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R5 is selected from H, halogen, OR6, N(R6)2, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, COOR6, and C(O)N(R6)2; each R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl; X1 is C(O); X2 is (C(R8)2)(1-3); each R8 is independently selected from the group consisting of H, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N(R6)2; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle; X3 is selected from the group consisting of COOR6, C(O)SR6, C(S)OR6, SO2R6, and C(O)N(R9)2; and each R9 is independently selected from the group consisting of H, COOR6, and SO2R6; wherein when X1—X2—X3 is X1—CHR8—X3 or X1—CHR8CH2—X3, at least one of R2 and R3 is not selected from the group consisting of halogen, OR6, C1-C6 alkyl, and C1-C6 haloalkyl.
In aspects of this embodiment, R1 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2. In instances of this aspect, R1 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, R1 is selected from the group consisting of H and F. In this aspect, all other groups are as provided in the general formula (Ia) above.
In aspects of this embodiment, R2 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6). In instances of this aspect, R2 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2. In particular instances of this aspect, R2 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, R3 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6). In instances of this aspect, R3 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2. In particular instances of this aspect, R3 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, R4 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2. In instances of this aspect, R4 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, R4 is selected from the group consisting of H and F. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, R5 is selected from the group consisting of H, halogen, OR6, N(R6)2, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, COOR6, and C(O)N(R6)2. In instances of this aspect, R5 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, R5 is H. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, each R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In instances of this aspect, each R6 is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, each R6 is independently selected from the group consisting of H and CH3. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, X3 is selected from the group consisting of COOR6, C(O)SR6, C(S)OR6, SO2R6, and C(O)N(R9)2. In instances of this aspect, X3 is selected from the group consisting of COOR6, SO2R6, and C(O)N(R9)2. In particular instances of this aspect, X3 is COOR6. In even more particular instances of this aspect, X3 is COOH. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, each R9 is independently selected from the group consisting of H, COOR6, and SO2R6. In instances of this aspect, each R9 is independently H. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, X2 is (C(R8)2)(1-3), wherein each R8 is independently selected from the group consisting of H, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N(R6)2; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle. In a first instance of this aspect, X2 is CH2CHR8, where R8 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl. In particular occurrences of this first instance, X2 is CH2CHR8, wherein R8 is selected from the group consisting of H, CH3, CH2OH, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3, and cyclopropyl. In a second instance of this aspect, X2 is CHR8CHR8, where R8 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring. In particular occurrences of this second instance, X2 is CHR8CHR8, where R8 is selected from the group consisting of H and C1-C3 alkyl, and optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring. In a third instance of this aspect, X2 is CH2C(R8)2, where R8 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle. In particular occurrences of this third instance, X2 is CH2C(R8)2, where R8 is selected from the group consisting of H and C1-C3 alkyl, and optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle. In this aspect, all other groups are as provided in the general formula (Ia) or aspects described above.
In aspects of this embodiment, le is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R2 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R3 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R4 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R5 is selected from the group consisting of H, F, Cl, OR6, C1-C3 alkyl, and C1-C3 haloalkyl; each R6 is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; X1—X2—X3 is selected from the group consisting of C(O)—CH2CHR8—COOR6, C(O)—CH2CHR8—SO2R6, and C(O)—CH2CHR8—C(O)N(R9)2; and each R8 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl. In instances of this aspect, le is selected from the group consisting of H and F; R2 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R3 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R4 is selected from the group consisting of H and F; R5 is H; each R6 is independently selected from the group consisting of H and CH3; X1—X2—X3 is C(O)—CH2CHR8—COOH; and R8 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3, and cyclopropyl. In this aspect, all other groups are as provided in the general formula (Ia) above.
In aspects of this embodiment, le is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R2 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R3 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R4 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R5 is selected from the group consisting of H, F, Cl, OR6, C1-C3 alkyl, and C1-C3 haloalkyl; each R6 is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; X1-—X2—X3 is selected from the group consisting of C(O)—CHR8CHR8—COOR6, C(O)—CHR8CHR8—SO2R6, and C(O)—CHR8CHR8—C(O)N(R9)2; and each R8 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and where optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring. In instances of this aspect, le is selected from the group consisting of H and F; R2 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R3 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R4 is selected from the group consisting of H and F; R5 is H; each R6 is independently selected from the group consisting of H and CH3; X1—X2—X3 is C(O)—CHR8CHR8—COOH; and each R8 is selected from the group consisting of H and C1-C3 alkyl, and where optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring. In this aspect, all other groups are as provided in the general formula (Ia) above.
In aspects of this embodiment, le is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R2 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R3 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R4 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R5 is selected from the group consisting of H, F, Cl, OR6, C1-C3 alkyl, and C1-C3 haloalkyl; each R6 is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; X1—X2—X3 is selected from the group consisting of C(O)—CH2C(R8)2—COOR6, C(O)—CH2C(R)2—SO2R6, and C(O)—CH2C(R8)2—C(O)N(R9)2; and each R8 is selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and where optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle. In instances of this aspect, le is selected from the group consisting of H and F; R2 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R3 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R4 is selected from the group consisting of H and F; R5 is H; each R6 is independently selected from the group consisting of H and CH3; X1—X2—X3 is C(O)—CH2C(R8)2—COOH; and each R8 is selected from the group consisting of H and C1-C3 alkyl, and where optionally 2 R8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle. In this aspect, all other groups are as provided in the general formula (Ia) above.
An additional aspect of this embodiment relates to a pharmaceutical composition, said pharmaceutical composition comprising (a) a compound according to general formula (Ia) or aspects described above or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
An additional aspect of this embodiment relates to methods of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a compound according to general formula (Ia) or aspects described above or a pharmaceutically acceptable salt thereof to the subject.
An additional aspect of this embodiment relates to methods of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a composition described above to the subject.
An additional aspect of this embodiment relates to methods of inducing a STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a compound according to general formula (Ia) or aspects described above or a pharmaceutically acceptable salt thereof to the subject.
An additional aspect of this embodiment relates to methods of inducing STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a composition described above to the subject.
An additional aspect of this embodiment relates to methods of inducing STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a compound according to general formula (Ia) or aspects described above or a pharmaceutically acceptable salt thereof to the subject.
An additional aspect of this embodiment relates to methods of inducing a STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a composition according described above to the subject.
In each embodiment described herein, variables R1, R2, R3, R4, R5, R6, R8, R9, X1, X2, and X3 of general formula (Ia), and the various aspects and instances thereof, are each selected independently from each other, with the proviso that at least one of R′, R2, R3, R4, R5, R6, R8, and R9 is not H.
A second embodiment relates to compounds of general formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R2 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R3 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R4 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R5 is selected from H, halogen, OR6, N(R6)2, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, COOR6, and C(O)N(R6)2; each R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl; X1 is C(O); X2 is CH2CHR8; each R8 is independently selected from the group consisting of halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N(R6)2; X3 is selected from the group consisting of COOR6, C(O)SR6, C(S)OR6, SO2R6, and C(O)N(R9)2; and each R9 is independently selected from the group consisting of H, COOR6, and SO2R6; wherein X1—X2—X3 is X1—CH2CHR8—X3.
In aspects of this embodiment, le is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2. In instances of this aspect, le is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, le is selected from the group consisting of H and F. In this aspect, all other groups are as provided in the general formula (Ib) above.
In aspects of this embodiment, R2 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6). In instances of this aspect, R2 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2. In particular instances of this aspect, R2 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, R3 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6). In instances of this aspect, R3 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2. In particular instances of this aspect, R3 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, R4 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2. In instances of this aspect, R4 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, R4 is selected from the group consisting of H and F. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, R5 is selected from the group consisting of H, halogen, OR6, N(R6)2, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, COOR6, and C(O)N(R6)2. In instances of this aspect, R5 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, R5 is H. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, each R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In instances of this aspect, each R6 is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl. In particular instances of this aspect, each R6 is independently selected from the group consisting of H and CH3. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, X3 is selected from the group consisting of COOR6, C(O)SR6, C(S)OR6, SO2R6, and C(O)N(R9)2. In instances of this aspect, X3 is selected from the group consisting of COOR6, SO2R6, and C(O)N(R9)2. In particular instances of this aspect, X3 is COOR6. In even more particular instances of this aspect, X3 is COOH. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, each R9 is independently selected from the group consisting of H, COOR6, and SO2R6. In instances of this aspect, each R9 is independently H. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, X2 is CH2CHR8, wherein each R8 is independently selected from the group consisting of halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N(R6)2. In instances of this aspect, R8 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl. In particular instances, R8 is selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3, and cyclopropyl. In this aspect, all other groups are as provided in the general formula (Ib) or aspects described above.
In aspects of this embodiment, le is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R2 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R3 is selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, C2-C3 alkenyl, and N(R6)2; R4 is selected from the group consisting of H, F, Cl, C1-C3 alkyl, and C1-C3 haloalkyl; R5 is selected from the group consisting of H, F, Cl, OR6, C1-C3 alkyl, and C1-C3 haloalkyl; each R6 is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 haloalkyl; X1—X2—X3 is selected from the group consisting of C(O)—CH2CHR8—COOR6, C(O)—CH2CHR8—SO2R6, and C(O)—CH2CHR8—C(O)N(R9)2; R8 is selected from the group consisting of C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl. In instances of this aspect, le is selected from the group consisting of H and F; R2 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R3 is selected from the group consisting of Br, Cl, CH3, CH2CH3, CH═CH2, OCH3, and N(R6)2; R4 is selected from the group consisting of H and F; R5 is H; each R6 is independently selected from the group consisting of H and CH3; X1—X2—X3 is C(O)—CH2CHR8—COOH; and R8 is selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3, and cyclopropyl. In this aspect, all other groups are as provided in the general formula (Ib) above.
An additional aspect of this embodiment relates to a pharmaceutical composition, said pharmaceutical composition comprising (a) a compound according to general formula (Ib) or aspects described above or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
An additional aspect of this embodiment relates to methods of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a compound according to general formula (Ib) or aspects described above or a pharmaceutically acceptable salt thereof to the subject.
An additional aspect of this embodiment relates to methods of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a composition described above to the subject.
An additional aspect of this embodiment relates to methods of inducing a STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a compound according to general formula (Ib) or aspects described above or a pharmaceutically acceptable salt thereof to the subject.
An additional aspect of this embodiment relates to methods of inducing a STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a composition described above to the subject.
An additional aspect of this embodiment relates to methods of inducing STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a compound according to general formula (Ib) or aspects described above or a pharmaceutically acceptable salt thereof to the subject.
An additional aspect of this embodiment relates to methods of inducing STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a composition described above to the subject.
In each embodiment described herein, variables R1, R2, R3, R4, R5, R6, R8, R9, X1, X2, and X3 of general formula (Ib), and the various aspects and instances thereof, are each selected independently from each other, with the proviso that at least one of R′, R2, R3, R4, R5, R6, R8, and R9 is not H.
Additional embodiments of this disclosure relate to uses of compounds of general formula (I), and pharmaceutically acceptable salts thereof. The compounds of general formula (I) may be useful as agents to induce immune responses, to induce STING-dependent type I interferon production, and/or to treat a cell proliferation disorder. In these embodiments, the compound of formula (I) is
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R2 is selected from the group consisting of H, halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R3 is selected from the group consisting of H, halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R4 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R5 is selected from H, halogen, OR6, N(R6)2, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, COOR6, and C(O)N(R6)2; each R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl; X1 is C(O); X2 is (C(R8)2)(1-3); each R8 is independently selected from the group consisting of H, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N(R6)2; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle; X3 is selected from the group consisting of COOR6, C(O)SR6, C(S)OR6, SO2R6, and C(O)N(R9)2; and each R9 is independently selected from the group consisting of H, COOR6, and SO2R6.
An additional embodiment relates to methods of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a compound of general formula (I) above or a pharmaceutically acceptable salt thereof to the subject.
An additional embodiment relates to methods of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a composition comprising a compound of general formula (I) above or a pharmaceutically acceptable salt thereof to the subject.
An additional embodiment relates to methods of inducing STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof to the subject.
An additional embodiment relates to methods of inducing STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a composition comprising a compound of general formula (I) above or a pharmaceutically acceptable salt thereof to the subject.
An additional embodiment relates to methods of inducing STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a compound of general formula (I) above or a pharmaceutically acceptable salt thereof to the subject.
An additional embodiment relates to methods of inducing STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a composition comprising a compound of general formula (I) above or a pharmaceutically acceptable salt thereof to the subject.
In each embodiment described herein, variables R1, R2, R3, R4, R5, R6, R8, R9, X1, X2, and X3 of general formula (I), and the various aspects and instances thereof, are each selected independently from each other, with the proviso that at least one of R1, R2, R3, R4, R5, R6, R8, and R9 is not H.
An additional embodiment relates to a compound selected from the group consisting of
and pharmaceutically acceptable salts thereof. In aspects of this embodiment, the compound is selected from the group consisting of
and pharmaceutically acceptable salts thereof.
Salts
As indicated above, the compounds of the present invention can be employed in the form of pharmaceutically acceptable salts. Those skilled in the art will recognize those instances in which the compounds of the invention may form salts. Examples of such compounds are described herein by reference to possible salts. Such reference is for illustration only. Pharmaceutically acceptable salts can be used with compounds for treating patients. Non-pharmaceutical salts may, however, be useful in the preparation of intermediate compounds.
The term “pharmaceutically acceptable salt” refers to a salt (including an inner salt such as a zwitterion) that possesses effectiveness similar to the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Thus, an embodiment of the invention provides pharmaceutically acceptable salts of the compounds of the invention. The term “salt(s)”, as employed herein, denotes any of the following: acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Salts of compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.), Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (—COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole, and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds of the invention may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the invention.
Methods of Preparing Compounds
Several methods for preparing the compounds of general formula (Ia), the compounds of general formula (Ib), the compounds of general formula (I), and pharmaceutically acceptable salts of the foregoing, are described in the following Schemes and Examples. Starting materials and intermediates are purchased from commercial sources, made from known procedures, or are otherwise illustrated. In some cases the order of carrying out the steps of the reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
In the following Methods and Schemes, LG represents a leaving group, which may be a halide or triflate group. The variables R2, R3, R4, R6, R8, and X2, have the same meaning as provided above.
Method 1
Benzo[b]thiophene 2-carboxylic acids are typically prepared from ortho-halo benzaldehydes. The sequence starts with treatment with an alpha-thio acetic acid ester under basic condition. Then, the ester in the resulting compound was cleaved to the carboxylic acid under basic condition to provide the desired substituted benzo[b]thiophene 2-carboxylic acid 1C.
Method 2
One method for the preparation of the compounds of general formula (Ia), the compounds of general formula (Ib), the compounds of general formula (I), and pharmaceutically acceptable salts of the foregoing, is detailed in Scheme 2. The sequence starts with a benzo[b]thiophene substituted at the 2-position with an appropriate 1,3-dicarbonyl group, such as a beta-keto ester. It was reacted with an alpha-halo ester under basic condition to afford substitution at the 2 position of the alkyl chain. Then, both esters were hydrolyzed using either acidic or basic condition; upon further exposure to basic condition, the carboxylic acid corresponding to the ester in the starting material underwent decarboxylation to give the desired benzo[b]thiophene keto acid 2C.
Method 3
Another method for the preparation of the compounds of general formula (Ia), the compounds of general formula (Ib), the compounds of general formula (I), and pharmaceutically acceptable salts of the foregoing, is detailed in Scheme 3. The sequence starts with a benzo[b]thiophene without substitution at the 2 position. It was treated with tert-butyllithium followed by a cyclic acid anhydride to give the desired 4-keto carboxylic acid product 3B.
Method 4
Another method for the preparation of the compounds of general formula (Ia), the compounds of general formula (Ib), the compounds of general formula (I), and pharmaceutically acceptable salts of the foregoing, is detailed in Scheme 4. The sequence starts with a benzo[b]thiophene substituted with a carboxylic acid at the 2 position. It was treated with oxalyl chloride/dichloromethane condition. The resulting acid chloride was reacted with an alkyl zinc reagent, typically containing an ester, using a transition metal such as copper or palladium to mediate the coupling. Then, the ester was cleaved under basic or acidic condition to provide the desired benzo[b]thiophene gamma-keto acid 4D.
Method 5
Another method for the preparation of the compounds of general formula (Ia), the compounds of general formula (Ib), the compounds of general formula (I), and pharmaceutically acceptable salts of the foregoing, is detailed in Scheme 5. The sequence starts with a benzo[b]thiophene substituted at the 2 position with a gamma-keto ester and with a halide or triflate on the benzo[b]thiophene. It was treated with a boronic ester, acid, or trifluoroborate salt and a palladium catalyst under aqueous basic condition. Then the ester in the resulting compound was cleaved to the carboxylic acid under basic condition to provide the desired substituted benzo[b]thiophene 5C. The following scheme depicts introduction of the R2 substituent, but this same general method couple bring in certain R3 substituents as well when employing a related substrate with an appropriately placed LG.
Administration
The present disclosure relates to methods of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist.
PD-1 antagonists may be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, monthly, bimonthly, quarterly, semiannually, annually etc. Doses may be provided, e.g., intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation. A total dose for a treatment interval is generally at least 0.05 μg/kg body weight, more generally at least 0.2 μg/kg, 0.5 μg/kg, 1 μg/kg, 10 ug/kg, 100 μg/kg, 0.25 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 5.0 mg/ml, 10 mg/kg, 25 mg/kg, 50 mg/kg or more (see, e.g., Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji, et al. (20003) Cancer Immunol. Immunother. 52:133-144). Doses may also be provided to achieve a pre-determined target concentration of PD-1 antagonists in the subject's serum, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg/mL or more. In embodiments, the PD-1 antagonist is administered as a 200 mg dose once every 21 days. In other embodiments, PD-1 antagonists are administered subcutaneously or intravenously, on a weekly, biweekly, “every 4 weeks,” monthly, bimonthly, or quarterly basis at 10, 20, 50, 80, 100, 200, 500, 1000 or 2500 mg/subject.
The benzo[b]thiophene STING agonists and a pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to a subject by a desired route of administration. For example, dosage forms include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients may be chosen for a particular function that they may serve in the composition. In embodiments, the benzo[b]thiophene STING agonist may be formulated into a dosage form that allows for systemic use, i.e., distribution of the benzo[b]thiophene STING agonist throughout the body of the subject; examples of such systemic administration include oral administration and intravenous administration. In additional embodiments, the benzo[b]thiophene STING agonist may be formulated into a dosage form that allows for targeted or isolated use, i.e., administration of the benzo[b]thiophene STING agonist only to the portion of the subject's body to be treated; examples of such targeted administration include intratumoral injection.
The benzo[b]thiophene STING agonist is administered once every 1 to 30 days. In embodiments, the benzo[b]thiophene STING agonist is administered once every 3 to 28 days. In particular embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days. In embodiments of such methods, the benzo[b]thiophene STING agonist is administered for from 2 to 36 months. In specific embodiments, the benzo[b]thiophene STING agonist is administered for up to 3 months. In additional embodiments of such methods, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for from 2 to 36 months. In further embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for up to 3 months. In specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for up to 3 months, followed by a period, lasting at least 2 months, in which the time interval between doses is increased by at least two-fold. In more specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for up to 3 months, followed by a period, lasting at least 2 months, in which the time interval between doses is increased by at least three-fold. For example, if the benzo[b]thiophene STING agonist is administered once every 7 days for up to 3 months, it may be followed by a period in which the benzo[b]thiophene STING agonist is administered once every 14 or 21 days for up to two years.
In some embodiments, at least one of the therapeutic agents (the PD-1 antagonist and the benzo[b]thiophene STING agonist) in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.
A combination therapy of the invention may be used prior to or following surgery to remove a tumor and may be used prior to, during, or after radiation treatment.
In some embodiments, a combination therapy of the invention is administered to a patient who has not previously been treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naïve. In other embodiments, the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with the biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
Thus, the present disclosure relates to methods of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist; wherein the PD-1 antagonist is administered once every 21 days; and the benzo[b]thiophene STING agonist is administered once every 1 to 30 days for 3 to 90 days, then optionally once every 1 to 30 days for up to 1050 days. In embodiments, the benzo[b]thiophene STING agonist is administered at least three times.
In specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3 to 30 days for 9 to 90 days, then optionally once every 3 to 30 days for up to 1050 days. In specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3 to 21 days for 9 to 63 days, then optionally once every 3 to 21 days for up to 735 days. In further specific embodiments, the benzo[b]thiophene STING agonist is administered once every 7 to 21 days for 21 to 63 days, then optionally once every 7 to 21 days for up to 735 days. In still further embodiments, the benzo[b]thiophene STING agonist is administered once every 7 to 10 days for 21 to 30 days, then optionally once every 21 days for up to 735 days. In still further embodiments, the benzo[b]thiophene STING agonist is administered once every 7 days for 21 days, then optionally once every 21 days for up to 735 days. In additional embodiments, the benzo[b]thiophene STING agonist is administered once every 21 days for 63 days, then optionally once every 21 days for up to 735 days. In specific embodiments of the foregoing, the benzo[b]thiophene STING agonist is administered at least three times.
In some embodiments, one or more optional “rest” periods, during which the benzo[b]thiophene STING agonist is not administered, may be included in the treatment period. In specific embodiments, the optional rest period may be for from 3 to 30 days, from 7 to 21 days, or from 7 to 14 days. Following the rest period, dosing of the benzo[b]thiophene STING agonist may be resumed as described above.
Cell-Proliferation Disorders
The combination therapies disclosed herein are potentially useful in treating diseases or disorders including, but not limited to, cell-proliferation disorders. Cell-proliferation disorders include, but are not limited to, cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma. The terms “cancer”, “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A variety of cancers where PD-L1 or PD-L2 are implicated, whether malignant or benign and whether primary or secondary, may be treated or prevented with a method provided by the disclosure. Particularly preferred cancers that may be treated in accordance with the present disclosure include those characterized by elevated expression of one or both of PD-L1 and PD-L2 in tested tissue samples.
In specific embodiments, the disease or disorder to be treated is a cell-proliferation disorder. In certain embodiments, the cell-proliferation disorder is cancer. In particular embodiments, the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (i.e., cancers in which a metastasized cancer is found but the original cancer site is not known). In particular embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related.
In specific embodiments, the cancer is selected from brain and spinal cancers. In particular embodiments, the brain and spinal cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (also known as olfactory blastomas). In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytoma/malignant glioma, visual pathway and hypothalmic glioma, and primary central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sPNET).
In specific embodiments, the cancer is selected from cancers of the head and neck, including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
In specific embodiments, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic.
In specific embodiments, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers. In specific embodiments, the skin cancer is unresectable or metastatic melanoma.
In specific embodiments, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, endometrial cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors. In specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In more specific instances of these embodiments, the breast cancer is triple-negative breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.
In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.
In specific embodiments, the cancer is selected from liver and bile duct cancers. In particular embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma). In particular embodiments, the cancer is bile duct cancer (also known as cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
In specific embodiments, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urothelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.
In specific embodiments, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, chordoma (cancer of the bone along the spine).
In specific embodiments, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
In specific embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
In specific embodiments, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.
In specific embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed-Sternberg cells), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, primary central nervous system lymphomas.
In specific embodiments, the cancer is selected from glandular cancers. In particular embodiments, the cancer is selected from the group consisting of adrenocortical cancer (also known as adrenocortical carcinoma or adrenal cortical carcinoma), pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.
In specific embodiments, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
In specific embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
In specific embodiments, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.
In specific embodiments, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).
In embodiments, the cell-proliferation disorder is a cancer that has metastasized, for example, a liver metastases from colorectal cancer.
In embodiments, the cell-proliferation disorder is selected from the group consisting of solid tumors and lymphomas. In particular embodiments, the cell-proliferation disorder is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In more particular embodiments, the cell-proliferation disorder is selected from the group consisting of malignant melanoma, head and neck squamous cell carcminoma, breast adenocarcinoma, and lymphomas. In aspects of such embodiments, the lymphomas are selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma/leukemia, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma.
In particular embodiments, the cell-proliferation disorder is classified as stage III cancer or stage IV cancer. In instances of these embodiments, the cancer is not surgically resectable.
Methods, Uses, and Medicaments
Products provided as therapeutic combinations may include a composition comprising a PD-1 antagonist and a benzo[b]thiophene STING agonist together in the same pharmaceutical composition, or may include a composition comprising a PD-1 antagonist, and a composition comprising a benzo[b]thiophene STING agonist in separate form, e.g. in the form of a kit or in any form designed to enable separate administration either concurrently or on separate dosing schedules.
The combination therapy may also comprise one or more additional therapeutic agents. The additional therapeutic agent may be, e.g., a chemotherapeutic, a biotherapeutic agent (including but not limited to antibodies to VEGF, VEGFR, EGFR, Her2/neu, other growth factor receptors, CD20, CD40, CD-40L, CTLA-4, OX-40, 4-1BB, and ICOS), an immunogenic agent (for example, attenuated cancerous cells, tumor antigens, antigen presenting cells such as dendritic cells pulsed with tumor derived antigen or nucleic acids, immune stimulating cytokines (for example, IL-2, IFNα2, GM-CSF), and cells transfected with genes encoding immune stimulating cytokines such as but not limited to GM-CSF). The one or more additional active agents may be co-administered either with the PD-1 antagonist or with the benzo[b]thiophene STING agonist. The additional active agent(s) may be administered in a single dosage form with one or more co-administered agent selected from the PD-1 antagonist and the benzo[b]thiophene STING agonist, or the additional active agent(s) may be administered in separate dosage form(s) from the dosage forms containing the PD-1 antagonist and/or the benzo[b]thiophene STING agonist.
The therapeutic combination disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cell-proliferation disorders). In one embodiment, a compound disclosed herein is combined with one or more other anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of a particular disease or condition for which the compounds disclosed herein are useful. Such other active agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure.
The additional active agent(s) may be one or more agents selected from the group consisting of STING agonists, anti-viral compounds, antigens, adjuvants, anti-cancer agents, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and immunomodulatory agents including but not limited to anti-cancer vaccines. It will be understood the descriptions of the above additional active agents may be overlapping. It will also be understood that the treatment combinations are subject to optimization, and it is understood that the best combination to use of the PD-1 antagonist and/or the benzo[b]thiophene STING agonist, and one or more additional active agents will be determined based on the individual patient needs.
When the therapeutic combination disclosed herein is used contemporaneously with one or more other active agents, the PD-1 antagonist and/or the benzo[b]thiophene STING agonist may be administered either simultaneously with, or before or after, one or more other active agent(s). Either of the PD-1 antagonist and/or the benzo[b]thiophene STING agonist may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).
The weight ratio of the PD-1 antagonist to the benzo[b]thiophene STING agonist may be varied and will depend upon the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. Combinations including at least one PD-1 antagonist, at least one benzo[b]thiophene STING agonist, and other active agents will generally include a therapeutically effective dose of each active agent. In such combinations, the PD-1 antagonist and/or the benzo[b]thiophene STING agonist disclosed herein and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agent(s).
In one embodiment, this disclosure provides a PD-1 antagonist and/or a benzo[b]thiophene STING agonist, and at least one other active agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a cell-proliferation disorder, such as cancer.
In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, one of which contains a PD-1 antagonist and another of which contains a benzo[b]thiophene STING agonist. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. A kit of this disclosure may be used for administration of different dosage forms, for example, oral and parenteral, for administration of the separate compositions at different dosage intervals, or for titration of the separate compositions against one another. To assist with compliance, a kit of the disclosure typically comprises directions for administration.
The disclosure also provides the use of a benzo[b]thiophene STING agonist for treating a cell-proliferation disorder, where the patient has previously (e.g., within 24 hours) been treated with a PD-1 antagonist. The disclosure also provides the use of a PD-1 antagonist for treating a cell-proliferation disorder, where the patient has previously (e.g., within 24 hours) been treated with a benzo[b]thiophene STING agonist.
Anti-viral compounds that may be used in combination with the therapeutic combinations disclosed herein include hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.
Antigens and adjuvants that may be used in combination with the therapeutic combinations disclosed herein include B7 costimulatory molecule, interleukin-2, interferon-γ, GM-CSF, CTLA-4 antagonists, OX-40/0X-40 ligand, CD40/CD40 ligand, sargramostim, levamisol, vaccinia virus, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surface active substances such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants, such as aluminum hydroxide or aluminum phosphate, can be added to increase the ability of the vaccine to trigger, enhance, or prolong an immune response. Additional materials, such as cytokines, chemokines, and bacterial nucleic acid sequences, like CpG, a toll-like receptor (TLR) 9 agonist as well as additional agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR9, including lipoprotein, lipopolysaccharide (LPS), monophosphoryllipid A, lipoteichoic acid, imiquimod, resiquimod, and in addition retinoic acid-inducible gene I (RIG-I) agonists such as poly I:C, used separately or in combination are also potential adjuvants.
Examples of cytotoxic agents that may be used in combination with the therapeutic combinations disclosed herein include, but are not limited to, arsenic trioxide (sold under the tradename TRISENOX®), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames ELSPAR® and KIDROLASE®).
Chemotherapeutic agents that may be used in combination with the therapeutic combinations disclosed herein include abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea andtaxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, nivolumab, onapristone, paclitaxel, pembrolizumab, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine, and pharmaceutically acceptable salts thereof.
Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark AVASTIN by Genentech/Roche), axitinib (described in PCT International Patent Publication No. WO01/002369), Brivanib Alaninate ((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide. and described in PCT International Patent Application Publication No. WO02/068470), pasireotide (also known as SO 230, and described in PCT International Patent Publication No. WO02/010192), and sorafenib (sold under the tradename NEXAVAR).
Examples of topoisomerase II inhibitors, include but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames TOPOSAR, VEPESID, and ETOPOPHOS), and teniposide (also known as VM-26, sold under the tradename VUMON).
Examples of alkylating agents, include but are not limited to, 5-azacytidine (sold under the trade name VIDAZA), decitabine (sold under the trade name of DECOGEN), temozolomide (sold under the trade names TEMODAR and TEMODAL), dactinomycin (also known as actinomycin-D and sold under the tradename COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename ALKERAN), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename HEXALEN), carmustine (sold under the tradename BCNU), bendamustine (sold under the tradename TREANDA), busulfan (sold under the tradenames BUSULFEX® and MYLERAN®), carboplatin (sold under the tradename PARAPLATIN®), lomustine (also known as CCNU, sold under the tradename CEENU®), cisplatin (also known as CDDP, sold under the tradenames PLATINOL® and PLATINOL®-AQ), chlorambucil (sold under the tradename LEUKERAN®), cyclophosphamide (sold under the tradenames CYTOXAN® and NEOSAR®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-DOME®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename HEXALEN®), ifosfamide (sold under the tradename IFEX®), procarbazine (sold under the tradename MATULANE®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename MUSTARGEN®), streptozocin (sold under the tradename ZANOSAR®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, and sold under the tradename THIOPLEX®, and pharmaceutically acceptable salts thereof.
Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin (sold under the tradenames ADRIAMYCIN® and RUBEX®, bleomycin (sold under the tradename LENOXANE®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename CERUBIDINE®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DAUNOXOME®, mitoxantrone (also known as DHAD, sold under the tradename NOVANTRONE®), epirubicin (sold under the tradename ELLENCE™), idarubicin (sold under the tradenames IDAMYCIN®, IDAMYCIN®, PFS®), and mitomycin C (sold under the tradename MUTAMYCIN®).
Examples of anti-metabolites include, but are not limited to, claribine (2-chlorodeoxyadenosine, sold under the tradename LEUSTATIN®), 5-fluorouracil (sold under the tradename ADRUCIL®), 6-thioguanine (sold under the tradename PURINETHOL®), pemetrexed (sold under the tradename ALIMTA®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename CYROSAR-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DEPOCYT™), decitabine (sold under the tradename DACOGEN®), hydroxyurea and (sold under the tradenames HYDREA®, DROXIA™ and MYLOCEL™) fludarabine (sold under the tradename FLUDARA®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename LEUSTATIN™), methotrexate (also known as amethopterin, methotrexate sodium (MTX), sold under the tradenames RHEUMATREX® and TREXALL™), and pentostatin (sold under the tradename NIPENT®).
Examples of retinoids include, but are not limited to, alitretinoin (sold under the tradename PANRETIN®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename VESANOID®), Isotretinoin (13-c/s-retinoic acid, sold under the tradenames ACCUTANE®, AMNESTEEM®, CLARAVIS®, CLARUS®, DECUTAN®, ISOTANE®, IZOTECH®, ORATANE®, ISOTRET®, and SOTRET®), and bexarotene (sold under the tradename TARGRETIN®).
Additional Embodiments
The present disclosure further relates to methods of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist; wherein the PD-1 antagonist is administered once every 21 days; and the benzo[b]thiophene STING agonist is administered once every 1 to 30 days. In embodiments, the benzo[b]thiophene STING agonist is administered once every 3 to 28 days. In particular embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days.
In embodiments of such methods, the benzo[b]thiophene STING agonist is administered for from 2 to 36 months. In specific embodiments, the benzo[b]thiophene STING agonist is administered for up to 3 months.
In additional embodiments of such methods, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for from 2 to 36 months. In further embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for up to 3 months. In specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for up to 3 months, followed by a period, lasting at least 2 months, in which the time interval between doses is increased by at least two-fold. In more specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3, 7, 14, 21, or 28 days for up to 3 months, followed by a period, lasting at least 2 months, in which the time interval between doses is increased by at least three-fold. For example, if the benzo[b]thiophene STING agonist is administered once every 7 days for up to 3 months, it may be followed by a period in which the benzo[b]thiophene STING agonist is administered once every 14 or 21 days for up to two years.
The present disclosure further relates to methods of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist; wherein the PD-1 antagonist is administered once every 21 days; and the benzo[b]thiophene STING agonist is administered once every 1 to 30 days for 3 to 90 days, then optionally once every 1 to 30 days for up to 1050 days. In embodiments, the benzo[b]thiophene STING agonist is administered at least three times.
In specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3 to 30 days for 9 to 90 days, then optionally once every 3 to 30 days for up to 1050 days. In specific embodiments, the benzo[b]thiophene STING agonist is administered once every 3 to 21 days for 9 to 63 days, then optionally once every 3 to 21 days for up to 735 days. In further specific embodiments, the benzo[b]thiophene STING agonist is administered once every 7 to 21 days for 21 to 63 days, then optionally once every 7 to 21 days for up to 735 days. In still further embodiments, the benzo[b]thiophene STING agonist is administered once every 7 to 10 days for 21 to 30 days, then optionally once every 21 days for up to 735 days. In still further embodiments, the benzo[b]thiophene STING agonist is administered once every 7 days for 21 days, then optionally once every 21 days for up to 735 days. In additional embodiments, the benzo[b]thiophene STING agonist is administered once every 21 days for 63 days, then optionally once every 21 days for up to 735 days. In specific embodiments of the foregoing, the benzo[b]thiophene STING agonist is administered at least three times.
Additionally, the present disclosure relates to methods of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a PD-1 antagonist; and (b) a benzo[b]thiophene STING agonist; wherein the cell-proliferation disorder is cancer. In specific embodiments, the cancer occurs as one or more solid tumors or lymphomas. In further specific embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In still further specific embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphomas. In additional embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma/leukemia, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma. In particular embodiments, the cell-proliferation disorder is a cancer that has metastasized, for example, a liver metastases from colorectal cancer. In additional embodiments, the cell-proliferation disorder is a cancer is classified as stage III cancer or stage IV cancer. In instances of these embodiments, the cancer is not surgically resectable.
In embodiments of the methods disclosed herein, the PD-1 antagonist is an anti-PD-1 monoclonal antibody. In particular aspects of these embodiments, the PD-1 antagonist is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP-224. In specific aspects of these embodiments, the PD-1 antagonist is selected from nivolumab and pembrolizumab. In a more specific aspect, the PD-1 antagonist is nivolumab. In a further specific aspect, the PD-1 antagonist is pembrolizumab.
In embodiments of the methods disclosed herein, the benzo[b]thiophene STING agonist is selected from compounds of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R2 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R3 is selected from the group consisting of halogen, CN, OR6, N(R6)2, COOR6, C(O)N(R6)2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R6); R4 is selected from the group consisting of H, halogen, OR6, N(R6)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C1-C6 alkyl substituted by N(R6)2, COOR6, and C(O)N(R6)2; R5 is selected from H, halogen, OR6, N(R6)2, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, COOR6, and C(O)N(R6)2; each R6 is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl; X1 is C(O); X2 is (C(R8)2)(1-3); each R8 is independently selected from the group consisting of H, halogen, C1-C6 alkyl, CN, OR6, N(R6)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N(R6)2; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring; optionally 2 R8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle; X3 is selected from the group consisting of COOR6, C(O)SR6, C(S)OR6, SO2R6, and C(O)N(R9)2; and each R9 is independently selected from the group consisting of H, COOR6, and SO2R6; wherein when X1—X2—X3 is X1—CHR8—X3 or X1—CHR8CH2—X3, and at least one of R2 and R3 is not selected from the group consisting of halogen, OR6, C1-C6 alkyl, and C1-C6 haloalkyl.
In instances of these embodiments, the benzo[b]thiophene STING agonist is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In embodiments of the methods disclosed herein, the PD-1 antagonist is administered by intravenous infusion, and the benzo[b]thiophene STING agonist is orally, by intravenous infusion, by intertumoral injection, or by subcutaneous injection.
In embodiments of the methods disclosed herein, the PD-1 antagonist is administered prior to administration of the benzo[b]thiophene STING agonist. In alternative embodiments of the methods disclosed herein, the benzo[b]thiophene STING agonist is administered prior to administration of the PD-1 antagonist.
In embodiments of the methods disclosed herein, the PD-1 antagonist is administered at a dose of 200 mg; and the benzo[b]thiophene STING agonist is administered at a dose of from 10 μg to 3000 μg. In aspects of such embodiments, the benzo[b]thiophene STING agonist is administered at a dose of from 10 μg to 270 μg.
Additional embodiments of the disclosure include the pharmaceutical compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.
General Methods
Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 2001 3rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif.). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, N.Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).
Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Harlow and Lane, supra). Standard techniques for characterizing ligand/receptor interactions are available (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).
Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, N.Y.; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6,329,511).
An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, Calif.; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).
Purification of antigen is not necessary for the generation of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).
Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N.J.; Givan (2001) Flow Cytometry, 2nd ed.; Wiley-Liss, Hoboken, N.J.; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, N.J.). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).
Standard methods of histology of the immune system are described (see, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, N.Y.; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, N.Y.).
Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g., GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, Md.); GCG Wisconsin Package (Accelrys, Inc., San Diego, Calif.); DeCypher® (TimeLogic Corp., Crystal Bay, Nev.); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).
The benzo[b]thiophene STING agonists of the disclosure may be prepared according to the methods disclosed in Provisional U.S. Patent Application No. 62/404,062, filed Oct. 4, 2016.
Advanced MC38 Mouse Syngenic Tumor Model
Synergistic tumor models are recognized to be appropriate models to evaluate anti-tumor efficacy of agents that target specific molecules, pathways, or cell types and to provide mechanistic rationale that targeting similar specific molecules, pathways, or cell types in human tumors will lead to favorable clinical outcomes. The mouse syngeneic MC38 tumor model is a mouse colon adenocarcinoma cell line that was established by carcinogenic induction of tumors in the C57BL/6 background. This cell line is considered immunogenic and is responsive to immune modulation. It is generally injected subcutaneously (SC) to evaluate tumor growth and response to treatment. Specifically, each animal is inoculated in the right lower flank with a SC dose of 1×106 MC38 colon adenocarcinoma cells in 100 μL of serum-free Dulbecco's modified Eagle's medium. Tumor progression is monitored by measuring tumor volume using Vernier calipers. See T. H. Corbett et al., Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure, 35(9) Cancer Res. 2434-2439 (Sep. 1, 1975).
Anti-Mouse PD-1 Antibody
In the Example below, the anti-tumor effects of selected benzo[b]thiophene STING agonists in combination with an anti-mouse PD1 antibody are evaluated in mouse syngeneic tumor models. Anti-tumor activity (tumor growth inhibition, tumor regression) is observed on treatment of mouse syngeneic tumors with the combination. Both mouse and human tumor infiltrating T cells express high levels of PD-1, associated with what is referred to as an “exhausted phenotype” (See Y. Jiang et al., “T-cell exhaustion in the tumor microenvironment”, Cell Death and Disease 2015, 6, e1792). Induction of anti-tumor efficacy in mouse syngeneic tumor models following treatment with anti-mouse PD-1 antibodies provides a mechanistic rationale that treatment of cancer patients with anti-human PD-1 antibodies will induce anti-tumor efficacy (See S. Hu-Lieskovan et al., “Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma”, Sci. Transl. Med. 2015 Mar. 18; 7(279):279ra41; C. D. Pham et al., “Differential immune microenvironments and response to immune checkpoint blockade among molecular subtypes of murine medulloblastoma”, Clin. Cancer Res. 2016 Feb. 1; 22(3):582-595; S. Budhu et al., “The importance of animal models in tumor immunity and immunotherapy”, Curr. Opin. Genet. Dev. 2014, 24, 46-51). Suitable anti-mouse PD-1 antibodies that may be used include muDX400 (Merck), InVivoMAb and InVivoPlusMAb anti-mouse PD-1 clone J43 (commercially available from BioXCell as catalog number BE0033-2), InVivoMAb anti-mouse PD-1 clone 29F.1A12 (commercially available from BioXCell as catalog number BE0273), and InVivoMAb and InVivoPlusMAb anti-mouse PD-1 clone RMP1-14 (commercially available from BioXCell as catalog number BE0146).
Examples
Example 1: Anti-Tumor Efficacy of a Benzo[b]Thiophene STING Agonist in Combination with an Anti-PD-1 Antibody in Advanced MC38 Mouse Syngenic Tumor Model
To assess the combination anti-tumor efficacy of a benzo[b]thiophene STING agonist and anti-mouse PD-1 antibody muDX400 in the advanced MC38 mouse syngeneic tumor model, a cohort of 8-12 week old female C57Bl/6 mice are implanted with 1×106 MC38 cells. When the tumors reach a median size of approximately 350 mm3, the animals are randomized into 6 treatment groups of 10 mice per group:
Treatment Group A: PBS and mIgG1 (5 mg/kg)
Treatment Group B: PBS and anti-PD-1 antibody muDX400 (5 mg/kg)
Treatment Group C: benzo[b]thiophene STING agonist (5 μg) and mIgG1 (5 mg/kg)
Treatment Group D: benzo[b]thiophene STING agonist (5 μg) and anti-PD-1 antibody muDX400 (5 mg/kg)
Benzo[b]thiophene STING agonist is administered intratumorally on every 3 to 7 days for up to 30 days. Antibodies are administered intraperitoneally every 5 days for 5 doses. The study period will be 30 days post initiation of the dosing regimens.
Tumors on animals in Treatment Group A are anticipated to progress rapidly. The remaining groups are observed for tumor regression and number of CRs. It is anticipated that benzo[b]thiophene STING agonist in combination with anti PD-1 muDX400 treatment (Treatment Group D) will demonstrate superior efficacy to single agent treatment groups.
When the foregoing experiment was conducted with selected combinations as described herein, the combination treatment (Treatment Group D) resulted in significant anti-tumor efficacy compared to Treatment Group A.
Example 2: Clinical Study Evaluating a Benzo[b]Thiophene STING Agonist in Combination with an Anti-PD-1 Antibody in Treatment of Patients with Advanced/Metastatic Solid Tumors or Lymphomas
A Phase I clinical study will be conducted to evaluate, in part, the effects of a combination therapy, consisting of administration of a pembrolizumab intravenous infusion and of a benzo[b]thiophene STING agonist as described above intratumoral injection, on advanced or metastatic solid tumors or lymphomas. The study is a non-randomized, 2-arm, multi-site, open-label trial of benzo[b]thiophene STING agonist monotherapy and benzo[b]thiophene STING agonist in combination with pembrolizumab in subjects with advanced/metastatic solid tumors or lymphomas. benzo[b]thiophene STING agonist will be administered intratumorally (IT).
Unless deemed medically unsafe by the Investigator, all subjects will be required to provide a sample of the tumor to be injected and a sample from a distant site prior to benzo[b]thiophene STING agonist administration during screening, as well as on Cycle 3, Day 15. Subjects with amenable lesions at both injected and non-injected sites may undergo an additional optional tumor biopsy on Cycle 6, Day 15 of both the injected lesion and the non-injected lesion. Subjects will undergo a 24-hour observation period following the first dose administration on Cycle 1, Day 1. Each cycle within the trial is a 21-day cycle. Dosing in the first 3 cycles is once a week (Q1W) and dosing in cycles 4 and beyond is once every 3 weeks (Q3W).
Dose escalation will proceed based on emerging safety and tolerability data of benzo[b]thiophene STING agonist as monotherapy and as combination therapy with pembrolizumab. For each dose level, an assessment will be made of the safety and tolerability data in order to define the next dose level to be tested. Both treatment arms will start with an accelerated titration design (ATD) followed by the modified toxicity probability interval (mTPI) method to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of benzo[b]thiophene STING agonist alone (Arm 1) or benzo[b]thiophene STING agonist in combination with pembrolizumab (Arm 2). Starting with a dose of 10 μg of benzo[b]thiophene STING agonist in single patient cohorts (Arm 1, Part A), the trial will proceed in an ATD up to a dose that meets at least 1 of the following 3 criteria: 1) The 270 μg cohort is completed, 2) ≥Grade 2 non-disease-related toxicity at any dose level, or 3) Elevation of systemic TNF-α in blood above baseline levels by ≥3 fold increase for a given subject at any time during the first cycle of benzo[b]thiophene STING agonist. Upon completion of the ADT phase by reaching at least one of the above triggering criteria, the monotherapy arm (Arm 1) of the study will proceed to a dose escalation and confirmation phase (Part B), using an mTPI design. In addition, Arm 2 (Part C), the combination therapy arm, will initiate once 2 dose levels within Arm 1 have been cleared by dose-limiting toxicity (DLT) evaluation.
Starting with a dose that is at least 2 dose levels behind benzo[b]thiophene STING agonist monotherapy, benzo[b]thiophene STING agonist combination therapy with pembrolizumab (Arm 2 Part C) will begin in single patient cohorts. In Arm 2 Part C, benzo[b]thiophene STING agonist combination arm with pembrolizumab, dose escalation will proceed in an ATD up to a dose level which meets at least 1 of the following 3 criteria: 1) The 270 μg cohort in combination is completed, 2) ≥Grade 2 non-disease-related toxicity at any dose level in combination, or 3) Elevation of systemic TNF-α in blood above baseline levels by ≥3 fold for a given subject at any time during the first cycle of benzo[b]thiophene STING agonist in combination with pembrolizumab. Arm 2 will then proceed to mTPI (Arm 2, Part D) to determine the MTD/MAD of the combination of benzo[b]thiophene STING agonist and pembrolizumab.
Intra-subject dose escalation of benzo[b]thiophene STING agonist to the next dose level is permitted only in Arm 1, including Parts A and B. Intrasubject dose escalation will be at the discretion of the Investigator, provided that the subject remains on study after receiving 3 cycles of treatment without ≥Grade 2 toxicity, and provided that the dose escalation has proceeded beyond the next dose level. Intra-subject dose escalation is not permitted in Arm 2 (Parts C and D).
During benzo[b]thiophene STING agonist dose escalation in both Arm 1 (Parts A and (b) and Arm 2 (Parts C and D), at least 7 days of observation will occur between each of the first 2 subjects at each dose level. Over-enrollment in ATD up to 3 subjects per cohort is permitted, provided that the first 2 subjects will receive benzo[b]thiophene STING agonist treatment at least 7 days apart. Dose escalation of benzo[b]thiophene STING agonist to determine the MTD/MAD will be guided by the mTPI design, targeting a DLT rate of 30%. Doses of benzo[b]thiophene STING agonist used in combination with pembrolizumab will be at least 2 dose levels behind the monotherapy benzo[b]thiophene STING agonist dose, and will not exceed the MTD for monotherapy. If an MTD for the monotherapy arm is established, then the dose of benzo[b]thiophene STING agonist in combination may continue escalation up to that dose. For example, if the MTD for monotherapy (Arm 1, Part A) is 90 μg , then the starting dose for combination therapy (Arm 2, Part C), if no DLTs occurred in monotherapy, may be 10 μg, with a maximum dose escalation to 90 μg. If the MTD for monotherapy (Arm 1, Part A) is ≤30 μg, then the starting dose for combination therapy will be 10 μg. In monotherapy (Arm 1, Part A), if the 270 μg dose level is completed, then the starting dose in combination therapy (Arm 2, Part C) will be 90 μg.
A fixed dose of intravenous pembrolizumab 200 mg will be administered every 3 weeks in Arm 2. A minimum of 3 subjects are required at each dose level during mTPI in both Arm 1 and Arm 2. The mTPI phase will have up to 3 to 6 subjects per cohort, and based on the occurrence of DLTs, up to 14 subjects may enroll per dose level. Therefore, during mTPI, up to 14 subjects may be enrolled per dose level, depending on the occurrence of a dose-limiting toxicity (DLT). Subjects may continue on their assigned treatment for up to 35 cycles (approximately 2 years) from the start of treatment. Treatment may continue until one of the following occurs: disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, Investigator decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trials treatment or procedure requirements, or administrative reasons requiring cessation of treatment.
Subjects who progress by either clinical or radiographic evaluation on monotherapy with benzo[b]thiophene STING agonist (Arm 1), may cross over into the combination arm of benzo[b]thiophene STING agonist and pembrolizumab (Arm 2), provided that they meet crossover eligibility criteria. Subjects who cross over from Arm 1 to Arm 2 are eligible for up to 35 cycles of treatment within Arm 2. Subjects who cross over will enter Arm 2 at the start of Arm 2.
Treatment allocation to Arm 1 will be accomplished by non-random assignment through an interactive voice response system/integrated web response system (IVRS/IWRS). When both treatment arms are open for enrollment, IVRS/IWRS will alternate subject assignment between Arm 1 and 2, starting with Arm 1. Establishment of the MTD/MAD in the combination therapy of benzo[b]thiophene STING agonist and pembrolizumab (Arm 2) requires that at least half of the subjects in Arm 2 have had no prior exposure to benzo[b]thiophene STING agonist (i.e. non-crossover subjects). New subjects who are benzo[b]thiophene STING agonist-naïve (non-crossover subjects) will be given priority for enrollment into Arm 2.
The final number of subjects enrolled in the dose escalation and confirmation parts of the study will depend on the empirical safety data (DLT observations, in particular, at which dose the mTPI design is triggered and at which dose the preliminary recommended Phase 2 dose is identified). For example, in a scenario where benzo[b]thiophene STING agonist monotherapy starts at 10 μg and continues to the highest dose, the sample size across Parts A and B may be approximately 40 subjects. For combination therapy of benzo[b]thiophene STING agonist with pembrolizumab, in a scenario where Arm 2 starts at 10 μg of benzo[b]thiophene STING agonist with 200 mg of pembrolizumab, and continues to the highest dose, the sample size across Parts C and D may be approximately 40 subjects. In this scenario, the total sample size across Parts A-D will be approximately 80 subjects. An administrative analysis may be conducted to enable future trial planning at the Sponsor's discretion, and data will be examined on a continuous basis to allow for dose escalation and confirmation decisions.
The trial will be conducted in conformance with Good Clinical Practices.
Adverse Experiences (AEs) will be evaluated according to criteria outlined in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.
It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.
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16635059
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merck sharp & dohme corp.
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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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Apr 27th, 2022 09:12AM
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Apr 27th, 2022 09:12AM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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May 21st, 2013 12:00AM
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https://www.uspto.gov?id=US11312908-20220426
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Liquid crystal medium and liquid crystal display
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Dielectrically positive liquid-crystalline media comprising a compound of the formula TINUVIN 770 and optionally one or more compounds of formula I,
in which the parameters have the respective meanings indicated in the specification, and optionally one or more further dielectrically positive compounds and optionally one or more further dielectrically neutral compounds, and to liquid-crystal displays, especially active-matrix displays and in particular TN, IPS and FFS displays, containing these media.
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11312908
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1. A liquid-crystal medium having positive dielectric anisotropy (Δε) in the range from 12 to 17 at 20° C. and 1 kHz,
comprising
a) a compound of the formula below,
and
b) a liquid crystal mixture comprising one or more compounds of formula II in a concentration of 33% to 60% by weight based on the weight of the liquid crystal mixture as a whole and one or more compounds of formula II-2;
in which
R2 denotes alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
on each appearance, independently of one another, denote
L21 L22, L23 and L24 independently of one another, denote H or F,
X2 denotes halogen, halogenated alkyl or alkoxy having 1 to 3 C atoms or halogenated alkenyl or alkenyloxy having 2 or 3 C atoms,
and
m denotes 0, 1, 2 or 3
wherein the total concentration of the compound of the following formula
in the medium is in the range from 1 ppm to 2000 ppm.
2. The liquid-crystal medium according to claim 1, which additionally comprises one or more compounds of formula III
in which
R3 denotes alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
on each appearance, independently of one another, denote
L31 and L32 independently of one another, denote H or F,
X3 denotes halogen, halogenated alkyl or alkoxy having 1 to 3 C atoms or halogenated alkenyl or alkenyloxy having 2 or 3 C atoms,
Z3 denotes —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O— or a single bond, and
N denotes 0, 1, 2 or 3.
3. The liquid-crystal medium according to claim 1, which additionally comprises one or more compounds of formula IV
in which
R41 and R42 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
independently of one another and, if
occurs twice, also these independently of one another, denote
Z41 and Z42 independently of one another and, if Z41 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, and
p denotes 0, 1 or 2.
4. The liquid-crystal medium according to claim 2, which additionally comprises one or more compounds of formula IV
in which
R41 and R42 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
independently of one another and, if
occurs twice, also these independently of one another, denote
Z41 and Z42 independently of one another and, if Z41 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, and
p denotes 0, 1 or 2.
5. The liquid-crystal medium according to claim 1, further comprising a stabilizer compound that is a di-ortho-(tert-butyl)phenol compound, which contains a structural element of the following formula
6. The liquid-crystal medium according to claim 1, further comprising a stabilizer compound of the following formula
wherein n is 1-7.
7. The liquid-crystal medium according to claim 1, which additionally comprises one or more compounds of formula I,
in which
n denotes an integer from 1 to 4,
m denotes (4−n),
denotes an organic radical having 4 bonding sites, in which, in addition to the m groups R12 present in the molecule, but independently thereof, a further H atom may be replaced by R12 or a plurality of further H atoms may be replaced by R12, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —(C═O)— in such a way that two O atoms are not bonded directly to one another, or denotes a substituted or unsubstituted aromatic or heteroaromatic hydrocarbon radical having 1 to 4 valences, in which, in addition to the m groups R12 present in the molecule, but independently thereof, a further H atom may be replaced by R12 or a plurality of further H atoms may be replaced by R12,
Z11 and Z12 independently of one another, denote —O—, —(C═O)—, —(N—R14)— or a single bond, but do not both simultaneously denote —O—,
r and s independently of one another, denote 0 or 1,
Y11 to Y14 each, independently of one another, denote alkyl having 1 to 4 C atoms and alternatively, independently of one another, one or both of the pairs Y11 and Y12 and/or Y13 and Y14 together also denote a divalent group having 3 to 6 C atoms,
R11 denotes O.,
R12 on each occurrence, independently of one another, denotes H, F, OR14, NR14R15, a straight-chain alkyl having 1-20 C atoms or branched alkyl chain having 3-20 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, or denotes a hydrocarbon radical which contains a cycloalkyl having 3 to 10 C atoms or alkylcycloalkyl unit having 4 to 10 C atoms, and in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, and in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16, or denotes an aromatic or heteroaromatic hydrocarbon radical, in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16,
R13 on each occurrence, independently of one another, denotes a straight-chain alkyl having 1-20 C atoms or branched alkyl chain having 3-20 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, or denotes a hydrocarbon radical which contains a cycloalkyl having 3 to 10 C atoms or alkylcycloalkyl unit having 4 to 10 C atoms, and in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, and in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16, or denotes an aromatic or heteroaromatic hydrocarbon radical, in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16, or can be 1,4-cyclohexylene of the following formula
in which one or more —CH2— groups may be replaced by —O—, —CO— or —NR14—, or an acetophenyl, isopropyl or 3-heptyl radical,
R14 on each occurrence, independently of one another, denotes a straight-chain alkyl having 1 to 10 C atoms or branched-chain alkyl having 3 to 10 C atoms or acyl group having 1 to 10 C atoms or an aromatic hydrocarbon or carboxyl radical having 6-12 C atoms,
R15 on each occurrence, independently of one another, denotes a straight-chain alkyl having 1 to 10 C atoms or branched-chain alkyl having 3 to 10 C atoms or acyl group having 1 to 10 C atoms or an aromatic hydrocarbon or carboxyl radical having 6-12 C atoms,
R16 on each occurrence, independently of one another, denotes a straight-chain alkyl having 1 to 10 C atoms or branched-chain alkyl group having 3 to 10 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—,
with the provisos that,
in the case where n=1, and
—[Z11—]r—[Z12—]s—═—O—, —(CO)—O—, —O—(CO)—, —O—(CO)—O—, —NR14 or
—NR14—(CO)—,
does not denote
straight-chain alkyl having 1 to 10 C atoms or branched-chain alkyl having 3 to 10 C atoms, also cycloalkyl having 3 to 10 C atoms, cycloalkylalkyl having 4 to 10 C atoms or alkylcycloalkyl having 1 to 10 C atoms, where in all these groups one or more —CH2— groups may be replaced by —O— in such a way that no two O atoms in the molecule are bonded directly to one another,
in the case where n=2,
does not denote
8. The medium according to claim 7, comprising
one or more compounds of formula III
in which
R3 denotes alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
on each appearance, independently of one another, denote
L31 and L32 independently of one another, denote H or F,
X3 denotes halogen, halogenated alkyl or alkoxy having 1 to 3 C atoms or halogenated alkenyl or alkenyloxy having 2 or 3 C atoms,
Z3 denotes —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O— or a single bond, and
n denotes 0, 1, 2 or 3.
9. The medium according to claim 8, which comprises more than one compound of the formula II and one or more compounds of formula II-2.
10. The medium according to claim 8, which comprises more than one compound of the formula III.
11. The liquid-crystal medium according to claim 8, which additionally comprises one or more compounds of formula IV
in which
R41 and R42 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
independently of one another and, if
occurs twice, also these independently of one another, denote
Z41 and Z42 independently of one another and, if Z41 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, and
p denotes 0, 1 or 2.
12. The liquid-crystal medium according to claim 8, wherein joint concentration of the compounds of formulae II and III within the liquid crystal medium ranges from 49% to 60% by weight based on the weight of the whole liquid crystal medium.
13. The medium according to claim 7, comprising
one or more compounds of formula IV
in which
R41 and R42 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 carbon atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 carbon atoms,
independently of one another and, if
occurs twice, also these independently of one another, denote
Z41 and Z42 independently of one another and, if Z41 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, and
p denotes 0, 1 or 2.
14. The medium according to claim 7, wherein the total concentration of the compounds of formula I and the compound of the following formula
in the medium combined is in the range from 1 ppm to 2000 ppm.
15. The medium according to claim 7, wherein the compounds of the formula I are compounds selected from the group of the compounds of the formulae I-1 to I-9
t denotes an integer from 1 to 12,
R17 denotes a straight-chain alkyl having 1 to 12 C atoms or branched alkyl chain having 3-12 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, or denotes an aromatic or heteroaromatic hydrocarbon radical, in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16.
16. The medium according to claim 7, comprising one or more dielectrically neutral compounds of formula V
in which
R51 and R52 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 carbon atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 carbon atoms,
on each occurrence, independently of one another, denotes
Z51 and Z52 independently of one another and, if Z51 occurs twice, also these independently of one another, denote
—CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—,
—CH2O—, —CF2O— or a single bond, and
r denotes 0, 1 or 2.
17. A liquid-crystal display, containing the medium according to claim 7.
18. The display according to claim 17, which is addressed by an active matrix.
19. A method of using a medium according to claim 7, comprising operating said medium in a liquid-crystal display to generate an image in said display.
20. A process for the preparation of the medium according to claim 7, wherein the compound of the following formula
is mixed with one or more compounds of formula I, one or more compounds of formula II, one or more compounds of formula II-2 and with
i) one or more compounds of formula III,
ii) one or more compounds of formula IV,
iii) one or more further mesogenic compounds, or
iv) one or more additives
or a combination thereof,
in which
R2 and R3 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms,
on each appearance, independently of one another, denote
L21, L22, L31 and L32 independently of one another, denote H or F,
X2 and X3 independently of one another, denote halogen, halogenated alkyl or alkoxy having 1 to 3 C atoms or halogenated alkenyl or alkenyloxy having 2 or 3 C atoms,
Z3 denotes —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O— or a single bond, and
m and n independently of one another, denote 0, 1, 2 or 3,
in which
R41 and R42 independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 carbon atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 carbon atoms,
independently of one another and, if
occurs twice, also these independently of one another, denote
Z41 and Z42 independently of one another and, if Z41 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, and
p denotes 0, 1 or 2.
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FIELD OF THE INVENTION
The present invention relates to liquid-crystalline media and to liquid-crystal displays containing these media, especially to displays addressed by an active matrix and in particular to displays of the twisted nematic (TN), in-plane switching (IPS) or fringe-field switching (FFS) type.
STATE OF THE ART AND PROBLEM TO BE SOLVED
Liquid-crystal displays (LCDs) are used in many areas for the display of information. LCDs are used both for direct-view displays and for projection-type displays. The electro-optical modes used are, for example, the twisted nematic (TN), super twisted nematic (STN), optically compensated bend (OCB) and electrically controlled birefringence (ECB) modes together with their various modifications, as well as others. All these modes utilise an electric field which is substantially perpendicular to the substrates or the liquid-crystal layer. Besides these modes, there are also electro-optical modes that utilise an electric field which is substantially parallel to the substrates or the liquid-crystal layer, such as, for example, the in-plane switching (IPS) mode (as disclosed, for example, in DE 40 00 451 and EP 0 588 568) and the fringe-field switching (FFS) mode, in which a strong “fringe field” is present, i.e. a strong electric field close to the edge of the electrodes and, throughout the cell, an electric field which has both a strong vertical component and a strong horizontal component. These latter two electro-optical modes in particular are used for LCDs in modern desktop monitors and are intended for use in displays for TV sets and multimedia applications. The liquid crystals in accordance with the present invention are preferably used in displays of this type. In general, dielectrically positive liquid-crystalline media having rather lower values of the dielectric anisotropy are used in FFS displays, but in some cases liquid-crystalline media having a dielectric anisotropy of only about 3 or even less are also used in IPS displays.
For these displays, novel liquid-crystalline media having improved properties are required. The addressing times in particular have to be improved for many types of application. Thus, liquid-crystalline media having lower viscosities (η), especially having lower rotational viscosities (γ1), are required. In particular for monitor applications, the rotational viscosity should be 80 mPa·s or less, preferably 60 mPa·s or less and especially 55 mPa·s or less. Besides this parameter, the media must have a nematic phase range of suitable width and position and an appropriate birefringence (Δn). In addition, the dielectric anisotropy (Δε) should be sufficiently high to allow a fairly low operating voltage. Δε should preferably be greater than 2 and very preferably greater than 3, but preferably not greater than 20 and in particular not greater than 17, as this would prevent an at least fairly high resistivity.
For applications as displays for notebooks or other mobile applications, the rotational viscosity should preferably be 120 mPa·s or less and particularly preferably 100 mPa·s or less. The dielectric anisotropy (Δε) here should preferably be greater than 8 and particularly preferably greater than 12.
The displays in accordance with the present invention are preferably addressed by an active matrix (active-matrix LCDs, AMDs for short), preferably by a matrix of thin-film transistors (TFTs). However, the liquid crystals according to the invention can also advantageously be used in displays having other known addressing means.
There are numerous different display modes which use composite systems of low-molecular-weight liquid-crystal materials together with polymeric materials. These are, for example, polymer dispersed liquid crystal (PDLC), nematic curvilinearly aligned phase (NCAP) and polymer network (PN) systems, as disclosed, for example, in WO 91/05 029, or axially symmetric microdomain (ASM) systems and others. In contrast to these, the modes that are especially preferred in accordance with the present invention use the liquid-crystal medium as such, oriented on surfaces. These surfaces are typically pretreated in order to achieve uniform alignment of the liquid-crystal material. The display modes in accordance with the present invention preferably use an electric field which is substantially parallel to the composite layer.
Liquid-crystal compositions which are suitable for LCDs and especially for IPS displays are known, for example, from JP 07-181 439 (A), EP 0 667 555, EP 0 673 986, DE 195 09 410, DE 195 28 106, DE 195 28 107, WO 96/23 851 and WO 96/28 521. However, these compositions have severe disadvantages. Amongst other deficiencies, most of them result in disadvantageously long addressing times, have inadequate values of the resistivity and/or require excessively high operating voltages. In addition, there is a need to improve the low-temperature behaviour of LCDs. Both an improvement in the operating properties and also in the shelf life and, in particular, in the stability to visible light and UV radiation, but also to heat and, in particular, to a combination of heat and light and/or UV radiation, are necessary here.
The compound TEMPOL, of the following formula:
is known; it is mentioned, for example, in Miéville, P. et al, Angew. Chem. 2010, 122, pages 6318-6321. It is commercially available from various manufacturers and is employed, for example, as polymerisation inhibitor and, in particular in combination with UV absorbers, as light or UV stabiliser in formulations for precursors of polyolefins, polystyrenes, polyamides, coatings and PVC.
Compounds of the following formula:
are constituents of the product commercially available under the name “Cyasorb UV-3852S” from Cytec, West Paterson, USA, which is employed as light stabiliser, for example in formulations for polypropylene plastic parts for the automobile industry and for garden furniture.
The as yet unpublished patent application DE 102011117937.6 describes liquid-crystal mixtures having negative dielectric anisotropy which comprise TINUVIN 7700 for stabilisation.
The likewise as yet unpublished patent applications DE 102011119144.9 and PCT/EP2011/005692 describe liquid-crystal mixtures having positive dielectric anisotropy which comprise, inter alia, HALS N-oxides for stabilisation.
The likewise as yet unpublished patent application U.S. Ser. No. 13/451,749 pro-poses stabilising liquid-crystal mixtures having negative dielectric anisotropy using compounds of the formula I of the present application.
Many liquid-crystal media, particularly those having large polarities or high dielectric anisotropy, do not meet the high stability requirements necessary for practical applications.
There is therefore a considerable demand for liquid-crystalline media having suitable properties for practical applications, such as a broad nematic phase range, suitable optical anisotropy Δn corresponding to the display type used, a high Δε and particularly low viscosities for particularly short response times.
PRESENT INVENTION
Surprisingly, it has now been found that it is possible to achieve liquid-crystalline media having a suitably high Δε, a suitable phase range and suitable Δn which do not have the disadvantages of the materials from the prior art, or at least only do so to a significantly reduced extent.
Surprisingly, it has been found here that the compounds of the formula I, as indicated below, result in considerable, in many cases adequate, stabilisation of liquid-crystal mixtures and in particular in combination with other stabilisers, in particular with ortho-(tert-butyl)phenol derivatives or diortho-(tert-butyl)phenol derivatives, i.e. compounds which contain a structural element of the formula
and/or compounds which contain a structural element of the formula
where these structural elements may optionally carry further substituents, preferably alkyl or halogen.
The invention relates to a liquid-crystalline medium having a nematic phase and positive dielectric anisotropy which comprises
a) one or more compounds selected from the group of the compounds of the formula I and TINUVIN 770®, preferably in a concentration in the range from 1 ppm to 2,000 ppm, preferably in the range from 1 ppm to 600 ppm, particularly preferably in the range from 1 ppm to 250 ppm, very particularly preferably in the range from 10 ppm to 200 ppm,
in which
n denotes an integer from 1 to 4, preferably 1, 2 or 3, particularly preferably 1 or 2, and very particularly preferably 2,
m denotes (4-n),
denotes an organic radical having 4 bonding sites, preferably an alkanetetrayl unit having 1 to 20 C atoms, in which, in addition to the m groups R12 present in the molecule, but independently thereof, a further H atom may be replaced by R12 or a plurality of further H atoms may be replaced by R12, preferably a straight-chain alkanetetrayl unit having one valence on each of the two terminal C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —(C═O)— in such a way that two O atoms are not bonded directly to one another, or denotes a substituted or unsubstituted aromatic or heteroaromatic hydrocarbon radical having 1 to 4 valences, in which, in addition to the m groups R12 present in the molecule, but independently thereof, a further H atom may be replaced by R12 or a plurality of further H atoms may be replaced by R12,
Z11 and Z12, independently of one another, denote —O—, —(C═O)—, —(N—R14)— or a single bond, but do not both simultaneously denote —O—,
r and s, independently of one another, denote 0 or 1,
Y11 to Y14 each, independently of one another, denote alkyl having 1 to 4 C atoms, preferably methyl or ethyl, particularly preferably all denote either methyl or ethyl and very particularly preferably methyl, and alternatively, independently of one another, one or both of the pairs (Y11 and Y12) and (Y13 and Y14) together also denote a divalent group having 3 to 6 C atoms, preferably having 5 C atoms, particularly preferably 1,5-pentylene,
R11 denotes O—R13, O. or OH, preferably O—R13 or O., particularly preferably O., isopropoxy, cyclohexyloxy, acetophenoxy or benzoxy and very particularly preferably O.,
R12 on each occurrence, independently of one another, denotes H, F, OR14, NR14R15, a straight-chain or branched alkyl chain having 1-20 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, or denotes a hydrocarbon radical which contains a cycloalkyl or alkylcycloalkyl unit, and in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, and in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16, or denotes an aromatic or heteroaromatic hydrocarbon radical, in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16,
R13 on each occurrence, independently of one another, denotes a straight-chain or branched alkyl chain having 1-20 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, or denotes a hydrocarbon radical which contains a cycloalkyl or alkylcycloalkyl unit, and in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, and in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16, or denotes an aromatic or heteroaromatic hydrocarbon radical, in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16,
or can be
(1,4-cyclohexylene), in which one or more —CH2— groups may be replaced by —O—, —CO— or —NR14—, or an acetophenyl, isopropyl or 3-heptyl radical,
R14 on each occurrence, independently of one another, denotes a straight-chain or branched alkyl or acyl group having 1 to 10 C atoms, preferably n-alkyl, or an aromatic hydrocarbon or carboxyl radical having 6-12 C atoms, preferably with the proviso that, in the case of N(R14)(R15), at least one acyl radical is present,
R15 on each occurrence, independently of one another, denotes a straight-chain or branched alkyl or acyl group having 1 to 10 C atoms, preferably n-alkyl, or an aromatic hydrocarbon or carboxyl radical having 6-12 C atoms, preferably with the proviso that, in the case of N(R14)(R15), at least one acyl radical is present,
R16 on each occurrence, independently of one another, denotes a straight-chain or branched alkyl group having 1 to 10 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—,
with the provisos that,
in the case where n=1, R11═O. and
—[Z11—]r—[Z12—]s—═—O—, —(CO)—O—, —O—(CO)—, —O—(CO)—O—, —NR14 or
—NR14—(CO)—,
does not denote
straight-chain or branched alkyl having 1 to 10 C atoms, also cycloalkyl, cycloalkylalkyl or alkylcycloalkyl, where in all these groups one or more —CH2— groups may be replaced by —O— in such a way that no two O atoms in the molecule are bonded directly to one another,
in the case where n=2 and R11═O.,
does not denote
and
in the case where n=2 and R11═O—R13,
R13 does not denote n-C1-9-alkyl,
and
b) one or more compounds selected from the group of the compounds of the formulae II and III
in which
R2 and R3, independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms, and R2 and R3 preferably denote alkyl or alkenyl,
to
on each appearance, independently of one another, denote
preferably
L21, L22, L31 and L32, independently of one another, denote H or F,
preferably
L21 and/or L31 denote F,
X2 and X3, independently of one another, denote halogen, halogenated alkyl or alkoxy having 1 to 3 C atoms or halogenated alkenyl or alkenyloxy having 2 or 3 C atoms, preferably F, Cl, —OCF3 or —CF3, very preferably F, Cl or —OCF3,
Z3 denotes —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O— or a single bond, preferably —CH2CH2—, —COO—, trans-CH═CH— or a single bond and very preferably —COO—, trans-CH═CH— or a single bond, and
m and n, independently of one another, denote 0, 1, 2 or 3,
m preferably denotes 1, 2 or 3, and
n preferably denotes 0, 1 or 2 and particularly preferably 1 or 2,
and/or
c) one or more compounds of the formula IV
in which
R41 and R42, independently of one another, have the meaning indicated for R2 above under formula II, preferably R41 denotes alkyl and R42 denotes alkyl or alkoxy or R41 denotes alkenyl and R42 denotes alkyl,
independently of one another and, if
occurs twice, also these independently of one another, denote
preferably one or more of
denote(s)
Z41 and Z42, independently of one another and, if Z41 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, preferably one or more of them denote(s) a single bond, and
p denotes 0, 1 or 2, preferably 0 or 1.
Preference is given to the following embodiments:
denotes
(benzene-1,2,4,5-tetrayl) or
—CH2—(CH—)—[CH2]q—(CH—)—CH2— or
>CH—[CH2]p—CH<, (where p∈{0, 1, 2, 3, 4, 5 to 18} and
q∈{0, 1, 2, 3 to 16}) or
denotes
>CH—[CH2]p—CH2— (where p∈{0, 1, 2, 3, 4, 5 to 18}) or
denotes
—CH2—[CH2]p—CH2— (where p∈{0, 1, 2, 3, 4, 5 to 18}),
propane-1,2-diyl, butane-1,2-diyl, ethane-1,2-diyl,
(1,4-phenylene),
(1,2-phenylene) or
(1,4-cyclohexylene).
In the present application, the elements all include their respective iso-topes. In particular, one or more H in the compounds may be replaced by D, and this is also particularly preferred in some embodiments. A correspondingly high degree of deuteration of the corresponding compounds enables, for example, detection and recognition of the compounds. This is very helpful in some cases, in particular in the case of the compounds of the formula I.
In the present application,
alkyl particularly preferably denotes straight-chain alkyl, in particular CH3—, C2H5—, n-C3H7—, n-C4H9— or n-C5H11—, and
alkenyl particularly preferably denotes CH2═CH—, E-CH3—CH═CH—, CH2═CH—CH2—CH2—, E-CH3—CH═CH—CH2—CH2— or E-(n-C3H7)—CH═CH—.
The liquid-crystalline media in accordance with the present application preferably comprise in total 1 ppm to 1000 ppm, preferably 1 ppm to 500 ppm, even more preferably 1 to 250 ppm, particularly preferably up to 200 ppm and, very particularly preferably, 1 ppm to 100 ppm, of compounds of the formula I.
The concentration of the compounds of the formula I and/or TINUVIN 770® in the media according to the invention is preferably 90 ppm or less, particularly preferably 50 ppm or less. The concentration of the compounds of the formula I and/or TINUVIN 770® in the media according to the invention is very particularly preferably 1 ppm or more to 100 ppm or less.
In a preferred embodiment of the present invention, in the compounds of the formula I,
denotes
(benzene-1,2,4,5-tetrayl) or
denotes
(benzene-1,3,5-triyl) or
denotes —(CH2—)2, —(CH2—)4, —(CH2—)6, —(CH2—)8,
propane-1,2-diyl, butane-1,2-diyl, ethane-1,2-diyl,
(1,4-phenylene),
(1,3-phenylene),
(1,2-phenylene) or
(trans-1,4-cyclohexylene) and/or
—[Z11—]r—[Z12—]s on each occurrence, independently of one another, denotes —O—, —(C═O)—O— or —O—(C═O)—, —(N—R14)— or a single bond, preferably —O— or —(C═O)—O— or —O—(C═O)—, and/or
R11 denotes —O., OH or O—R13, preferably:
—O., —O—CH(—CH3)2, —O—CH(—CH3)(—CH2)3—CH3,
—O—CH(—C2H5)(—CH2)3—CH3,
and/or
R12, if present, denotes alkyl or alkoxy, and/or
R13 denotes isopropyl or 3-heptyl, acetophenyl or cyclo-hexyl.
In a preferred embodiment of the present invention, the group
in the compounds of the formula I on each occurrence, independently of one another, denotes
preferably
In a particularly preferred embodiment of the present invention, all groups
present in the compounds of the formula I have the same meaning.
These compounds are highly suitable as stabilisers in liquid-crystal mixtures. In particular, they stabilise the VHR of the mixtures against UV exposure.
In a preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the compounds of the formulae I-1 to I-9, preferably selected from the group of the compounds of the formulae I-1 to I-4,
in which the parameters have the meanings indicated above under formula I, and
t denotes an integer from 1 to 12,
R17 denotes a straight-chain or branched alkyl chain having 1-12 C atoms, in which one —CH2— group or a plurality of —CH2— groups may be replaced by —O— or —C(═O)—, but two adjacent —CH2— groups cannot be replaced by —O—, or denotes an aromatic or heteroaromatic hydrocarbon radical, in which one H atom or a plurality of H atoms may be replaced by OR14, N(R14)(R15) or R16.
In an even more preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-1a-1 to I-8a-1:
In an even more preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-2a-1 and I-2a-2:
In an alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-1 b-1 and I-1 b-2,
In an alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-1c-1 and I-1c-2,
In a further alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-1d-1 to I-1d-4:
In a further alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-3d-1 to I-3d-8,
In a further alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-4d-1 and I-4d-2,
In a further alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-1e-1 and I-1e-2,
In a further alternative, preferred embodiment of the present invention, the media according to the invention in each case comprise one or more compounds of the formula I selected from the group of the following compounds, of the formulae I-5e-1 to I-8e-1,
In a preferred embodiment of the present invention, the media according to the invention comprise the compound TINUVIN 770®
and
one or more compounds of the formula I, preferably selected from the preferred sub-formulae thereof,
and/or
one or more compounds which contain a structural element of the formula
where these structural elements may optionally carry further substituents, preferably alkyl or halogen,
and/or one or more compounds which contain a structural element of the formula
where this structural element may optionally carry further substituents, preferably alkyl or halogen,
and/or
one or more compounds of the formula II, preferably selected from the preferred sub-formulae thereof,
and/or
one or more compounds of the formula III, preferably selected from the preferred sub-formulae thereof,
and/or
one or more compounds of the formula IV, preferably selected from the preferred sub-formulae thereof.
In addition to the compounds of the formula I and/or TINUVIN 770® or preferred sub-formulae thereof, the media in accordance with the present invention preferably comprise one or more dielectrically neutral compounds of the formula Iv in a total concentration in the range from 5% or more to 90% or less, preferably from 10% or more to 80% or less, particularly preferably from 20% or more to 70% or less.
The compounds of the formulae II and III are preferably dielectrically positive compounds, preferably having a dielectric anisotropy of greater than 3.
The compounds of the formula IV are preferably dielectrically neutral compounds, preferably having a dielectric anisotropy in the range from −1.5 to 3.
The liquid-crystalline media in accordance with the present application preferably comprise in total 1 ppm to 2000 ppm, preferably 1 ppm to 1000 ppm and very particularly preferably 1 ppm to 300 ppm, of one or more compounds of the formula I and/or TINUVIN 770®.
These compounds are eminently suitable as stabilisers in liquid-crystal mixtures. In particular, they stabilise the “voltage holding ratio” (VHR or just HR for short) of the mixtures after exposure to UV radiation and/or LCD backlighting and/or elevated temperature.
The individual compounds of the formulae II and/or III are employed in a concentration of 1 to 20%, preferably 1 to 15%. These limits apply, in particular, if in each case two or more homologous compounds, i.e. compounds of the same formula, are employed. If only a single substance, i.e. only one homologue, of the compounds of a formula is employed, its concentration can thus be in the range from 2 to 20%, preferably from 3 to 14%.
In addition to the compounds of the formula I and/or TINUVIN 770® or preferred sub-formulae thereof, the media according to the present invention preferably comprise one or more dielectrically positive compounds having a dielectric anisotropy of greater than 3, selected from the group of the formulae II and III.
In a preferred embodiment of the present invention, the media according to the invention comprise one or more compounds selected from the group of the compounds of the formulae II-1 to II-4, preferably of the formulae II-1 and/or II-2
in which the parameters have the respective meanings indicated above under formula II, and L23 and L24, independently of one another, denote H or F, preferably L23 denotes F, and
has one of the meanings given for
and, in the case of the formulae II-1 and II-4, X2 preferably denotes F or OCF3, particularly preferably F, and, in the case of the formula II-3,
independently of one another, preferably denote
and/or are selected from the group of the compounds of the formulae III-1 and III-2:
in which the parameters have the meaning given under formula III.
In a preferred embodiment, the media according to the present invention alternatively or in addition to the compounds of the formulae III-1 and/or III-2 comprise one or more compounds of the formula III-3
in which the parameters have the respective meanings indicated above, and the parameters L31 and L32, independently of one another and of the other parameters, denote H or F.
The media according to the invention preferably comprise one or more compounds selected from the group of the compounds of the formulae II-1 to II-4 in which L21 and L22 and/or L23 and L24 both denote F.
In a preferred embodiment, the media comprise one or more compounds which are selected from the group of the compounds of the formulae II-2 and II-4 in which L21, L22, L23 and L24 all denote F.
The media preferably comprise one or more compounds of the formula II-1. The compounds of the formula II-1 are preferably selected from the group of the compounds of the formulae II-1a to II-1f
in which the parameters have the respective meanings indicated above, and L23 to L25, independently of one another and of the other parameters, denote H or F, and
preferably
in the formulae II-1a and II-1 b
L21 and L22 both denote F,
in the formulae II-1c and II-1d
L21 and L22 both denote F and/or L23 and L24 both denote F, and
in formula II-1e
L21, L22 and L25 denote F, and in each case the other parameters have the respective meanings given above.
Especially preferred compounds of the formula II-1 are
in which R2 has the meaning indicated above, in particular compounds of the formula II-1a-2.
The media preferably comprise one or more compounds of the formula II-2, which are preferably selected from the group of the compounds of the formulae II-2a to II-2k
in which the parameters have the respective meanings indicated above, and L25 to L28, independently of one another, denote H or F, preferably L27 and L28 both denote H, particularly preferably L26 denotes H, and the other parameters have the respective meanings given above.
The media according to the invention preferably comprise one or more compounds selected from the group of the compounds of the formulae II-2a to II-2k in which L21 and L22 both denote F and/or L23 and L24 both denote F, and the other parameters have the respective meanings given above.
In a preferred embodiment, the media according to the invention comprise one or more compounds selected from the group of the compounds of the formulae II-2a to II-2k in which L21, L22, L23 and L24 all denote F, and the other parameters have the respective meanings given above.
Especially preferred compounds of the formula II-2 are the compounds of the following formulae:
in which R2 and X2 have the meanings indicated above, and X2 preferably denotes F, particularly preferably compounds of the formula II-2a-1 and/or II-2h-1 and/or II-2j-1 and/or II-2k-1.
The media according to the invention preferably comprise one or more compounds of the formula II-3, preferably selected from the group of the compounds of the formulae II-3a to II-3c
in which the parameters have the respective meanings indicated above, and L21 and L22 preferably both denote F.
In a preferred embodiment, the media according to the invention comprise one or more compounds of the formula II-4, preferably of the formula II-4a
in which the parameters have the meaning given above, and X2 preferably denotes F or OCF3, particularly preferably F.
The media according to the invention preferably comprise one or more compounds of the formula III-1, preferably selected from the group of the compounds of the formulae III-1a and III-1b
in which the parameters have the respective meanings indicated above, and the parameters L33 and L34, independently of one another and of the other parameters, denote H or F.
The media according to the invention preferably comprise one or more compounds of the formula III-1a, preferably selected from the group of the compounds of the formulae III-1a-1 to III-1a-6
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-1 b, preferably selected from the group of the compounds of the formulae III-1 b-1 to III-1 b-4, preferably of the formula III-1 b-4,
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-2, preferably selected from the group of the compounds of the formulae III-2a to III-2k
in which the parameters have the meaning given above and preferably in which the parameters have the respective meanings indicated above, and the parameters L33, L34, L35 and L36, independently of one another and of the other parameters, denote H or F.
The media according to the invention preferably comprise one or more compounds of the formula III-2a, preferably selected from the group of the compounds of the formulae III-2a-1 to III-2a-5
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-2b, preferably selected from the group of the compounds of the formulae III-2b-1 and III-2b-2, preferably of the formula III-2b-2
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-2c, preferably selected from the group of the compounds of the formulae III-2c-1 to III-2c-6
in which R3 has the meaning indicated above, particularly preferably compounds of the formula III-2c-1 and/or III-2c-2 and/or III-2c-4.
The media according to the invention preferably comprise one or more compounds selected from the group of the compounds of the formulae III-2d and III-2e, preferably selected from the group of the compounds of the formulae III-2d-1 and III-2e-1
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-2f, preferably selected from the group of the compounds of the formulae III-2f-1 to III-2f-5
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-2g, preferably selected from the group of the compounds of the formulae III-2g-1 to III-2g-5
in which R3 has the meaning indicated above.
The media according to the invention preferably comprise one or more compounds of the formula III-2h, preferably selected from the group of the compounds of the formulae III-2h-1 to III-2h-3, preferably of the formula III-2h-3
in which the parameters have the meaning given above, and X3 preferably denotes F.
The media according to the invention preferably comprise one or more compounds of the formula III-2i, preferably selected from the group of the compounds of the formulae III-2i-1 and III-2i-2, particularly preferably of the formula III-2i-2
in which the parameters have the meaning given above, and X3 preferably denotes F.
The media according to the invention preferably comprise one or more compounds of the formula III-2j, preferably selected from the group of the compounds of the formulae III-2j-1 and III-2j-2, particularly preferably of the formula III-2j-1
in which the parameters have the meaning given above.
The media according to the invention preferably comprise one or more compounds of the formula III-2k, preferably of the formula III-2k-1
in which the parameters have the meaning given above and X3 preferably denotes F.
Alternatively or in addition to the compounds of the formulae III-1 and/or III-2, the media according to the present invention may comprise one or more compounds of the formula III-3
in which the parameters have the respective meanings indicated above under formula III.
These compounds are preferably selected from the group of the formulae III-3a and III-3b
in which R3 has the meaning indicated above.
The liquid-crystalline media according to the present invention preferably comprise a dielectrically neutral component, component C. This component has a dielectric anisotropy in the range from −1.5 to 3. It preferably comprises, more preferably predominantly consists of, even more preferably essentially consists of and especially preferably entirely consists of dielectrically neutral compounds having a dielectric anisotropy in the range from −1.5 to 3. This component preferably comprises one or more dielectrically neutral compounds, more preferably predominantly consists of, even more preferably essentially consists of and very preferably entirely consists of dielectrically neutral compounds of the formula IV having a dielectric anisotropy in the range from −1.5 to 3.
The dielectrically neutral component, component C, preferably comprises one or more compounds selected from the group of the compounds of the formulae IV-1 to IV-8
in which R41 and R42 have the respective meanings indicated above under formula IV, and in formulae IV-1, IV-6 and IV-7 R41 preferably denotes alkyl or alkenyl, preferably alkenyl, and R42 preferably denotes alkyl or alkenyl, preferably alkyl. In formula IV-2 R41 and R42 preferably denote alkyl. In formula IV-5 R41 preferably denotes alkyl or alkenyl, more preferably alkyl, and R42 preferably denotes alkyl, alkenyl or alkoxy, more preferably alkenyl or alkoxy, and in formulae IV-4 and IV-8 R41 preferably denotes alkyl and R42 preferably denotes alkyl or alkoxy, more preferably alkoxy.
The dielectrically neutral component, component C, preferably comprises one or more compounds selected from the group of the compounds of the formulae IV-1, IV-5, IV-6 and IV-7, preferably one or more compounds of the formula IV-1 and one or more compounds selected from the group of the formulae IV-5 and IV-6, more preferably one or more compounds of each of the formulae IV-1, IV-5 and IV-6 and very preferably one or more compounds of each of the formulae IV-1, IV-5, IV-6 and IV-7.
In a preferred embodiment, the media according to the invention comprise one or more compounds of the formula IV-4, more preferably selected from the respective sub-formulae thereof of the formulae CP-V-n and/or CP-nV-m and/or CP-Vn-m, more preferably of the formulae CP-V-n and/or CP-V2-n and very preferably selected from the group of the formulae CP-V-1 and CP-V2-1. The definitions of these abbreviations (acronyms) are indicated below in Table D or are evident from Tables A to C.
In a preferred embodiment, the media according to the invention comprise one or more compounds of the formula IV-5, more preferably selected from the respective sub-formulae thereof of the formulae CCP-V-n and/or CCP-nV-m and/or CCP-Vn-m, more preferably of the formulae CCP-V-n and/or CCP-V2-n and very preferably selected from the group of the formulae CCP-V-1 and CCP-V2-1. The definitions of these abbreviations (acronyms) are indicated below in Table D or are evident from Tables A to C.
In a likewise preferred embodiment, the media according to the invention comprise one or more compounds of the formula IV-1, more preferably selected from the respective sub-formulae thereof of the formulae CC-n-m, CC-n-V, CC-n-Vm, CC-V-V, CC-V-Vn and/or CC-nV-Vm, more preferably of the formulae CC-n-V and/or CC-n-Vm and very preferably selected from the group of the formulae CC-3-V, CC-4-V, CC-5-V, CC-3-V1, CC-4-V1, CC-5-V1, CC-3-V2 and CC-V-V1. The definitions of these abbreviations (acronyms) are likewise indicated below in Table D or are evident from Tables A to C.
In a further preferred embodiment of the present invention, which may be the same as the previous one or a different one, the liquid-crystal mixtures according to the present invention comprise component C which comprises, preferably predominantly consists of and very preferably entirely consists of compounds of the formula IV selected from the group of the compounds of the formulae IV-1 to IV-8 as shown above and optionally of the formulae IV-9 to IV-15
in which
R41 and R42, independently of one another, denote alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms, and
L4 denotes H or F.
In a preferred embodiment, the media according to the invention comprise one or more compounds of the formula IV-10, more preferably selected from the respective sub-formulae thereof of the formulae CPP-3-2, CPP-5-2 and CGP-3-2, more preferably of the formulae CPP-3-2 and/or CGP-3-2 and very particularly preferably of the formula CPP-3-2. The definitions of these abbreviations (acronyms) are indicated below in Table D or are evident from Tables A to C.
The liquid-crystalline media according to the present invention preferably comprise one or more compounds of the formula V
in which
R51 and R52, independently of one another, have the meaning indicated for R2 under formula II above, preferably R51 denotes alkyl and R52 denotes alkyl or alkenyl,
if it occurs twice in each case independently of one another on each occurrence, denotes
preferably one or more of
denote
Z51 and Z52, independently of one another and, if Z51 occurs twice, also these independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O— or a single bond, preferably one or more of them denote(s) a single bond, and
r denotes 0, 1 or 2, preferably 0 or 1, particularly preferably 1.
The compounds of the formula V are preferably dielectrically neutral compounds having a dielectric anisotropy in the range from −1.5 to 3.
The media according to the invention preferably comprise one or more compounds selected from the group of the compounds of the formulae V-1 and V-2
in which R51 and R52 have the respective meanings indicated above under formula V, and R51 preferably denotes alkyl, and in formula V-1 R52 preferably denotes alkenyl, preferably —(CH2)2—CH═CH—CH3, and in formula V-2 R52 preferably denotes alkyl or alkenyl, preferably —CH═CH2, —(CH2)2—CH═CH2 or —(CH2)2—CH═CH—CH3.
The media according to the invention preferably comprise one or more compounds selected from the group of the compounds of the formulae V-1 and V-2 in which R51 preferably denotes n-alkyl, and in formula V-1 R52 preferably denotes alkenyl, and in formula V-2 R52 preferably denotes n-alkyl.
In a preferred embodiment, the media according to the invention comprise one or more compounds of the formula V-1, more preferably of the sub-formula PP-n-2Vm thereof, even more preferably of the formula PP-1-2V1. The definitions of these abbreviations (acronyms) are indicated below in Table D or are evident from Tables A to C.
In a preferred embodiment, the media according to the invention comprise one or more compounds of the formula V-2, more preferably of the sub-formulae PGP-n-m, PGP-n-V, PGP-n-2Vm, PGP-n-2V and PGP-n-2Vm thereof, even more preferably of the sub-formulae PGP-3-m, PGP-n-2V and PGP-n-V1 thereof, very preferably selected from the formulae PGP-3-2, PGP-3-3, PGP-3-4, PGP-3-5, PGP-1-2V, PGP-2-2V and PGP-3-2V. The definitions of these abbreviations (acronyms) are likewise indicated below in Table D or are evident from Tables A to C.
Alternatively or in addition to the compounds of the formulae II and/or III, the media according to the present invention may comprise one or more dielectrically positive compounds of the formula VI
in which
R6 denotes alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy having 1 to 7 C atoms, alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl having 2 to 7 C atoms and preferably alkyl or alkenyl,
to
independently of one another, denote
L61 and L62, independently of one another, denote H or F, preferably L61 denotes F,
X6 denotes halogen, halogenated alkyl or alkoxy having 1 to 3 C atoms or halogenated alkenyl or alkenyloxy having 2 or 3 C atoms, preferably F, Cl, —OCF3 or —CF3, very preferably F, Cl or —OCF3,
Z6 denotes —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O— or —CF2O—, preferably —CH2CH2—, —COO— or trans-CH═CH— and very preferably —COO— or trans-CH═CH—, and
q denotes 0 or 1.
The media according to the present invention preferably comprise one or more compounds of the formula VI, preferably selected from the group of the compounds of the formulae VI-1 and VI-2
in which the parameters have the respective meanings indicated above, and the parameters L63 and L64, independently of one another and of the other parameters, denote H or F, and Z6 preferably denotes —CH2—CH2—.
The compounds of the formula VI-1 are preferably selected from the group of the compounds of the formulae VI-1a and VI-1b
in which R6 has the meaning indicated above.
The compounds of the formula VI-2 are preferably selected from the group of the compounds of the formulae VI-2a to VI-2d
in which R6 has the meaning indicated above.
In addition, the liquid-crystal media according to the present invention may comprise one or more compounds of the formula VII
in which
R7 has the meaning indicated for R2 above under formula one of the rings
to
that is present denotes
preferably
preferably
denotes
and the others have the same meaning or, independently of one another, denote
preferably
Z71 and Z72, independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O— or a single bond, preferably one or more of them denote(s) a single bond and very preferably both denote a single bond,
t denotes 0, 1 or 2, preferably 0 or 1, more preferably 1, and
X7 has the meaning indicated for X2 above under formula II or alternatively, independently of R7, may have one of the meanings indicated for R7.
The compounds of the formula VII are preferably dielectrically positive compounds.
In addition, the liquid-crystal media according to the present invention may comprise one or more compounds of the formula VIII
in which
R81 and R82, independently of one another, have the meaning indicated for R2 above under formula II, and
denotes
preferably
denotes
Z81 and Z82, independently of one another, denote —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O— or a single bond, preferably one or more of them denote(s) a single bond and very preferably both denote a single bond,
L81 and L82, independently of one another, denote C—F or N, preferably one of L81 and L82 or both denote(s) C—F and very preferably both denote C—F, and
s denotes 0 or 1.
The compounds of the formula VIII are preferably dielectrically negative compounds.
The media according to the invention preferably comprise one or more compounds of the formula VIII, preferably selected from the group of the compounds of the formulae VIII-1 to VIII-3
in which
R81 and R82 have the respective meanings indicated above under formula VIII.
In formulae VIII-1 to VIII-3, R81 preferably denotes n-alkyl or 1-E-alkenyl and R82 preferably denotes n-alkyl or alkoxy.
The liquid-crystalline media according to the present invention preferably comprise one or more compounds selected from the group of the compounds of the formulae I to VIII, preferably of the formulae I to VII and more preferably of the formulae I and II and/or III and/or IV and/or VI. They particularly preferably predominantly consist of, even more preferably essentially consist of and very preferably entirely consist of these compounds.
In this application, “comprise” in connection with compositions means that the entity in question, i.e. the medium or the component, comprises the component or components or compound or compounds indicated, preferably in a total concentration of 10% or more and very preferably 20% or more.
In this connection, “predominantly consist of” means that the entity in question comprises 55% or more, preferably 60% or more and very preferably 70% or more of the component or components or compound or compounds indicated.
In this connection, “essentially consist of” means that the entity in question comprises 80% or more, preferably 90% or more and very preferably 95% or more of the component or components or compound or compounds indicated.
In this connection, “virtually completely consist of” or “entirely consist of” means that the entity in question comprises 98% or more, preferably 99% or more and very preferably 100% of the component or components or compound or compounds indicated.
Other mesogenic compounds which are not explicitly mentioned above can optionally and advantageously also be used in the media according to the present invention. Such compounds are known to the person skilled in the art.
The liquid-crystal media according to the present invention preferably have a clearing point of 70° C. or more, more preferably 75° C. or more, particularly preferably 80° C. or more and very particularly preferably 85° C. or more.
The nematic phase of the media according to the invention preferably extends at least from 0° C. or less to 70° C. or more, more preferably at least from −20° C. or less to 75° C. or more, very preferably at least from −30° C. or less to 75° C. or more and in particular at least from −40° C. or less to 80° C. or more.
The Δε of the liquid-crystal medium according to the invention, at 1 kHz and 20° C., is preferably 2 or more, more preferably 3 or more, even more preferably 4 or more and very preferably 6 or more. Δε is preferably 30 or less, Δε is particularly preferably 20 or less.
The Δn of the liquid-crystal media according to the present invention, at 589 nm (NaD) and 20° C., is preferably in the range from 0.070 or more to 0.150 or less, more preferably in the range from 0.080 or more to 0.140 or less, even more preferably in the range from 0.090 or more to 0.135 or less and very particularly preferably in the range from 0.100 or more to 0.130 or less.
In a first preferred embodiment of the present application, the Δn of the liquid-crystal media according to the present invention is preferably 0.080 or more to 0.120 or less, more preferably in the range from 0.090 or more to 0.110 or less and very particularly preferably in the range from 0.095 or more to 0.105 or less, while Δε is preferably in the range from 6 or more to 11 or less, preferably in the range from 7 or more to 10 or less and particularly preferably in the range from 8 or more to 9 or less.
In this embodiment, the nematic phase of the media according to the invention preferably extends at least from −20° C. or less to 70° C. or more, more preferably at least from −20° C. or less to 70° C. or more, very preferably at least from −30° C. or less to 70° C. or more and in particular at least from −40° C. or less to 70° C. or more.
In a second preferred embodiment of the present application, the Δn of the liquid-crystal media according to the present invention is preferably in the range from 0.100 or more to 0.140 or less, more preferably in the range from 0.110 or more to 0.130 or less and very particularly preferably in the range from 0.115 or more to 0.125 or less, while Δε is preferably in the range from 7 or more to 13 or less, preferably in the range from 9 or more to 20 or less and particularly preferably in the range from 10 or more to 17 or less.
In this embodiment, the nematic phase of the media according to the invention preferably extends at least from −20° C. or less to 80° C. or more, more preferably at least from −20° C. or less to 85° C. or more, very preferably at least from −30° C. or less to 80° C. or more and in particular at least from −40° C. or less to 85° C. or more.
In accordance with the present invention, the compounds of the formula I and/or TINUVIN 770® together are preferably used in the media in a total concentration of 1% to 50%, more preferably 1% to 30%, more preferably 2% to 30%, more preferably 3% to 30% and very preferably 5% to 25% of the mixture as a whole.
The compounds selected from the group of the formulae II and III are preferably used in a total concentration of 2% to 60%, more preferably 3% to 35%, even more preferably 4% to 20% and very preferably 5% to 15% of the mixture as a whole.
The compounds of the formula IV are preferably used in a total concentration of 5% to 70%, more preferably 20% to 65%, even more preferably 30% to 60% and very preferably 40% to 55% of the mixture as a whole.
The compounds of the formula V are preferably used in a total concentration of 0% to 30%, more preferably 0% to 15% and very preferably 1% to 10% of the mixture as a whole.
The compounds of the formula VI are preferably used in a total concentration of 0% to 50%, more preferably 1% to 40%, even more preferably 5% to 30% and very preferably 10% to 20% of the mixture as a whole.
The media according to the invention may optionally comprise further liquid-crystal compounds in order to adjust the physical properties. Such compounds are known to the person skilled in the art. Their concentration in the media according to the present invention is preferably 0% to 30%, more preferably 0.1% to 20% and very preferably 1% to 15%.
In a preferred embodiment, the concentration of the compound of the formula CC-3-V in the media according to the invention can be 50% to 65%, particularly preferably 55% to 60%.
The liquid-crystal media preferably comprise in total 50% to 100%, more preferably 70% to 100% and very preferably 80% to 100% and in particular 90% to 100% of the compounds of the formulae I to VII, preferably selected from the group of the compounds of the formulae IA, IB and II to VI, particularly preferably of the formulae I to V, in particular of the formulae IA, IB, II, III, IV, V and VII and very particularly preferably of the formulae IA, IB, II, III, IV and V. They preferably predominantly consist of and very preferably virtually completely consist of these compounds. In a preferred embodiment, the liquid-crystal media in each case comprise one or more compounds of each of these formulae.
In the present application, the expression dielectrically positive describes compounds or components where Δε>3.0, dielectrically neutral describes those where −1.5≤Δε≤3.0 and dielectrically negative describes those where Δε<−1.5. Δε is determined at a frequency of 1 kHz and at 20° C.
The dielectric anisotropy of the respective compound is determined from the results of a solution of 10% of the respective individual compound in a nematic host mixture. If the solubility of the respective compound in the host mixture is less than 10%, the concentration is reduced to 5%. The capacitances of the test mixtures are determined both in a cell having homeotropic alignment and in a cell having homogeneous alignment. The cell thickness of both types of cells is approximately 20 μm. The voltage applied is a rectangular wave having a frequency of 1 kHz and an effective value of typically 0.5 V to 1.0 V, but it is always selected to be below the capacitive threshold of the respective test mixture.
Δε is defined as (ε∥−ε⊥), while εav, is (ε∥+2ε⊥)/3.
The host mixture used for dielectrically positive compounds is mixture ZLI-4792 and that used for dielectrically neutral and dielectrically negative compounds is mixture ZLI-3086, both from Merck KGaA, Germany. The absolute values of the dielectric constants of the compounds are determined from the change in the respective values of the host mixture on addition of the compounds of interest. The values are extrapolated to a concentration of the compounds of interest of 100%.
Components having a nematic phase at the measurement temperature of 20° C. are measured as such, all others are treated like compounds.
The expression threshold voltage in the present application refers to the optical threshold and is quoted for 10% relative contrast (V10), and the expression saturation voltage refers to the optical saturation and is quoted for 90% relative contrast (V90), in both cases unless expressly stated otherwise. The capacitive threshold voltage (V0), also called the Freedericks threshold (VFr), is only used if expressly mentioned.
The ranges of the parameters indicated in this application all include the limit values, unless expressly stated otherwise.
The different upper and lower limit values indicated for various ranges of properties in combination with one another give rise to additional preferred ranges.
Throughout this application, the following conditions and definitions apply, unless expressly stated otherwise. All concentrations are indicated in percent by weight and relate to the respective mixture as a whole, all temperatures are quoted in degrees Celsius and all temperature differences are quoted in differential degrees. All physical properties are determined in accordance with “Merck Liquid Crystals, Physical Properties of Liquid Crystals”, Status November 1997, Merck KGaA, Germany, and are quoted for a temperature of 20° C., unless expressly stated otherwise. The optical anisotropy (Δn) is determined at a wavelength of 589.3 nm. The dielectric anisotropy (Δε) is determined at a frequency of 1 kHz. The threshold voltages, as well as all other electro-optical properties, are determined using test cells produced at Merck KGaA, Germany. The test cells for the determination of Δε have a cell thickness of approximately 20 μm. The electrode is a circular ITO electrode having an area of 1.13 cm2 and a guard ring. The orientation layers are SE-1211 from Nissan Chemicals, Japan, for homeotropic orientation (ε∥) and polyimide AL-1054 from Japan Synthetic Rubber, Japan, for homogeneous orientation (ε⊥). The capacitances are determined using a Solatron 1260 frequency response analyser using a sine wave with a voltage of 0.3 Vrms. The light used in the electro-optical measurements is white light. A set-up using a commercially available DMS instrument from Autronic-Melchers, Germany, is used here. The characteristic voltages have been determined under perpendicular observation. The threshold (V10), mid-grey (V50) and saturation (V90) voltages have been determined for 10%, 50% and 90% relative contrast, respectively.
The liquid-crystal media according to the present invention may comprise further additives and chiral dopants in the usual concentrations. The total concentration of these further constituents is in the range from 0% to 10%, preferably 0.1% to 6%, based on the mixture as a whole. The concentrations of the individual compounds used are each preferably in the range from 0.1% to 3%. The concentration of these and similar additives is not taken into consideration when quoting the values and concentration ranges of the liquid-crystal components and compounds of the liquid-crystal media in this application.
The liquid-crystal media according to the invention consist of a plurality of compounds, preferably 3 to 30, more preferably 4 to 20 and very preferably 4 to 16 compounds. These compounds are mixed in a conventional manner. In general, the desired amount of the compound used in the smaller amount is dissolved in the compound used in the larger amount. If the temperature is above the clearing point of the compound used in the higher concentration, it is particularly easy to observe completion of the dissolution process. It is, however, also possible to prepare the media in other conventional ways, for example using so-called pre-mixes, which can be, for example, homologous or eutectic mixtures of compounds, or using so-called “multibottle” systems, the constituents of which are themselves ready-to-use mixtures.
By addition of suitable additives, the liquid-crystal media according to the present invention can be modified in such a way that they can be used in all known types of liquid-crystal displays, either using the liquid-crystal media as such, such as TN, TN-AMD, ECB-AMD, VAN-AMD, IPS-AMD, FFS-AMD LCDs, or in composite systems, such as PDLC, NCAP, PN LCDs and especially in ASM-PA LCDs.
All temperatures, such as, for example, the melting point T(C,N) or T(C,S), the transition from the smectic (S) to the nematic (N) phase T(S,N) and the clearing point T(N,I) of the liquid crystals, are quoted in degrees Celsius. All temperature differences are quoted in differential degrees.
In the present invention and especially in the following examples, the structures of the mesogenic compounds are indicated by means of abbreviations, also called acronyms. In these acronyms, the chemical formulae are abbreviated as follows using Tables A to C below. All groups CnH2n+1, CmH2m+1 and ClH2l+1 or CnH2n−1, CmH2m−1 and ClH2l−1 denote straight-chain alkyl or alkenyl, preferably 1E-alkenyl, each having n, m and l C atoms respectively. Table A lists the codes used for the ring elements of the core structures of the compounds, while Table B shows the linking groups. Table C gives the meanings of the codes for the left-hand or right-hand end groups. The acronyms are composed of the codes for the ring elements with optional linking groups, followed by a first hyphen and the codes for the left-hand end group, and a second hyphen and the codes for the right-hand end group. Table D shows illustrative structures of compounds together with their respective abbreviations.
TABLE A
Ring elements
C
P
D
DI
A
AI
G
GI
U
UI
Y
M
MI
N
NI
Np
dH
N3f
N3fI
tH
tHI
tH2f
tH2fI
K
KI
L
LI
F
FI
Nf
NfI
TABLE B
Linking groups
E
—CH2CH2—
Z
—CO—O—
V
—CH═CH—
ZI
—O—CO—
X
—CF═CH—
O
—CH2—O—
XI
—CH═CF—
OI
—O—CH2—
B
—CF═CF—
Q
—CF2—O—
T
—C≡C—
QI
—O—CF2—
W
—CF2CF2—
T
—C≡C—
TABLE C
End groups
Left-hand side
Right-hand side
Use alone
-n-
CnH2n+1—
-n
—CnH2n+1
-nO-
CnH2n+1—O—
-nO
—O—CnH2n+1
-V-
CH2═CH—
-V
—CH═CH2
-nV-
CnH2n+1—CH═CH—
-nV
—CnH2n—CH═CH2
-Vn-
CH2═CH—CnH2n+1—
-Vn
—CH═CH—CnH2n+1
-nVm-
CnH2n+1—CH═CH—CmH2m—
-nVm
—CnH2n—CH═CH—CmH2m+1
-N-
N≡C—
-N
—C≡N
-S-
S═C═N—
-S
—N═C═S
-F-
F—
-F
—F
-CL-
Cl—
-CL
—Cl
-M-
CFH2—
-M
—CFH2
-D-
CF2H—
-D
—CF2H
-T-
CF3—
-T
—CF3
-MO-
CFH2O—
-OM
—OCFH2
-DO-
CF2HO—
-OD
—OCF2H
-TO-
CF3O—
-OT
—OCF3
-OXF-
CF2═CH—O—
-OXF
—O—CH═CF2
-A-
H—C≡C—
-A
—C≡C—H
-nA-
CnH2n+1—C≡C—
-An
—C≡C—CnH2n+1
-NA-
N≡C—C≡C—
-AN
—C≡C—C≡N
Use together with one another and with others
-...A...-
—C≡C—
-...A...
—C≡C—
-...V...-
CH═CH—
-...V...
—CH═CH—
-...Z...-
—CO—O—
-...Z...
—CO—O—
-...ZI...-
—O—CO—
-...ZI...
—O—CO—
-...K...-
—CO—
-...K...
—CO—
-...W...-
—CF═CF—
-...W...
—CF═CF—
in which n and m each denote integers, and the three dots “ . . . ” are place-holders for other abbreviations from this table.
The following table shows illustrative structures together with their respective abbreviations. These are shown in order to illustrate the meaning of the rules for the abbreviations. They furthermore represent compounds which are preferably used.
TABLE D
Illustrative structures
CC-n-m
CC-n-Om
CC-n-V
CC-n-Vm
CC-n-mV
CC-n-mVI
CC-V-V
CC-V-mV
CC-V-Vm
CC-Vn-mV
CC-nV-mV
CC-nV-Vm
CP-n-m
CP-nO-m
CP-n-Om
CP-V-m
CP-Vn-m
CP-nV-m
CP-V-V
CP-V-mV
CP-V-Vm
CP-Vn-mV
CP-nV-mV
CP-nV-Vm
PP-n-m
PP-nO-m
PP-n-Om
PP-n-V
PP-n-Vm
PP-n-mV
PP-n-mVI
CCP-n-m
CCP-nO-m
CCP-n-Om
CCP-n-V
CCP-n-Vm
CCP-n-mV
CCP-n-mVI
CCP-V-m
CCP-nV-m
CCP-Vn-m
CCP-nVm-I
CPP-n-m
CPG-n-m
CGP-n-m
CPP-nO-m
CPP-n-Om
CPP-V-m
CPP-nV-m
CPP-Vn-m
CPP-nVm-I
PGP-n-m
PGP-n-V
PGP-n-Vm
PGP-n-mV
PGP-n-mVI
CCEC-n-m
CCEC-n-Om
CCEP-n-m
CCEP-n-Om
CPPC-n-m
CGPC-n-m
CCPC-n-m
CCZPC-n-m
CPGP-n-m
CPGP-n-mV
CPGP-n-mVI
PGIGP-n-m
CP-n-F
CP-n-CL
GP-n-F
GP-n-CL
CCP-n-OT
CCG-n-OT
CCP-n-T
CCG-n-F
CCG-V-F
CCG-V-F
CCU-n-F
CDU-n-F
CPG-n-F
CPU-n-F
CGU-n-F
PGU-n-F
GGP-n-F
GGP-n-CL
PGIGI-n-F
PGIGI-n-CL
CCPU-n-F
CCGU-n-F
CPGU-n-F
CPGU-n-OT
DPGU-n-F
PPGU-n-F
CCZU-n-F
CCQP-n-F
CCQG-n-F
CCQU-n-F
PPQG-n-F
PPQU-n-F
PGQU-n-F
GGQU-n-F
PUQU-n-F
MUQU-n-F
NUQU-n-F
CDUQU-n-F
CPUQU-n-F
CGUQU-n-F
PGPQP-n-F
PGPQG-n-F
PGPQU-n-F
PGUQU-n-F
APUQU-n-F
DGUQU-n-F
in which n, m and l preferably, independently of one another, denote 1 to 7.
The following table, Table E, shows illustrative compounds which can be used as additional stabilisers in the mesogenic media according to the present invention.
TABLE E
In a preferred embodiment of the present invention, the mesogenic media comprise one or more compounds selected from the group of the compounds from Table E.
Table F below shows illustrative compounds which can preferably be used as chiral dopants in the mesogenic media according to the present invention.
TABLE F
C15
CB 15
CM 21
CM 44
CM 45
CM 47
CC
CN
R/S-811
R/S-1011
R/S-2011
R/S-3011
R/S-4011
R/S-5011
In a preferred embodiment of the present invention, the mesogenic media comprise one or more compounds selected from the group of the compounds from Table F.
The mesogenic media according to the present application preferably comprise two or more, preferably four or more, compounds selected from the group consisting of the compounds from the above tables.
The liquid-crystal media according to the present invention preferably comprise
seven or more, preferably eight or more, individual compounds, preferably of three or more, particularly preferably of four or more, different formulae, selected from the group of the compounds from Table D.
EXAMPLES
The examples below illustrate the present invention without limiting it in any way.
However, the physical properties show the person skilled in the art what properties can be achieved and in what ranges they can be modified. In particular, the combination of the various properties which can preferably be achieved is thus well defined for the person skilled in the art.
Liquid-crystal mixtures having the composition and properties as indicated in the following tables are prepared.
SUBSTANCE EXAMPLES
The following substances are substances of the formula I preferably to be employed in accordance with the present application.
Synthesis Example 1
Synthesis of bis(2,2,6,6-tetramethyl-4-piperidyl)-N,N1-dioxyl succinate (Substance Example 1
2.15 g (12.26 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, 40 mg (0.33 mmol) of 4-(dimethylamino)pyridine and 1 ml (12.4 mmol) of dried pyridine are initially introduced in 20 ml of dry dichloromethane. 4 Ångström activated molecular sieve is subsequently added, and the mixture is stirred at room temperature (RT for short; about 22° C.) for 90 min. The reaction solution is cooled to a temperature in the range from 7 to 10° C., and 0.71 ml (6.13 mmol) of succinyl dichloride is slowly added, and the mixture is stirred at RT for 18 h. Sufficient sat. NaHCO3 solution and dichloromethane are added to the reaction solution, and the organic phase is separated off, washed with water and sat. NaCl solution, dried over Na2SO4, filtered and evaporated. The crude product is purified over silica gel with dichloromethane/methyl tert-butyl ether (95:5), giving the product as a white solid having a purity of >99.5%.
Synthesis Example 2
Synthesis of bis(2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl) decanedioate (Substance Example 4
28.5 g (166 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (free radical) and 250 mg (2.05 mmol) of 4-(dimethylamino)pyridine are dissolved in 300 ml of degassed dichloromethane, and 50.0 ml (361 mmol) of triethylamine are added. The mixture is subsequently degassed and cooled to 0° C., and 10 g (41.4 mmol) of sebacoyl chloride dissolved in 100 ml of degassed dichloromethane are added dropwise at 0-5° C., and the mixture is stirred at room temperature for 18 h. When the reaction is complete, water and HCl (pH=4-5) are added with ice-cooling, and the mixture is stirred for a further 30 min. The organic phase is separated off, and the water phase is subsequently extracted with dichloromethane, and the combined phases are washed with saturated NaCl solution and dried over Na2SO4, filtered and evaporated, giving 24.4 g of a red liquid, which together are passed through 100 g of basic Al2O3 and 500 g of silica gel on a frit with dichloromethane/methyl tert-butyl ether (95/5), giving orange crystals, which are dissolved in degassed acetonitrile at 50° C. and crystallised at −25° C., giving the product as orange crystals having an HPLC purity of 99.9%.
Synthesis Example 3
Synthesis of bis(2,2,6,6-tetramethyl-4-piperidyl)-N,N′-dioxylbutanediol (Substance Example 7
Sufficient pentane is added to 15.0 g (60% in mineral oil, 375 mmol) of NaH under a protective gas, and the mixture is allowed to settle. The pentane supernatant is pipetted off and carefully quenched with isopropanol with cooling. 100 ml of THF are then carefully added to the washed NaH. The reaction mixture is heated to 55° C., and a solution of 50.0 g (284 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl in 400 ml of THF is carefully added dropwise. The hydrogen formed is discharged directly. When the addition of the solution is complete, stirring is continued at 60° C. overnight (16 h). The reaction mixture is subsequently cooled to 5° C., and 1,4-butanediol dimethylsulfonate is added in portions. The mixture is subsequently slowly heated to 60° C. and stirred at this temperature for 16 h. When the reaction is complete, the mixture is cooled to RT, and 200 ml of 6% ammonia solution in water are added with cooling, and the mixture is stirred for 1 h. The organic phase is subsequently separated off, the aqueous phase is rinsed with methyl tert-butyl ether, the combined organic phases are washed with sat. NaCl solution, dried and evaporated. The crude product is purified over silica gel with dichloromethane/methyl tert-butyl ether (8:2) and crystallised from acetonitrile at −20° C., giving the product as a pink crystalline solid having a purity of >99.5%.
Synthesis Example 4
Synthesis of bis[2,2,6,6-tetramethyl-1-(1-phenyl-ethoxy)piperidin-4-yl] succinate (Substance Example 24
Step 4.1: Synthesis of 2,2,6,6-tetramethyl-1-(1-phenylethoxy)piperidin-4-ol
5.0 g (29.03 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, 7.80 g (58.1 mmol) of 2-phenylpropionaldehyde and 100.6 mg (1.02 mmol) of copper(I) chloride are initially introduced in 20 ml of tert-butanol. 6.45 ml (58.06 mmol) of 35% hydrogen peroxide solution are then carefully and slowly added dropwise at such a rate that the internal temperature does not exceed 30° C. The mixture is therefore cooled by means of ice-cooling during the dropwise addition. Oxygen is formed in the reaction and would spontaneously be released in large quantities if the addition were too fast and the temperature too high. When the addition is complete, the reaction solution is stirred at RT for a further 16 h, and sufficient water/methyl tert-butyl ether is subsequently added, and the organic phase is separated off. The organic phase is washed with 10% ascorbic acid until peroxide-free, and the peroxide content is checked. The mixture is subsequently washed with 10% NaOH solution, water and sat. NaCl solution, dried over Na2SO4, filtered and evaporated. The crude product obtained is purified over silica gel with heptane/methyl tert-butyl ether (1:1), giving the product as colourless crystals.
Step 4.2: Synthesis of bis[2,2,6,6-tetramethyl-1-(1-phenylethoxyl)piperidin-4-yl] succinate
1.52 g (5.5 mmol) of the product from the preceding step, the compound 2,2,6,6-tetramethyl-1-(1-phenylethoxyl)piperidin-4-ol, 15.3 mg (0.125 mmol) of dimethylaminopyridine and 1.02 ml (12.6 mmol) of dried pyridine are initially introduced in 10 ml of dichloromethane and cooled to a temperature in the range from 7 to 10° C. 0.255 ml (2.199 mmol) of succinoyl dichloride is then added dropwise as such and if necessary topped up if hydroxyl compound is still present. When the reaction is complete, the reaction mixture is filtered directly through silica gel with dichloromethane and subsequently eluted with heptane/methyl tert-butyl ether (1:1) and pure methyl tert-butyl ether. The product obtained is dissolved in acetonitrile and purified by means of preparative HPLC (2 Chromolith columns with 50 ml/min of acetonitrile), giving the product as a yellow oil having a purity of >99.9%.
Synthesis Example 5
Synthesis of 2,2,6,6-tetramethyl-1-(1-phenyl-ethoxy)piperidin-4-yl pentanoate (Substance Example 31
2.5 g (9.01 mmol) of the compound 2,2,6,6-tetramethyl-1-(1-phenyl-ethoxy)piperidin-4-ol from step 3.1 and 55.1 mg (0.45 mmol) of (4-dimethylaminopyridine) are dissolved in 50.0 ml of dry dichloromethane and cooled to 3° C. 5.47 ml (27.03 mmol) of valeric anhydride are added at this temperature, and the mixture is stirred at room temperature for 14 h. When the reaction is complete, the mixture is carefully poured into ice-water, adjusted to pH 6 using 2N HCl, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with saturated NaCl solution, a mixture of water and triethylamine (300:50 ml) and dried over MgSO4, filtered and evaporated. Purification on silica gel with heptane/methyl tert-butyl ether (9:1) gives the product as a colourless oil.
Synthesis Example 6
Synthesis of 1,4-bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) butanedioate (Substance Example 49
40 ml of water and 80 ml of dioxane are mixed and carefully degassed by means of a stream of argon. 2.0 g (4.7 mmol) of the free radical from Substance Example 1 (Synthesis Example 1) are dissolved in the solvent mixture, and 4.95 g (28.1 mmol) of ascorbic acid are added in portions. The reaction mixture becomes colourless during this addition and is stirred at 40° C. for 18 h under a protective-gas atmosphere. The mixture is cooled to room temperature, and 100 ml of water are added, the mixture is stirred briefly, and the crystals formed are filtered off with suction. The crystals are dissolved in 50 ml of hot degassed THF, and the insoluble constituents are filtered off, and the filtrate is crystallised at −25° C. The pale-pink crystals are then washed by stirring in acetonitrile at room temperature for 18 h, giving the product as pale-pink crystals having an HPLC purity of 100%.
Synthesis Example 8
Synthesis of 1,10-bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decanedioate (Substance Example 50
All solvents used are thoroughly degassed in advance by means of a stream of argon. During work-up, brown glass equipment must be used. 1.70 g (3.32 mmol) of the free radical from Substance Example 4 (Synthesis Example 2) are dissolved in 60 ml of dioxane. 3.6 g (20 mmol) of ascorbic acid dissolved in 30 ml of water are subsequently added dropwise to the solution at room temperature. The reaction solution starts to become colourless during this dropwise addition, and the reaction is complete after stirring at room temperature for 1 h. The mixture is extracted with 100 ml of dichloromethane, and the organic phase is washed with water, dried over Na2SO4, filtered and evaporated. The yellow crystals formed are dried at 160° C. and 10−2 mbar for 5 min, giving a viscous, slowly crystallising oil.
Liquid-crystal mixtures having the compositions and properties as indicated in the following tables are prepared and investigated.
USE EXAMPLES
Use Example 1
Comparative Example 1 and Use Example 1.1
Mixture M-1:
Composition
Compound
No.
Abbreviation
c/%
1
APUQU-3-F
4.5
2
PGUQU-3-F
5.0
3
PGUQU-4-F
9.0
4
PGUQU-5-F
1.5
5
CCQU-3-F
4.0
6
CCQU-5-F
9.0
7
CCU-3-F
9.0
8
CCU-5-F
9.0
9
CC-3-V
38.5
10
CC-3-V1
4.0
11
PGP-2-3
6.5
Σ
100.0
Physical properties
T(N, I) = 80.5° C.
ne (20° C., 589.3 nm) = 1.5780
Δn (20° C., 589.3 nm) = 0.0990
ε|| (20° C., 1 kHz) = 12.3
Δε (20° C., 1 kHz) = 9.1
k1(20° C.) = 12.6 pN
k3(20° C.) = 14.0 pN
γ1 (20° C.) = 76 mPa · s
V0 (20° C.) = 1.24 V
This mixture (mixture M-1) is prepared and divided into two parts. The first part is investigated without addition of a further compound. 100 ppm of the compound to be investigated, here the compound of the formula I-1a-1, are added to the second part of the mixture. The two parts of the mixture are investigated as follows.
In each case, six test cells having the alignment layer AL-16301 (Japan Synthetic Rubber (JSR), Japan) and a layer thickness of 3.2 μm and transversal electrodes as for TN cells are filled and investigated with respect to their voltage holding ratio. The initial value and the value after UV exposure with an Execure 3000 high-pressure mercury vapour lamp from Hoya with an edge filter (T=50% at 340 nm), at a certain exposure intensity in J/cm2, are determined at a temperature of 25° C. The respective exposure intensity is measured at a wavelength of 365 nm using an Ushio UIT-101+UVD-365PD sensor. In each case, the HR is measured at a temperature of 100° C. after 5 minutes in the oven. The voltage is 1 V at 60 Hz. The results are summarised in the following table.
IUV/J/cm2
0
3
6
12
Example
X: formula
c(X)/ppm
HR0/%
HRUV/%
V1.0
None
0
98.6
94.2
90.8
85.2
1.1
I-1a-1
100
98.0
95.7
94.8
93.9
Notes:
X: compound of the formula I-1a-1
IUV at 365 nm.
The mixtures of Use Example 1.1, which comprise a compound of the formula I (I-1a-2), are distinguished, in particular, by excellent stability to UV irradiation.
Corresponding investigations of the two different mixtures were then carried out in sealed test cells with exposure to commercial LCD TV backlighting (CCFL). The temperature of the test cells here was about 40° C. due to the heat evolution by the backlighting. The results are summarised in the following table.
t/h
0
24
168
1000
Example
X: formula
c(X)/ppm
HR0/%
HRBL/%
V1.0
None
0
98.1
89.8
69.3
36
1.1
I-1a-1
100
97.9
98.3
95.8
68.5
Note:
X: compound of the formula I-1a-1.
Corresponding investigations were subsequently carried out on the two different mixtures in sealed test cells with heating. The temperature stability is checked by a heat test. To this end, the HR is determined before and after heating. To this end, the cells are stored in an oven at a temperature of 100° C. for certain times. The HR is then determined as described above. The results are summarised in the following table.
t/h
0
24
72
336
Example
X: formula
c(X)/ppm
HR0/%
HRT (t)/%
V1.0
None
0
98.5
97.1
95.8
93.9
1.1
I-1a-1
100
98.0
97.8
97.5
95.8
Notes:
X: compound of the formula I-1a-1
Temperature: 100° C.
Use Example 2
Comparative Example 2.0 and Use Examples 2.1 to 2.4
Mixture M-2:
Composition
Compound
No.
Abbreviation
c/%
1
DGUQU-4-F
8.0
2
APUQU-2-F
8.0
3
APUQU-3-F
6.5
4
PGUQU-3-F
3.5
5
PGUQU-4-F
9.0
6
DPGU-4-F
6.0
7
CCP-3-OT
8.0
8
CC-3-V
33.5
9
CC-3-V1
11.5
10
CCP-V2-1
6.0
Σ
100.0
Physical properties
T(N, I) = 93.0° C.
ne (20° C., 589.3 nm) = 1.5876
Δn (20° C., 589.3 nm) = 0.1086
ε|| (20° C., 1 kHz) = 19.0
Δε (20° C., 1 kHz) = 15.4
k1(20° C.) = 14.7 pN
k3(20° C.) = 15.6 pN
γ1 (20° C.) = 97 mPa · s
V0 (20° C.) = 1.03 V
Mixture M-2 is prepared here as in Use Example 1, but is divided into five parts here. The first part is investigated without addition of a further compound. 100 ppm or 200 ppm of the compound of the formula TINUVIN 770® or 100 ppm or 200 ppm of the compound of the formula I-1a-1 are added to the four further parts of the mixture.
In each case, six test cells having the alignment layer AL-16301 (Japan Synthetic Rubber (JSR), Japan) and a layer thickness of 3.2 μm are filled (electrodes: TN layout) and investigated with respect to their voltage holding ratio. The initial value and the value after UV exposure with a high-pressure mercury vapour lamp from Hoya (Execure 3000) with an edge filter (T=50% at 340 nm), at a certain exposure intensity in J/cm2, are determined at a temperature of 25° C. The exposure intensity is measured using an Ushio UIT-101+UVD-365PD sensor at a wavelength of 365 nm. In each case, the HR is measured at a temperature of 100° C. after 5 minutes in the oven. The voltage is 1 V at 60 Hz. The results are summarised in the following table.
IUV/J/cm2
0
3
Example
X: formula
c(X)/ppm
HR0/%
HRUV/%
V2.0
None
0
95.8
90.0
2.1
TINUVIN 770 ®
100
97.0
94.5
2.2
TINUVIN 770 ®
200
97.7
96.8
2.3
I-1a-1
100
95.1
93.4
2.4
I-1a-1
200
95.2
94.1
Notes:
X: TINUVIN 770 ® in the case of Examples 2.1 and 2.2 and the compound of the formula I-1a-1 in the case of Examples 2.3 and 2.4, IUV at 365 nm.
The mixtures of Use Examples 2.1 to 2.4, each of which comprise a compound of the formula TINUVIN 770® or a compound of the formula I (I-1a-2), are distinguished, in particular, by excellent stability to UV irradiation. In the case of the corresponding two mixture pairs, the stability here increases with increasing concentration of the compound of the formula TINUVIN 770® or of the formula I-1a-2.
Corresponding investigations of the five different mixtures were then carried out in test cells with exposure to LCD backlighting as described above. The results are summarised in the following table.
t/h
0
24
168
Example
X: formula
c(X)/ppm
HR0/%
HRBL/(t)/%
V2.0
None
0
96.2
82.9
56.8
2.1
TINUVIN 770 ®
100
97.6
95.1
93.0
2.2
TINUVIN 770 ®
200
98.7
98.5
95.8
2.3
I-1a-1
100
96.1
97.2
92.4
2.4
I-1a-1
200
95.7
97.3
95.5
Note:
X: TINUVIN 770 ® in the case of Examples 2.1 and 2.2 and the compound of the formula I-1a-1 in the case of Examples 2.3 and 2.4.
The difference in the HR of the host in the case of Comparative Example 2.0 in this table from those in the preceding table of this comparative example is attributable to the reproducibility of the measurement values. Within a measurement series in an example and the associated comparative measurements, the reproducibility is significantly better (about ½ to ⅓ times as great) and the variation latitude is thus correspondingly significantly lower.
Corresponding investigations of the five different mixtures were subsequently carried out in test cells with heating, as described above. The results are summarised in the following table.
t/h
0
24
48
96
Example
X: formula
c(X)/ppm
HR0/%
HRT (t)/%
V2.0
None
0
95.8
95.0
93.7
92.8
2.1
TINUVIN 770 ®
100
97.0
98.3
98.8
98.8
2.2
TINUVIN 770 ®
200
97.7
98.8
98.9
98.9
2.3
I-1a-1
100
95.1
96.1
96.8
96.6
2.4
I-1a-1
200
95.2
96.6
96.8
96.7
Notes:
X: TINUVIN 770 ® in the case of Examples 2.1 and 2.2 and the compound of the formula I-1a-1 in the case of Examples 2.3 and 2.4
Temperature: 100° C.
Use Example 3
Comparative Example 3.0 and Use Example 3.1
Mixture M-3:
Composition
Compound
No.
Abbreviation
c/%
1
CDUQU-3-F
8.0
2
APUQU-2-F
8.0
3
APUQU-3-F
8.5
4
PGUQU-3-F
1.5
5
PGUQU-4-F
9.0
6
PGUQU-5-F
4.0
7
DPGU-4-F
6.0
8
CCP-3-OT
8.0
9
CC-3-V
32.5
10
CC-3-V1
12.5
11
CCP-V2-1
2.0
Σ
100.0
Physical properties
T(N, I) = 93.0° C.
ne (20° C., 589.3 nm) = 1.5870
Δn (20° C., 589.3 nm) = 0.1089
ε|| (20° C., 1 kHz) = 19.2
Δε (20° C., 1 kHz) = 15.4
k1(20° C.) = 14.9 pN
k3(20° C.) = 15.2 pN
γ1 (20° C.) = 99 mPa · s
V0 (20° C.) = 1.03 V
Mixture M-3 is prepared here as in Use Example 1 and divided into two parts. The first part is investigated without addition of a further compound. 200 ppm of the compound to be investigated, here the compound of the formula I-1a-1, are added to the second part of the mixture. In each case, six test cells having the alignment layer AL-16301 (Japan Synthetic Rubber (JSR), Japan) and a layer thickness of 3.2 μm are filled (electrodes: TN layout) and investigated with respect to their voltage holding ratio. The initial value and the value after UV exposure to a high-pressure mercury vapour lamp from Hoya (Execure 3000) with an edge filter (T=50% at 340 nm), at a certain exposure intensity in J/cm2, are determined at a temperature of 25° C. The exposure intensity is measured using an Ushio UIT-101+UVD-365PD sensor at a wavelength of 365 nm. In each case, the HR is measured at a temperature of 100° C. after 5 minutes in the oven. The voltage is 1 V at 60 Hz. The results are summarised in the following table.
IUV/J/cm2
0
3
6
12
Example
c(X)/ppm
HR0/%
HRUV/%
V3.0
0
97.0
91.6
t.b.d.
t.b.d.
3.1
200
96.0
93.4
t.b.d.
t.b.d.
Notes:
X: compound of the formula I-1a-1,
t.b.d.: to be determined, IUV at 365 nm.
The mixtures of Use Example 3.1, which comprise a compound of the formula I (formula I-1a-1), are distinguished, in particular, by excellent stability to UV irradiation.
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14405423
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merck patent gmbh
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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 27th, 2022 09:11AM
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Apr 27th, 2022 09:11AM
|
Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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Apr 18th, 2019 12:00AM
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https://www.uspto.gov?id=US11312907-20220426
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Liquid crystal mixture and liquid crystal display
|
The invention relates to a compound of formula I,
wherein R11, R21, A11, A, Z, X11, X21, Y11, Y12, Sp11, Sp21, o and p have one of the meanings as given in claim 1. The invention further relates to method of production of a compound of formula I, to the use of said compounds in LC media and to LC media comprising one or more compounds of formula I. Further, the invention relates to a method of production of such LC media, to the use of such media in LC devices, and to LC device comprising a LC medium according to the present invention. The present invention further relates to a process for the fabrication such liquid crystal display and to the use of the liquid crystal mixtures according to the invention for the fabrication of such liquid crystal display.
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11312907
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1. A compound of formula I,
wherein
A11 denotes a radical
where, in addition, one or more H atoms in these radical may each be replaced by L, and/or one or more and/or one or more CH groups may each be replaced by N,
A denotes, independently of one another, in each occurrence
a) the group consisting of 1,4-phenylene and 1,3-phenylene, wherein, in addition, one or two CH groups may each be replaced by N and wherein, in addition, one or more H atoms may each be replaced by L,
b) the group consisting of saturated, partially unsaturated or fully unsaturated, and optionally substituted, polycyclic radicals having 5 to 20 cyclic C atoms, one or more of which may, in addition, be replaced by heteroatoms, selected from the group consisting of
where, in addition, one or more H atoms in these radicals may each be replaced by L, and/or one or more double bonds may each be replaced by single bonds, and/or one or more CH groups may each be replaced by N,
c) group consisting of trans-1,4-cyclohexylene, 1,4-cyclohexenylene, wherein, in addition, one or more non-adjacent CH2 groups may each be replaced by —O— or —S— and wherein, in addition, one or more H atoms may each be replaced by F, or
d) a group consisting of tetrahydropyran-2,5-diyl, 1,3-dioxane-2,5-diyl, tetrahydrofuran-2,5-diyl, cyclobutane-1,3-diyl, piperidine-1,4-diyl, thiophene-2,5-diyl and selenophene-2,5-diyl, each of which may also be mono- or polysubstituted by L,
L on each occurrence, identically or differently, denotes —OH, —F, —Cl, —Br, —I, —CN, —NO2, SF5, —NCO, —NCS, —OCN, —SCN, —C(═O)N(Rz)2, —C(═O)Rz, —N(Rz)2, optionally substituted silyl, optionally substituted aryl having 6 to 20 C atoms, or straight-chain or branched or cyclic alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having 1 to 25 C atoms, in which, in addition, one or more H atoms may each be replaced by F or Cl, or X21-Sp21-R21,
M denotes —O—, —S—, —CH2—, —CHRz— or —CRyRz—, and
Ry and Rz each, independently of one another, denote H, CN, F or alkyl having 1-12 C atoms, wherein, in addition, one or more H atoms may each be replaced by F,
Y11 and Y12 each, independently of one another, denote H, F, phenyl or optionally fluorinated alkyl having 1-12 C atoms,
Z denotes, independently of each other, in each occurrence, a single bond, —COO—, —OCO—, —O—CO—O—, —OCH2—, —CH2O—, —OCF2—, —CF2O—, —(CH2)n—, —CF2CF2—, —CH═CH—, —CF═CF—, —CH═CH—COO—, —OCO—CH═CH—, —CO—S—, —S—CO—, —CS—S—, —S—CS—, —S—CSS— or —C≡C—,
n denotes an integer between 2 and 8,
o and p denote each and independently 0, 1 or 2,
X11 and X21 denote independently from one another, in each occurrence a single bond, —CO—O—, —O—CO—, —O—COO—, —O—, —CH═CH—, —C≡C—, —CF2—O—, —O—CF2—, —CF2—CF2—, —CH2—O—, —O—CH2—, —CO—S—, —S—CO—, —CS—S—, —S—CS—, —S—CSS— or —S—,
Sp11 and Sp21 denote each and independently, in each occurrence a single bond or a spacer group comprising 1 to 20 C atoms, wherein one or more non-adjacent and non-terminal CH2 groups may also each be replaced by —O—, —S—, —NH—, —N(CH3)—, —CO—, —O—CO—, —S—CO—, —O—COO—, —CO—S—, —CO—O—, —CF2—, —CF2O—, —OCF2— —C(OH)—, —CH(alkyl)-, —CH(alkenyl)-,-CH(alkoxyl)-, —CH(oxaalkyl)-, —CH═CH— or C≡C—, however in such a way that no two O-atoms are adjacent to one another and no two groups selected from —O—CO—, —S—CO—, —O—COO—, —CO—S—, —CO—O— and —CH═CH— are adjacent to each other,
R11 denotes P,
R21 denotes P, or halogen, CN, optionally fluorinated alkyl or alkenyl with up to 15 C atoms in which one or more non adjacent CH2-groups may each be replaced by —O—, —S—, —CO—, —C(O)O—, —O—C(O)—, O—C(O)—O—, and
P each and independently from another in each occurrence a polymerizable group.
2. The compound according to claim 1, wherein the compound is selected from compounds of -sub-formulae I-1 to I-9,
wherein
R11, R21, A11, X11, X12, Y11, Y12, Sp11, and Sp12 have one of the meanings as given above in claim 1, A12 to A23 have one of the meanings for A as given in claim 1, and Z11 to Z22 have one of the meanings for Z as given above in claim 1.
3. The compound according to claim 1, wherein the compound is selected from compounds sub-formulae I-1a-1, I-2a-1, and I-3a-1,
wherein
R11, R21, X11, X21, Sp11, and Sp21 have one of the meanings as given above in claim 1, Z11 and Z21 have one of the meanings for Z as given above in claim 1 and
the group
is each and independently
or
denotes
furthermore
wherein L is F, Cl, CH3, OCH3 and COCH3 or alkylene having 1 to 6 C atoms, or X21-Sp21-R21.
4. The compound according to claim 1, wherein said compound is selected from compounds of sub formulae I-3a-1a, I-3a-1b, and I-3a-1c,
wherein
R11, R21, X21, and Sp21 have one of the meanings as given above in claim 1, Z21 has one of the meanings for Z as given above under claim 1, r, s, t and q denote each and independently from another an integer from 1 to 8, Y denotes each and independently from each other methyl or H, and
the group
is each and independently
or
denotes
furthermore
wherein L is F, Cl, CH3, OCH3 and COCH3 or alkylene having 1 to 6 C atoms, or X21-Sp21-R21.
5. The compound according to claim 1, wherein said compound is selected from compounds of sub-formulae I-3-1a-1 to I-3-1a-8,
wherein Sp21 has one of the meanings as given above in formula I, and L denotes F, Cl, OCH3 and COCH3 or alkylene having 1 to 6 C atoms.
6. The compound according to claim 1, wherein said compound is selected from compounds of sub-formulae I-3-1b-1 to I-3-1b-4,
wherein Sp21 has one of the meanings as given above in formula I, and L denotes F, Cl, OCH3 and COCH3 or alkylene having 1 to 6 C atoms.
7. A method of photoaligning a liquid crystal mixture comprising irradiating a liquid crystal mixture with linearly polarized light wherein said liquid crystal mixture contains one or more compounds of formula I according to claim 1.
8. A liquid crystal mixture, comprising:
a component A) comprising one or more compounds of formula I according to claim 1, and
a liquid-crystalline component B), comprising one or more mesogenic or liquid-crystalline compounds.
9. The liquid crystal mixture according to claim 8, wherein the total concentration of compounds of formula I in the mixture is in the range of from 0.01 to 10% by weight.
10. The liquid crystal mixture according to claim 8, further comprising a polymerizable component C) comprising one or more polymerizable mesogenic or polymerizable isotropic compounds.
11. The liquid crystal mixture according to claim 10, wherein the concentration of polymerizable mesogenic or polymerizable isotropic compounds is in the range of from 0.01 to 10% by weight.
12. The liquid crystal mixture according to claim 10, wherein said mixture contains one or more polymerizable compounds of formula P
Pa-(Spa)s1-A2-(Za-A1)n2-(Spb)s2—Pb P
wherein
Pa, Pb each, independently of one another, denote a polymerizable group,
Spa, Spb on each occurrence, identically or differently, denote a spacer group,
s1, s2 each, independently of one another, are 0 or 1,
A1, A2 each, independently of one another, denote a radical selected from the following groups:
a) the group consisting of trans-1,4-cyclohexylene, 1,4-cyclohexenylene and 4,4’-bicyclohexylene, wherein, in addition, one or more non-adjacent CH2 groups may each be replaced by —O—or —S— and wherein, in addition, one or more H atoms may each be replaced by F,
b) the group consisting of 1,4-phenylene and 1,3-phenylene, wherein, in addition, one or two CH groups may each be replaced by N and wherein, in addition, one or more H atoms may each be replaced by L,
c) the group consisting of tetrahydropyran-2,5-diyl, 1,3-dioxane-2,5-diyl, tetrahydrofuran-2,5-diyl, cyclobutane-1,3-diyl, piperidine-1,4-diyl, thiophene-2,5-diyl and selenophene-2,5-diyl, each of which may also be mono- or polysubstituted by L,
d) the group consisting of saturated, partially unsaturated or fully unsaturated, and optionally substituted, polycyclic radicals having 5 to 20 cyclic C atoms, one or more of which may, in addition, be replaced by heteroatoms, that are selected from:
where, in addition, one or more H atoms in these radicals may be replaced by L, and/or one or more double bonds may each be replaced by single bonds, and/or one or more CH groups may each be replaced by N,
n2 is 0,1,2 or 3,
Z1 in each case, independently of one another, denotes —CO—O—, —O—CO—, —CH2O—, —OCH2—, —CF2O—, —OCF2—, —(CH2)n— where n is 2, 3 or 4, —O—, —CO—, —C(R0R00)—, —CH2CF2—, —CF2CF2— or a single bond,
L on each occurrence, identically or differently, denotes F, Cl, CN, SCN, SF5 or straight-chain or branched, in each case optionally fluorinated, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having up to 12 C atoms,
R0, R00 each, independently of one another, denote H, F or straight-chain or branched alkyl having 1 to 12 C atoms, wherein, in addition, one or more H atoms may each be replaced by F,
M denotes —O—, —S—, —CH2—, —CHY1— or —CY1Y2—, and
Y1 and Y2 each, independently of one another, have one of the meanings indicated above for R0 or denote Cl or CN.
13. The liquid crystal mixture according to claim 8, wherein component B has negative dielectric anisotropy.
14. The liquid crystal mixture according to claim 13, wherein component B comprises one or more compounds selected from formulae CY and PY:
wherein
a is 1 or 2,
b is 0 or 1,
denotes
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may each be replaced by —O—, —CH═CH—, —CO—, —O—CO— or —CO—O—in such a way that O atoms are not linked directly to one another,
ZX denotes —CH═CH—, —CH2O—, —OCH2—, —CF2O—, —OCF2—, —O—, —CH2—, —CH2CH2— or a single bond, and
L1-4 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
15. The liquid crystal mixture according to claim 8, wherein component B has positive dielectric anisotropy.
16. The liquid crystal mixture according to claim 15, wherein component B comprises one or more compounds selected from compounds of formulae II and III,
wherein
R20 each, identically or differently, denote a halogenated or unsubstituted alkyl or alkoxy radical having 1 to 15 C atoms, where, in addition, one or more CH2 groups in these radicals may each be replaced, independently of one another, by —C≡C—, —CF2O—, —CH═CH—,
—O—, —CO—O— or —O—CO— in such a way that O atoms are not linked directly to one another,
X20 each, identically or differently, denote F, Cl, CN, SF5, SCN, NCS, a halogenated alkyl radical, a halogenated alkenyl radical, a halogenated alkoxy radical or a halogenated alkenyloxy radical, each having up to 6 C atoms, and
Y20-24 each, identically or differently, denote H or F,
W denotes H or methyl, and
each, identically or differently, denote
17. The liquid crystal mixture according to claim 15, wherein said mixture comprises one or more compounds selected from compounds of formulae XI and XII
wherein
R20 denotes a halogenated or unsubstituted alkyl or alkoxy radical having 1 to 15 C atoms, where, in addition, one or more CH2 groups in these radicals may each be replaced, independently of one another, by —C≡C—, —CF2O—, —CH═CH—,
—O—, —CO—O— or —O—CO— in such a way that O atoms are not linked directly to one another,
X20 each, identically or differently, denote F, Cl, CN, SF5, SCN, NCS, a halogenated alkyl radical, a halogenated alkenyl radical, a halogenated alkoxy radical or a halogenated alkenyloxy radical, each having up to 6 C atoms,
Y20-23 each identically or differently, denote H or F,
W denotes H or methyl, and
each, independently of one another, denote
and
denotes
18. The liquid crystal mixture according to claim 8, wherein component B comprises one or more compounds of formula ZK:
in which the individual radicals have the following meanings:
denotes
denotes
R3 and R4 each, independently of one another, denote alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —O—CO— or —CO—O— in such a way that O atoms are not linked directly to one another, and
Zy denotes —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, -C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond.
19. The liquid crystal mixture according to claim 8, wherein component B comprises one or more compounds of the following formula
wherein the propyl, butyl and pentyl groups are straight-chain groups.
20. The liquid crystal mixture according to claim 8, wherein component B comprises one or more compounds selected from the formulae B1 to B3:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-6 C atoms.
21. The liquid crystal mixture according to claim 8, wherein component B comprises one or more compounds selected from the following formulae:
in which alkyl* denotes an alkyl radical having 1-6 C atoms.
22. A method of photoaligning the liquid crystal mixture according to claim 8 comprising irradiating the liquid crystal mixture with linearly polarized light.
23. A process the fabrication of a liquid crystal display, comprising:
providing a first substrate which includes a pixel electrode and a common electrode for generating an electric field substantially parallel to a surface of the first substrate in the pixel region;
providing a second substrate, the second substrate being disposed opposite to the first substrate;
interposing a liquid crystal mixture according to claim 8;
irradiating the liquid crystal mixture with linearly polarized light causing photoalignment of the liquid crystal; and
curing the polymerizable compounds of the liquid crystal mixture by irradiation with ultraviolet light or visible light having a wavelength of 450 nm or below.
24. The process according to claim 23, wherein the linearly polarized light is ultraviolet light or visible light having a wavelength of 450 nm or below.
25. A display obtainable by a process according to claim 23.
26. The display according to claim 25, wherein component B is homogeneously aligned without the application of an electric field.
27. The display according to claim 25, wherein the display is an IPS or FFS display.
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27
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The invention relates to compounds of formula I,
wherein R11, R21, A11, A, Z, X11, X21, Y11, Y12, Sp11, Sp21, o and p have one of the meanings as given in claim 1. The invention further relates to a method of production of said compounds, to the use of said compounds in LC media and to LC media comprising one or more compounds of formula I. Further, the invention relates to a method of production of such LC media, to the use of such media in LC devices, and to a LC device comprising a LC medium according to the present invention. The present invention further relates to a process for the fabrication such liquid crystal display and to the use of the liquid crystal mixtures according to the invention for the fabrication of such liquid crystal display.
BACKGROUND AND PRIOR ART
Liquid-crystalline media have been used for decades in electro-optical displays for information display. The liquid crystal displays used at present are usually those of the TN (“twisted nematic”) type. However, these have the disadvantage of a strong viewing-angle dependence of the contrast.
In addition, so-called VA (“vertically aligned”) displays are known which have a broader viewing angle. The LC cell of a VA display contains a layer of an LC medium between two transparent electrodes, where the LC medium usually has a negative value of the dielectric (DC) anisotropy. In the switched-off state, the molecules of the LC layer are aligned perpendicular to the electrode surfaces (homeotropically) or have a tilted homeotropic alignment. On application of an electrical voltage to the two electrodes, a realignment of the LC molecules parallel to the electrode surfaces takes place. Furthermore, so-called IPS (“in plane switching”) displays and later, FFS (“fringe-field switching”) displays have been reported (see, inter alia, S. H. Jung et al., Jpn. J. Appl. Phys., Volume 43, No. 3, 2004, 1028), which contain two electrodes on the same substrate, one of which is structured in a comb-shaped manner and the other is unstructured. A strong, so-called “fringe field” is thereby generated, i.e. a strong electric field close to the edge of the electrodes, and, throughout the cell, an electric field which has both a strong vertical component and a strong horizontal component. FFS displays have a low viewing-angle dependence of the contrast. FFS displays usually contain an LC medium with positive dielectric anisotropy, and an alignment layer, usually of polyimide, which provides planar alignment to the molecules of the LC medium.
Furthermore, FFS displays have been disclosed (see S. H. Lee et al., Appl. Phys. Lett. 73(20), 1998, 2882-2883 and S. H. Lee et al., Liquid Crystals 39(9), 2012, 1141-1148), which have similar electrode design and layer thickness as FFS displays, but comprise a layer of an LC medium with negative dielectric anisotropy instead of an LC medium with positive dielectric anisotropy. The LC medium with negative dielectric anisotropy shows a more favorable director orientation that has less tilt and more twist orientation compared to the LC medium with positive dielectric anisotropy, as a result of which these displays have a higher transmission.
A further development are the so-called PS (polymer sustained) or PSA (polymer sustained alignment) displays, for which the term “polymer stabilised” is also occasionally used. The PSA displays are distinguished by the shortening of the response times without significant adverse effects on other parameters, such as, in particular, the favourable viewing-angle dependence of the contrast.
In these displays, a small amount (for example 0.3% by weight, typically <1% by weight) of one or more polymerizable compound(s) is added to the LC medium and, after introduction into the LC cell, is polymerised or crosslinked in situ, usually by UV photopolymerization, between the electrodes with or without an applied electrical voltage. The addition of polymerizable mesogenic or liquid-crystalline compounds, also known as reactive mesogens or “RMs”, to the LC mixture has proven particularly suitable. PSA technology has hitherto been employed principally for LC media having negative dielectric anisotropy.
Unless indicated otherwise, the term “PSA” is used below as representative of PS displays and PSA displays.
In the meantime, the PSA principle is being used in diverse classical LC displays. Thus, for example, PSA-VA, PSA-OCB, PSA-IPS, PSA-FFS and PSA-TN displays are known. The polymerisation of the polymerizable compound(s) preferably takes place with an applied electrical voltage in the case of PSA-VA and PSA-OCB displays, and with or without an applied electrical voltage in the case of PSA-IPS displays. As can be demonstrated in test cells, the PS(A) method results in a ‘pretilt’ in the cell. In the case of PSA-OCB displays, for example, it is possible for the bend structure to be stabilised so that an offset voltage is unnecessary or can be reduced. In the case of PSA-VA displays, the pretilt has a positive effect on the response times. A standard MVA or PVA pixel and electrode layout can be used for PSA-VA displays. In addition, however, it is also possible, for example, to manage with only one structured electrode side and no protrusions, which significantly simplifies production and at the same time results in very good contrast at the same time as very good light transmission.
PSA-VA displays are described, for example, in JP 10-036847 A, EP 1 170 626 A2, U.S. Pat. Nos. 6,861,107, 7,169,449, US 2004/0191428 A1, US 2006/0066793 A1 and US 2006/0103804 A1. PSA-OCB displays are described, for example, in T.-J-Chen et al., Jpn. J. Appl. Phys. 45, 2006, 2702-2704 and S. H. Kim, L.-C-Chien, Jpn. J. Appl. Phys. 43, 2004, 7643-7647. PSA-IPS displays are described, for example, in U.S. Pat. No. 6,177,972 and Appl. Phys. Lett. 1999, 75(21), 3264. PSA-TN displays are described, for example, in Optics Express 2004, 12(7), 1221. PSAVA-IPS displays are disclosed, for example, in WO 2010/089092 A1.
Like the conventional LC displays described above, PSA displays can be operated as active-matrix or passive-matrix displays. In the case of active-matrix displays, individual pixels are usually addressed by integrated, non-linear active elements, such as, for example, transistors (for example thin-film transistors or “TFTs”), while in the case of passive-matrix displays, individual pixels are usually addressed by the multiplex method, both methods being known from the prior art.
In the prior art, polymerizable compounds of the following formula, for example, are used for PSA-VA:
in which P denotes a polymerizable group, usually an acrylate or methacrylate group, as described, for example, in U.S. Pat. No. 7,169,449.
Below the polymer layer which induces the above mentioned pretilt, an orientation layer—usually a polyimide—provides the initial alignment of the liquid crystal regardless of the polymer stabilisation step of the production process.
The effort for the production of a polyimide layer, treatment of the layer and improvement with bumps or polymer layers is relatively great. A simplifying technology which on the one hand reduces production costs and on the other hand helps to optimise the image quality (viewing-angle dependence, contrast, response times) would therefore be desirable. Rubbed polyimide has been used for a long time to align liquid crystals. The rubbing process causes a number of problems: mura, contamination, problems with static discharge, debris, etc.
Photoalignment is a technology for achieving liquid crystal (LC) alignment that avoids rubbing by replacing it with a light-induced orientational ordering of the alignment surface. This can be achieved through the mechanisms of photodecomposition, photodimerization, and photoisomerization (N. A. Clark et al. Langmuir 2010, 26(22), 17482-17488, and literature cited therein) by means of polarised light. However, still a suitably derivatised polyimide layer is required that comprises the photoreactive group. A further improvement would be to avoid the use of polyimide at all. For VA displays this was achieved by adding a self-alignment agent to the LC that induces homeotropic alignment in situ by a self-assembling mechanism as disclosed in WO 2012/104008 and WO 2012/038026.
N. A. Clark et al. Langmuir 2010, 26(22), 17482-17488 have shown that it is possible to self-assemble a compound of the following structure
onto a substrate to give a monolayer that is able to be photoaligned to induce homogeneous alignment of a liquid crystal. However, a separate step of self-assembly before manufacture of the LC cell is required and the nature of the azo-group causes reversibility of the alignment when exposed to light.
Another functional group known to enable photoalignment is the phenylethenylcarbonyloxy group (cinnamate). Photocrosslinkable cinnamates are known from the prior art, e.g. of the following structure
as disclosed in EP0763552. From such compounds, polymers can be obtained, for example the following
This material was used in a photoalignment process, as disclosed in WO 99/49360, to give an orientation layer for liquid crystals. A disadvantage of orientation layers obtained by this process is that they give lower voltage holding ratios (VHR) than polyimides.
In WO 00/05189 polymerizable direactive mesogenic cinnamates are disclosed for the use in polymerizable LC mixtures for e.g. optical retarders.
A structurally related compound of the following formula
comprising two cinnamic acid moieties is disclosed in GB 2 306 470 A for the use as component in liquid crystalline polymer films. This type of compound has not been used or proposed for the use as photoalignment agent.
A very similar compound is published in B.M.I. van der Zande et al., Liquid Crystals, Vol. 33, No. 6, June 2006, 723-737, in the field of liquid crystalline polymers for patterned retarders, and has the following structure:
WO 2017/102068 A1 discloses the same structure for the purpose of a polyimide-free homogeneous photoalignment method.
Further, M. H. Lee et al. published in Liquid Crystals (https://doi.org/10.1080/02678292.2018.1441459) a polyimide-free homogeneous photoalignment method induced by polymerizable liquid crystal containing cinnamate moiety of the following formula:
Thus, there is a great demand for new photoreactive mesogens that enable photoalignment of a liquid crystal mixture in situ, i.e. after assembly of the display, by means of linearly polarized light.
In addition to this requirement, the corresponding photoreactive mesogen should provide, preferably at the same time, a liquid crystal display having favourable high dark state and a favourable high voltage holding ratio. Furthermore, the amount of photoreactive mesogens in the nematic LC medium should be a low as possible and the process for the production should be obtainable from a process that is compatible with common mass production processes, e.g. in terms of favourable short processing times.
Other aims of the present invention are immediately evident to the person skilled in the art from the following detailed description.
Surprisingly, the inventors have found out that one or more of the above-mentioned aims can be achieved by providing a compound according to claim 1.
Terms and Definitions
A photoreactive group according to the present invention is a functional group of a molecule that causes a change of the geometry of the molecule either by bond rotation, skeletal rearrangement or atom- or group-transfer, or by dimerization, upon irradiation with light of a suitable wavelength that can be absorbed by the molecule.
The term “mesogenic group” as used herein is known to the person skilled in the art and described in the literature, and means a group which, due to the anisotropy of its attracting and repelling interactions, essentially contributes to causing a liquid-crystal (LC) phase in low-molecular-weight or polymeric substances. Compounds containing mesogenic groups (mesogenic compounds) do not necessarily have to have an LC phase themselves. It is also possible for mesogenic compounds to exhibit LC phase behaviour only after mixing with other compounds and/or after polymerisation. Typical mesogenic groups are, for example, rigid rod- or disc-shaped units. An overview of the terms and definitions used in connection with mesogenic or LC compounds is given in Pure Appl. Chem. 2001, 73(5), 888 and C. Tschierske, G. Pelzl, S. Diele, Angew. Chem. 2004, 116, 6340-6368.
A photoreactive mesogen according to the present invention is a mesogenic compound comprising one or more photoreactive groups.
Examples of photoreactive groups are —C═C— double bonds and azo groups (—N═N—).
Examples of molecular structures and sub-structures comprising such photoreactive groups are stilbene, (1,2-difluoro-2-phenyl-vinyl)-benzene, cinnamate, 4-phenylbut-3-en-2-one, chalcone, coumarin, chromone, pentalenone and azobenzene.
According to the present application, the term “linearly polarised light” means light, which is at least partially linearly polarized. Preferably, the aligning light is linearly polarized with a degree of polarization of more than 5:1. Wavelengths, intensity and energy of the linearly polarised light are chosen depending on the photosensitivity of the photoalignable material. Typically, the wavelengths are in the UV-A, UV-B and/or UV-C range or in the visible range. Preferably, the linearly polarised light comprises light of wavelengths less than 450 nm, more preferably less than 420 nm at the same time the linearly polarised light preferably comprises light of wavelengths longer than 280 nm, preferably more than 320 nm, more preferably over 350 nm.
The term “organic group” denotes a carbon or hydrocarbon group.
The term “carbon group” denotes a mono- or polyvalent organic group containing at least one carbon atom, where this either contains no further atoms (such as, for example, —C≡C—) or optionally contains one or more further atoms, such as, for example, N, O, S, P, Si, Se, As, Te or Ge (for example carbonyl, etc.). The term “hydrocarbon group” denotes a carbon group which additionally contains one or more H atoms and optionally one or more heteroatoms, such as, for example, N, O, S, P, Si, Se, As, Te or Ge.
“Halogen” denotes F, Cl, Br or I.
A carbon or hydrocarbon group can be a saturated or unsaturated group. Unsaturated groups are, for example, aryl, alkenyl or alkynyl groups. A carbon or hydrocarbon radical having 3 or more atoms can be straight-chain, branched and/or cyclic and may also contain spiro links or condensed rings.
The terms “alkyl”, “aryl”, “heteroaryl”, etc., also encompass polyvalent groups, for example alkylene, arylene, heteroarylene, etc.
The term “aryl” denotes an aromatic carbon group or a group derived therefrom. The term “heteroaryl” denotes “aryl” as defined above, containing one or more heteroatoms.
Preferred carbon and hydrocarbon groups are optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy and alkoxycarbonyloxy having 1 to 40, preferably 1 to 25, particularly preferably 1 to 18, C atoms, optionally substituted aryl or aryloxy having 6 to 40, preferably 6 to 25, C atoms, or optionally substituted alkylaryl, arylalkyl, alkylaryloxy, arylalkyloxy, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy and aryloxycarbonyloxy having 6 to 40, preferably 6 to 25, C atoms.
Further preferred carbon and hydrocarbon groups are C1-C40 alkyl, C2-C40 alkenyl, C2-C40 alkynyl, C3-C40 allyl, C4-C40 alkyldienyl, C4-C40 polyenyl, C6-C40 aryl, C6-C40 alkylaryl, C6-C40 arylalkyl, C6-C40 alkylaryloxy, C6-C40 arylalkyloxy, C2-C40 heteroaryl, C4-C40 cycloalkyl, C4-C40 cycloalkenyl, etc. Particular preference is given to C1-C22 alkyl, C2-C22 alkenyl, C2-C22 alkynyl, C3-C22 allyl, C4-C22 alkyldienyl, C6-C12 aryl, C6-C20 arylalkyl and C2-C20 heteroaryl.
Further preferred carbon and hydrocarbon groups are straight-chain, branched or cyclic alkyl radicals having 1 to 40, preferably 1 to 25, C atoms, which are unsubstituted or mono- or polysubstituted by F, Cl, Br, I or CN and in which one more non-adjacent CH2 groups may each be replaced, independently of one another, by —C(Rz)═C(Rz)—, —C≡C—, —N(Rz)—, —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a way that 0 and/or S atoms are not linked directly to one another.
Rz preferably denotes H, halogen, a straight-chain, branched or cyclic alkyl chain having 1 to 25 C atoms, in which, in addition, one or more non-adjacent C atoms may be replaced by —O—, —S—, —CO—, —CO—O—, —O—CO— or —O—CO—O— and in which one or more H atoms may be replaced by fluorine, an optionally substituted aryl or aryloxy group having 6 to 40 C atoms, or an optionally substituted heteroaryl or heteroaryloxy group having 2 to 40 C atoms.
Preferred alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, 2-methylbutyl, n-pentyl, s-pentyl, cyclopentyl, n-hexyl, cyclohexyl, 2-ethylhexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, trifluoromethyl, perfluoro-n-butyl, 2,2,2-trifluoroethyl, perfluorooctyl and perfluorohexyl.
Preferred alkenyl groups are, for example, ethenyl, propenyl, butenyl, pentenyl, cyclopentenyl, hexenyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl and cyclooctenyl.
Preferred alkynyl groups are, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl.
Preferred alkoxy groups are, for example, methoxy, ethoxy, 2-methoxyethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 2-methylbutoxy, n-pentoxy, n-hexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecoxy and n-dodecoxy.
Preferred amino groups are, for example, dimethylamino, methylamino, methylphenylamino and phenylamino.
Aryl and heteroaryl groups can be monocyclic or polycyclic, i.e. they can contain one ring (such as, for example, phenyl) or two or more rings, which may also be fused (such as, for example, naphthyl) or covalently bonded (such as, for example, biphenyl), or contain a combination of fused and linked rings. Heteroaryl groups contain one or more heteroatoms, preferably selected from O, N, S and Se. A ring system of this type may also contain individual non-conjugated units, as is the case, for example, in the fluorene basic structure.
Particular preference is given to mono-, bi- or tricyclic aryl groups having 6 to 25 C atoms and mono-, bi- or tricyclic heteroaryl groups having 2 to 25 C atoms, which optionally contain fused rings and are optionally substituted. Preference is furthermore given to 5-, 6- or 7-membered aryl and heteroaryl groups, in which, in addition, one or more CH groups may be replaced by N, S or O in such a way that O atoms and/or S atoms are not linked directly to one another.
Preferred aryl groups are derived, for example, from the parent structures benzene, biphenyl, terphenyl, [1,1′:3′,1″]terphenyl, naphthalene, anthracene, binaphthyl, phenanthrene, pyrene, dihydropyrene, chrysene, perylene, tetracene, pentacene, benzopyrene, fluorene, indene, indenofluorene, spirobifluorene, etc.
Preferred heteroaryl groups are, for example, 5-membered rings, such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 6-membered rings, such as pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, or condensed groups, such as indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran, dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline, benzo-6,7-quinoline, benzo-7,8-quinoline, benzoisoquinoline, acridine, phenothiazine, phenoxazine, benzopyridazine, benzopyrimidine, quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline, phenanthridine, phenanthroline, thieno[2,3b]thiophene, thieno[3,2b]thiophene, dithienothiophene, dihydrothieno [3,4-b]-1,4-dioxin, isobenzothiophene, dibenzothiophene, benzothiadiazothiophene, or combinations of these groups. The heteroaryl groups may also be substituted by alkyl, alkoxy, thioalkyl, fluorine, fluoroalkyl or further aryl or heteroaryl groups.
The (non-aromatic) alicyclic and heterocyclic groups encompass both saturated rings, i.e. those containing exclusively single bonds, and also partially unsaturated rings, i.e. those which may also contain multiple bonds. Heterocyclic rings contain one or more heteroatoms, preferably selected from Si, O, N, S and Se.
The (non-aromatic) alicyclic and heterocyclic groups can be monocyclic, i.e. contain only one ring (such as, for example, cyclohexane), or polycyclic, i.e. contain a plurality of rings (such as, for example, decahydronaphthalene or bicyclooctane). Particular preference is given to saturated groups. Preference is furthermore given to mono-, bi- or tricyclic groups having 3 to 25 C atoms, which optionally contain fused rings and are optionally substituted. Preference is furthermore given to 5-, 6-, 7- or 8-membered carbocyclic groups, in which, in addition, one or more C atoms may be replaced by Si and/or one or more CH groups may be replaced by N and/or one or more non-adjacent CH2 groups may be replaced by —O— and/or —S—.
Preferred alicyclic and heterocyclic groups are, for example, 5-membered groups, such as cyclopentane, tetrahydrofuran, tetrahydrothiofuran, pyrrolidine, 6-membered groups, such as cyclohexane, silinane, cyclohexene, tetrahydropyran, tetrahydrothiopyran, 1,3-dioxane, 1,3-dithiane, piperidine, 7-membered groups, such as cycloheptane, and fused groups, such as tetrahydronaphthalene, decahydronaphthalene, indane, bicyclo[1.1.1]pentane-1,3-diyl, bicyclo[2.2.2]octane-1,4-diyl, spiro[3.3]heptane-2,6-diyl, octahydro-4,7-methanoindane-2,5-diyl.
The aryl, heteroaryl, carbon and hydrocarbon radicals optionally have one or more substituents, which are preferably selected from the group comprising silyl, sulfo, sulfonyl, formyl, amine, imine, nitrile, mercapto, nitro, halogen, C1-12 alkyl, C6-12 aryl, C1-12 alkoxy, hydroxyl, or combinations of these groups.
Preferred substituents are, for example, solubility-promoting groups, such as alkyl or alkoxy, and electron-withdrawing groups, such as fluorine, nitro or nitrile.
Preferred substituents, unless stated otherwise, also referred to as “L” above and below, are F, Cl, Br, I, —CN, —NO2, —NCO, —NCS, —OCN, —SCN, —C(═O)N(Rz)2, —C(═O)Y1, —C(═O)Rz, —N(Rz)2, in which Rz has the meaning indicated above, and Y1 denotes halogen, optionally substituted silyl or aryl having 6 to 40, preferably 6 to 20, C atoms, and straight-chain or branched alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having 1 to 25 C atoms, preferably 2 to 12, in which one or more H atoms may optionally be replaced by F or Cl.
“Substituted silyl or aryl” preferably means substituted by halogen, —CN, Ry1, —ORy1, —CO—Ry1, —CO—O—Ry1, —O—CO—Ry1 or —O—CO—O—Ry1, in which Ry1 has the meaning indicated above.
Particularly preferred substituents L are, for example, F, Cl, CN, CH3, C2H5, —CH(CH3)2, OCH3, OC2H5, CF3, OCF3, OCHF2, OC2F5, furthermore phenyl.
Above and below “halogen” denotes F, Cl, Br or I.
Above and below, the terms “alkyl”, “aryl”, “heteroaryl”, etc., also encompass polyvalent groups, for example alkylene, arylene, heteroarylene, etc.
The term “director” is known in prior art and means the preferred orientation direction of the long molecular axes (in case of calamitic compounds) or short molecular axes (in case of discotic compounds) of the liquid-crystalline molecules. In case of uniaxial ordering of such anisotropic molecules, the director is the axis of anisotropy.
The term “alignment” or “orientation” relates to alignment (orientation ordering) of anisotropic units of material such as small molecules or fragments of big molecules in a common direction named “alignment direction”. In an aligned layer of liquid-crystalline material, the liquid-crystalline director coincides with the alignment direction so that the alignment direction corresponds to the direction of the anisotropy axis of the material.
The term “planar orientation/alignment”, for example in a layer of an liquid-crystalline material, means that the long molecular axes (in case of calamitic compounds) or the short molecular axes (in case of discotic compounds) of a proportion of the liquid-crystalline molecules are oriented substantially parallel (about 180°) to the plane of the layer.
The term “homeotropic orientation/alignment”, for example in a layer of a liquid-crystalline material, means that the long molecular axes (in case of calamitic compounds) or the short molecular axes (in case of discotic compounds) of a proportion of the liquid-crystalline molecules are oriented at an angle θ (“tilt angle”) between about 80° to 90° relative to the plane of the layer.
The terms “uniform orientation” or “uniform alignment” of an liquid-crystalline material, for example in a layer of the material, mean that the long molecular axes (in case of calamitic compounds) or the short molecular axes (in case of discotic compounds) of the liquid-crystalline molecules are oriented substantially in the same direction. In other words, the lines of liquid-crystalline director are parallel.
The wavelength of light generally referred to in this application is 550 nm, unless explicitly specified otherwise.
The birefringence Δn herein is defined by the following equation
Δn=ne−no
wherein ne is the extraordinary refractive index and no is the ordinary refractive index and the effective average refractive index nay is given by the following equation
nav.=[(2no2+ne2)/3]1/2
The extraordinary refractive index ne and the ordinary refractive index no can be measured using an Abbe refractometer.
In the present application the term “dielectrically positive” is used for compounds or components with Δε>3.0, “dielectrically neutral” with −1.5≤Δε≤3.0 and “dielectrically negative” with Δε<−1.5. Δε is determined at a frequency of 1 kHz and at 20° C. The dielectric anisotropy of the respective compound is determined from the results of a solution of 10% of the respective individual compound in a nematic host mixture. In case the solubility of the respective compound in the host medium is less than 10% its concentration is reduced by a factor of 2 until the resultant medium is stable enough at least to allow the determination of its properties. Preferably, the concentration is kept at least at 5%, however, to keep the significance of the results as high as possible. The capacitance of the test mixtures are determined both in a cell with homeotropic and with homogeneous alignment. The cell gap of both types of cells is approximately 20 μm. The voltage applied is a rectangular wave with a frequency of 1 kHz and a root mean square value typically of 0.5 V to 1.0 V; however, it is always selected to be below the capacitive threshold of the respective test mixture.
Δε is defined as (ε∥−ε⊥), whereas εav. is (ε∥+2ε⊥)/3. The dielectric permittivity of the compounds is determined from the change of the respective values of a host medium upon addition of the compounds of interest. The values are extrapolated to a concentration of the compounds of interest of 100%. A typical host medium is ZLI-4792 or ZLI-2857 both commercially available from Merck, Darmstadt.
For the present invention,
denote trans-1,4-cyclohexylene,
denote 1,4-phenylene.
For the present invention the groups —CO—O—, —COO— —C(═O)O— or —CO2— denote an ester group of formula
and the groups —O—CO— —OCO—, —OC(═O)—, —O2C— or —OOC— denote an ester group of formula
Furthermore, the definitions as given in C. Tschierske, G. Pelzl and S. Diele, Angew. Chem. 2004, 116, 6340-6368 shall apply to non-defined terms related to liquid crystal materials in the instant application.
DETAILED DESCRIPTION
In detail, the present invention relates to photoreactive mesogens of formula I
wherein
A11 denotes a radical
where, in addition, one or more H atoms in these radical may be replaced by L, and/or one or more and/or one or more CH groups may be replaced by N,
A denotes, independently of one another, in each occurrence
a) the group consisting of 1,4-phenylene and 1,3-phenylene, wherein, in addition, one or two CH groups may be replaced by N and wherein, in addition, one or more H atoms may be replaced by L,
b) the group consisting of saturated, partially unsaturated or fully unsaturated, and optionally substituted, polycyclic radicals having 5 to 20 cyclic C atoms, one or more of which may, in addition, be replaced by heteroatoms, preferably selected from the group consisting of
where, in addition, one or more H atoms in these radicals may be replaced by L, and/or one or more double bonds may be replaced by single bonds, and/or one or more CH groups may be replaced by N,
c) group consisting of trans-1,4-cyclohexylene, 1,4-cyclohexenylene, wherein, in addition, one or more non-adjacent CH2 groups may be replaced by —O— and/or —S— and wherein, in addition, one or more H atoms may be replaced by F, or
d) a group consisting of tetrahydropyran-2,5-diyl, 1,3-dioxane-2,5-diyl, tetrahydrofuran-2,5-diyl, cyclobutane-1,3-diyl, piperidine-1,4-diyl, thiophene-2,5-diyl and selenophene-2,5-diyl,
each of which may also be mono- or polysubstituted by L,
L on each occurrence, identically or differently, denotes —OH, —F, —Cl, —Br, —I, —CN, —NO2, SF5, —NCO, —NCS, —OCN, —SCN, —C(═O)N(Rz)2, —C(═O)Rz, —N(Rz)2, optionally substituted silyl, optionally substituted aryl having 6 to 20 C atoms, or straight-chain or branched or cyclic alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having 1 to 25 C atoms, preferably 1 to 12 C atoms, more preferably 1 to 6 C atoms, in which, in addition, one or more H atoms may be replaced by F or Cl, or X21-Sp21-R21,
M denotes —O—, —S—, —CH2—, —CHRz— or —CRyRz—, and
Ry and Rz each, independently of one another, denote H, CN, F or alkyl having 1-12 C atoms, wherein, in addition, one
or more H atoms may be replaced by F,
preferably H, methyl, ethyl, propyl, butyl,
more preferably H or methyl,
in particular H,
Y11 and Y12 each, independently of one another, denote H, F, phenyl or optionally fluorinated alkyl having 1-12 C atoms, preferably H, methyl, ethyl, propyl, butyl, more preferably H or methyl,
in particular H,
Z denotes, independently of each other, in each occurrence, a single bond, —OOC—, —OCO—, —O—CO—O—, —OCH2—, —CH2O—, —OCF2—, —CF2O—, —(CH2)n—, —CF2CF2—, —CH═CH—, —CF═CF—, —CH═CH—OOC—, —OCO—CH═CH—, —CO—S—, —S—CO—, —CS—S—, —S—CS—, —S—CSS— or —C≡C—,
preferably a single bond, —OOC—, —OOC—, —OCF2—, —CF2O—, or —(CH2)n—,
more preferably a single bond, —OOC—, or —OOC—,
n denotes an integer between 2 and 8, preferably 2,
o and p denotes each and independently 0, 1 or 2, preferably 1,
X11 and X21 denote independently from one another, in each occurrence a single bond, —CO—O—, —O—CO—, —O—COO—, —O—, —CH═CH—, —C≡C—, —CF2—O—, —O—CF2—, —CF2—CF2—, —CH2—O—, —O—CH2—, —CO—S—, —S—CO—, —CS—S—, —S—CS—, —S—CSS— or —S—,
preferably, a single bond, —CO—O—, —O—CO—, —O—OOC—, or —O—,
more preferably a single bond or —O—,
Sp11 and Sp21 denote each and independently, in each occurrence a single bond or a spacer group comprising 1 to 20 C atoms, wherein one or more non-adjacent and non-terminal CH2 groups may also be replaced by —O—, —S—, —NH—, —N(CH3)—, —CO—, —O—CO—, —S—CO—, —O—COO—, —CO—S—, —CO—O—, —CF2—, —CF2O—, —OCF2— —C(OH)—, —CH(alkyl)-, —CH(alkenyl)-, —CH(alkoxyl)-, —CH(oxaalkyl)-, —CH═CH— or —C≡C—, however in such a way that no two O-atoms are adjacent to one another and no two groups selected from —O—CO—, —S—CO—, —O—OOC—, —CO—S—, —CO—O— and —CH═CH— are adjacent to each other,
preferably alkylene having 1 to 20, preferably 1 to 12, C atoms, which is optionally mono- or polysubstituted by F, Cl, Br, I or CN,
more preferably straight-chain ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene,
R11 denotes P,
R21 denotes P, or halogen, CN, optionally fluorinated alkyl or alkenyl with up to 15 C atoms in which one or more non-adjacent CH2-groups may be replaced by —O—, —S—, —CO—, —C(O)O—, —O—C(O)—, O—C(O)—O—, preferably P,
P each and independently from another in each occurrence a polymerizable group.
The polymerizable groups P are groups that are suitable for a polymerisation reaction, such as, for example, free-radical or ionic chain polymerisation, polyaddition or polycondensation, or for a polymer-analogous reaction, for example addition or condensation onto a main polymer chain. Particular preference is given to groups for chain polymerisation, in particular those containing a C═C double bond or —C≡C— triple bond, and groups which are suitable for polymerisation with ring opening, such as, for example, oxetane or epoxide groups.
Preferred groups P are selected from the group consisting of
CH2═CW2—(O)k3—, CW1═CH—CO—(O)k3—, CW1═CH—CO—NH—, CH2═CW1—CO—NH—, CH3—CH═CH—O—, (CH2═CH)2CH—OCO—, (CH2═CH—CH2)2CH—OCO—, (CH2═CH)2CH—O—, (CH2═CH—CH2)2N—, (CH2═CH—CH2)2N—CO—, HO—CW2W3—, HS—CW2W3—, HW2N—, HO—CW2W3—NH—, CH2═CW1—CO—NH—, CH2═CH—(COO)k1-Phe-(O)k2—, CH2═CH—(CO)k1-Phe-(O)k2—, Phe-CH═CH—, HOOC—, OCN— and W4W5W6Si—, wherein W1 denotes H, F, Cl, CN, CF3, phenyl or alkyl having 1 to 5 C atoms, in particular H, F, Cl or CH3, W2 and W3 each, independently of one another, denote H or alkyl having 1 to 5 C atoms, in particular H, methyl, ethyl or n-propyl, W4, W5 and W6 each, independently of one another, denote Cl, oxaalkyl or oxacarbonylalkyl having 1 to 5 C atoms, W7 and W8 each, independently of one another, denote H, Cl or alkyl having 1 to 5 C atoms, Phe denotes 1,4-phenylene, which is optionally substituted by one or more radicals L as defined above which are other than P-Sp-, k1, k2 and k3 each, independently of one another, denote 0 or 1, k3 preferably denotes 1, and k4 denotes an integer from 1 to 10.
Particularly preferred groups P and Pa,b are selected from the group consisting of CH2═CW1—CO—O—, in particular CH2═CH—CO—O—, CH2═C(CH3)—CO—O— and CH2═CF—CO—O—, furthermore CH2═CH—O—, (CH2═CH)2CH—O—CO—, (CH2═CH)2CH—O—,
Very particularly preferred groups P and Pa,b are selected from the group consisting of acrylate, methacrylate, fluoroacrylate, furthermore vinyloxy, chloroacrylate, oxetane and epoxide groups, and of these preferably an acrylate or methacrylate group.
In another preferred embodiment, the polymerizable group P denotes the radical
wherein
Y denotes H, F, phenyl or optionally fluorinated alkyl having 1-12 C atoms, preferably H, methyl, ethyl, propyl, butyl,
more preferably H or methyl,
in particular H,
q and r denotes each and independently an integer from 0 to 8, preferably q+r≥1 and ≤16, more preferably q and r each and independently denotes an integer from 1 to 8, and
P denotes acrylate or methacrylate,
The compounds of formula I are preferably selected from compounds of the sub-formulae I-1 to I-9.
wherein R11, R21, A11, X11, X12, Y11, Y12, Sp11, and Sp12 have one of the meanings as given above in formula I, A12 to A23 have one of the meanings for A, and Z11 to Z22 have one of the meanings for Z as given above under formula I.
Further preferred compounds of formula I are selected from the compounds of formulae I-1 to I-3.
Preferred compounds of formula I-1 to I-3 are selected from compounds of formulae I-1a to I-3a:
wherein R11, R21, X11, X21, Sp11 and Sp21 have one of the meanings as given above in formula I, Z11 and Z21 have one of the meanings for Z as given above under formula I, and A12, A21 and A22 have one of the meanings for A, preferably A12, A21 and A22 denote each and independently a group consisting of 1,4-phenylene wherein one or two CH groups may be replaced by N and wherein, in addition, one or more H atoms may be replaced by L as given above under formula I, or a group consisting of trans-1,4-cyclohexylene, 1,4-cyclohexenylene, wherein, in addition, one or more non-adjacent CH2 groups may be replaced by —O— and/or —S— and wherein, in addition, one or more H atoms may be replaced by F.
Further preferred compounds of formula I are compounds of the following sub-formula:
R11, R21, X21, Sp11 and Sp21 have one of the meanings as given above in formula I, Z11 and Z21 have one of the meanings for Z as given above under formula I. In the above given preferred subformulae, the group
is each and independently
or denotes
furthermore
wherein L is preferably F, Cl, CH3, OCH3 and COCH3 or alkylene having 1 to 6 C Atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cylobutyl, cyclopentyl, cyclohexyl, or X21-Sp21-R21.
Further preferred compounds of formulae I-2a-1 are those wherein Z11 denotes a single bond.
Further preferred compounds of formulae I-1a-1 to I-3a-1 are those wherein X11 and X21 denote each and independently a single bond, —O—, —CO—O— or —O—CO—, more preferably —O— or a single bond.
Further preferred compounds of formula I-1a-1 to I-3a-1 are those wherein Sp11 and Sp21 denote each and independently a single bond or —(CH2)n— wherein n is an integer between 1 and 8, more preferably 2 and 6.
Further preferred compounds of formulae I-1a-1 to I-3a-1 are those wherein R11 and R21 denote each and independently acrylate, methacrylate or a group
wherein
Y denotes H, F, phenyl or optionally fluorinated alkyl having 1-12 C atoms, preferably H, methyl, ethyl, propyl, butyl,
more preferably H or methyl,
in particular H,
q and r denotes each and independently an integer from 0 to 8, preferably q+r≥1 and ≤16, more preferably q and r each and independently denotes an integer from 1 to 8.
Further preferred compounds of formulae I-1a-1 to I-3a-1 are those wherein R11 denotes a group
wherein
Y denotes H or methyl,
in particular H,
q and r denotes each and independently an integer from 1 to 8, preferably 1 or 2, and
wherein R11 denotes acrylate or methacrylate.
Further preferred compounds of formulae I-1-1a-1 to I-3a-1 are those wherein both groups R11 and R21 denote acrylate or methacrylate. Preferred compounds of formulae I-3a-1 are compounds of the following sub-formulae:
R11, R21, X21, and Sp21 have one of the meanings as given above in formula I, Z21 has one of the meanings for Z as given above under formula I, r, s, t and q denote each and independently from another an integer from 1 to 8, Y denotes each and independently from each other methyl or H, and
the group
is each and independently
or denotes
furthermore
wherein L is preferably F, Cl, CH3, OCH3 and COCH3 or alkylene having 1 to 6 C Atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cylobutyl, cyclopentyl, cyclohexyl, or X21-Sp21-R21.
Further preferred compounds of formulae I-3a-1a are compounds of the following sub-formulae:
wherein Sp21 has one of the meanings as given above in formula I and L denotes F, Cl, OCH3 and COCH3 or alkylene having 1 to 6 C Atoms, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cylobutyl, cyclopentyl, or cyclohexyl.
Further preferred compounds of formulae I-3a-1b are compounds of the following sub-formulae:
wherein Sp21 has one of the meanings as given above in formula I and L denotes F, Cl, OCH3 and COCH3 or alkylene having 1 to 6 C Atoms, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cylobutyl, cyclopentyl, or cyclohexyl and s denotes an integer from 1 to 8.
Further preferred compounds of formulae I-3a-1c are compounds of the following sub-formulae:
wherein L denotes F, Cl, OCH3 and COCH3 or alkylene having 1 to 6 C Atoms, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cylobutyl, cyclopentyl, or cyclohexyl, and
s and t denotes each and independently an integer from 1 to 8, preferably s and t are identical.
The compounds of formula I and subformulae thereof are preferably synthesised according to or in analogy to the procedures described in WO 2017/102068 and JP 2006-6232809.
Preferred intermediate compounds (5) from which the compounds of formula I are preferably synthesised, are obtainable or obtained according to or in analogy to the procedure described in the following scheme:
The compounds of formula I and subformulae thereof can be preferably utilized in a mixture comprising one or more mesogenic or liquid-crystalline compounds.
Therefore, the present invention relates to the use compounds of formula I and subformulae thereof in a liquid crystal mixture.
Further the present invention relates to liquid crystal mixtures comprising a photoalignment component A) comprising one or more photoreactive mesogens of formula I, and a liquid-crystalline component B), hereinafter also referred to as “LC host mixture”, comprising one or more mesogenic or liquid-crystalline compounds.
The media according to the invention preferably comprise from 0.01 to 10%, particularly preferably from 0.05 to 5% and most preferably from 0.1 to 3% of component A) comprising compounds of formula I according to the invention.
The media preferably comprise one, two or three, more preferably one or two and most preferably one compound of the formula I according to the invention.
In a preferred embodiment component A) consists of compounds of formula I.
In a preferred embodiment, the LC-host mixture (component B) according to the present invention comprises one or more, preferably two or more, low-molecular-weight (i.e. monomeric or unpolymerized) compounds. The latter are stable or unreactive with respect to a polymerisation reaction or photoalignment under the conditions used for the polymerisation of the polymerizable compounds or photoalignment of the photoreactive mesogen of formula I.
In principle, a suitable host mixture is any dielectrically negative or positive LC mixture which is suitable for use in conventional VA, IPS or FFS displays.
Suitable LC mixtures are known to the person skilled in the art and are described in the literature. LC media for VA displays having negative dielectric anisotropy are described in for example EP 1 378 557 A1.
Suitable LC mixtures having positive dielectric anisotropy which are suitable for LCDs and especially for IPS displays are known, for example, from JP 07-181 439 (A), EP 0 667 555, EP 0 673 986, DE 195 09 410, DE 195 28 106, DE 195 28 107, WO 96/23 851, WO 96/28 521 and WO2012/079676.
Preferred embodiments of the liquid-crystalline medium having negative or positive dielectric anisotropy according to the invention are indicated below and explained in more detail by means of the working examples.
The LC host mixture is preferably a nematic LC mixture, and preferably does not have a chiral LC phase.
In a preferred embodiment of the present invention the LC medium contains an LC host mixture with negative dielectric anisotropy. Preferred embodiments of such an LC medium, and the corresponding LC host mixture, are those of sections a)-z) below:
a) LC medium which comprises one or more compounds of the formulae CY and/or PY:
wherein
a denotes 1 or 2,
b denotes 0 or 1,
denotes
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced
by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
Zx and Zy each, independently of one another, denote —CH2CH2—, —CH═CH—, —CF2O—, —OCF2O—, —CH2O—, —O CH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond, preferably a single bond,
L1-4 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
Preferably, both L1 and L2 denote F or one of L1 and L2 denotes F and the other denotes Cl, or both L3 and L4 denote F or one of L3 and L4 denotes F and the other denotes Cl.
The compounds of the formula CY are preferably selected from the group consisting of the following sub-formulae:
wherein a denotes 1 or 2, alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms, and (O) denotes an oxygen atom or a single bond. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
The compounds of the formula PY are preferably selected from the group consisting of the following sub-formulae:
wherein alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms, and (O) denotes an oxygen atom or a single bond. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
b) LC medium which additionally comprises one or more compounds of the following formula:
in which the individual radicals have the following meanings:
denotes
denotes
R3 and R4 each, independently of one another, denote alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced
by —O—, —CH═CH—, —CO—, —O—CO— or —CO—O— in such a way that O atoms are not linked directly to one another,
Zy
denotes —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond, preferably a single bond.
The compounds of the formula ZK are preferably selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Especially preferred are compounds of formula ZK1 and ZK3.
Particularly preferred compounds of formula ZK are selected from the following sub-formulae:
wherein the propyl, butyl and pentyl groups are straight-chain groups.
Most preferred are compounds of formula ZK1a and ZK3a.
c) LC medium which additionally comprises one or more compounds of the following formula:
in which the individual radicals on each occurrence, identically or differently, have the following meanings:
R5 and R6 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
denotes
denotes
and
e denotes 1 or 2.
The compounds of the formula DK are preferably selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
d) LC medium which additionally comprises one or more compounds of the following formula:
in which the individual radicals have the following meanings:
denotes
with at least one ring F being different from cyclohexylene,
f denotes 1 or 2,
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced
by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another,
Zx
denotes —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —O CH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond, preferably a single bond,
L1 and L2 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
Preferably, both radicals L1 and L2 denote F or one of the radicals L1 and L2 denotes F and the other denotes Cl.
The compounds of the formula LY are preferably selected from the group consisting of the following sub-formulae:
in which R1 has the meaning indicated above, alkyl denotes a straight-chain alkyl radical having 1-6 C atoms, (0) denotes an oxygen atom or a single bond, and v denotes an integer from 1 to 6. R1 preferably denotes straight-chain alkyl having 1 to 6 C atoms or straight-chain alkenyl having 2 to 6 C atoms, in particular CH3, C2H5, n-C3H7, n-C4H9, n-C5H11, CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
e) LC medium which additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which alkyl denotes C1-6-alkyl, Lx denotes H or F, and X denotes F, Cl, OCF3, OCHF2 or OCH═CF2. Particular preference is given to compounds of the formula G1 in which X denotes F.
f) LC medium which additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which R5 has one of the meanings indicated above for R1, alkyl denotes C1-6-alkyl, d denotes 0 or 1, and z and m each, independently of one another, denote an integer from 1 to 6. R5 in these compounds is particularly preferably C1-6-alkyl or -alkoxy or C2-6-alkenyl, d is preferably 1. The LC medium according to the invention preferably comprises one or more compounds of the above-mentioned formulae in amounts of 5% by weight.
g) LC medium which additionally comprises one or more biphenyl compounds selected from the group consisting of the following formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
The proportion of the biphenyls of the formulae B1 to B3 in the LC mixture is preferably at least 3% by weight, in particular ≥5% by weight.
The compounds of the formula B2 are particularly preferred.
The compounds of the formulae B1 to B3 are preferably selected from the group consisting of the following sub-formulae:
in which alkyl* denotes an alkyl radical having 1-6 C atoms. The medium according to the invention particularly preferably comprises one or more compounds of the formulae B1a and/or B2e.
h) LC medium which additionally comprises one or more terphenyl compounds of the following formula:
in which R5 and R6 each, independently of one another, have one of the meanings indicated above, and
each, independently of one another, denote
in which L5 denotes F or Cl, preferably F, and L6 denotes F, Cl, OCF3, CF3, CH3, CH2F or CHF2, preferably F.
The compounds of the formula T are preferably selected from the group consisting of the following sub-formulae:
in which R denotes a straight-chain alkyl or alkoxy radical having 1-7 C atoms, R* denotes a straight-chain alkenyl radical having 2-7 C atoms, (O) denotes an oxygen atom or a single bond, and m denotes an integer from 1 to 6. R* preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
R preferably denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy or pentoxy.
The LC medium according to the invention preferably comprises the terphenyls of the formula T and the preferred sub-formulae thereof in an amount of 0.5-30% by weight, in particular 1-20% by weight.
Particular preference is given to compounds of the formulae T1, T2, T3 and T21. In these compounds, R preferably denotes alkyl, furthermore alkoxy, each having 1-5 C atoms.
The terphenyls are preferably employed in mixtures according to the invention if the Δn value of the mixture is to be ≥0.1. Preferred mixtures comprise 2-20% by weight of one or more terphenyl compounds of the formula T, preferably selected from the group of compounds T1 to T22.
i) LC medium which additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which R1 and R2 have the meanings indicated above and preferably each, independently of one another, denote straight-chain alkyl having 1 to 6 C atoms or straight-chain alkenyl having 2 to 6 C atoms.
Preferred media comprise one or more compounds selected from the formulae O1, O3 and O4.
k) LC medium which additionally comprises one or more compounds of the following formula:
in which
denotes
R9 denotes H, CH3, C2H5 or n-C3H7, (F) denotes an optional fluorine substituent, and q denotes 1, 2 or 3, and R7 has one of the meanings indicated for R1, preferably in amounts of >3% by weight, in particular ≥5% by weight and very particularly preferably 5-30% by weight.
Particularly preferred compounds of the formula FI are selected from the group consisting of the following sub-formulae:
in which R7 preferably denotes straight-chain alkyl, and R9 denotes CH3, C2H5 or n-C3H7. Particular preference is given to the compounds of the formulae FI1, FI2 and FI3.
l) LC medium which additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which R8 has the meaning indicated for R1, and alkyl denotes a straight-chain alkyl radical having 1-6 C atoms.
m) LC medium which additionally comprises one or more compounds which contain a tetrahydronaphthyl or naphthyl unit, such as, for example, the compounds selected from the group consisting of the following formulae:
in which
R10 and R11 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced
by —O—, —CH═CH—, —CO—, —OCO— or —OOC— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
and R10 and R11 preferably denote straight-chain alkyl or alkoxy having 1 to 6 C atoms or straight-chain alkenyl having 2 to 6 C atoms, and
Z1 and Z2 each, independently of one another,
denote —C2H4—, —CH═CH—, —(CH2)4—, —(CH2)3O—, —O(CH2)3—, —CH═CH—
CH2CH2—, —CH2CH2CH═CH—, —CH2O—, —OCH2—, —CO O—, —O—
CO—, —C2F4—, —CF═CF—, —CF═CH—, —CH═CF—, —CH2— or a single bond.
n) LC medium which additionally comprises one or more difluoro-dibenzochromans and/or chromans of the following formulae:
in which
R11 and R12 each, independently of one another, have one of the meanings indicated above for R11 under formula N1
ring M is trans-1,4-cyclohexylene or 1,4-phenylene,
Zm —C2H4—, —CH2O—, —OCH2—, —CO—O— or —O—CO—,
c is 0, 1 or 2,
preferably in amounts of 3 to 20% by weight, in particular in amounts of 3 to 15% by weight.
Particularly preferred compounds of the formulae BC, CR and RC are selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, (O) denotes an oxygen atom or a single bond, c is 1 or 2, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Very particular preference is given to mixtures comprising one, two or three compounds of the formula BC-2.
o) LC medium which additionally comprises one or more fluorinated phenanthrenes and/or dibenzofurans of the following formulae:
in which R11 and R12 each, independently of one another, have one of the meanings indicated above for R11 under formula N1, b denotes 0 or 1, L denotes F, and r denotes 1, 2 or 3.
Particularly preferred compounds of the formulae PH and BF are selected from the group consisting of the following sub-formulae:
in which R and R′ each, independently of one another, denote a straight-chain alkyl or alkoxy radical having 1-7 C atoms.
p) LC medium which additionally comprises one or more monocyclic compounds of the following formula
wherein
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced
by —O—, —CH═CH—, —CO—, —OCO— or —OOC— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
L1 and L2 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
Preferably, both L1 and L2 denote F or one of L1 and L2 denotes F and the other denotes Cl,
The compounds of the formula Y are preferably selected from the group consisting of the following sub-formulae:
in which, Alkyl and Alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, Alkoxy denotes a straight-chain alkoxy radical having 1-6 C atoms, Alkenyl and Alkenyl* each, independently of one another, denote a straight chain alkenyl radical having 2-6 C atoms, and O denotes an oxygen atom or a single bond. Alkenyl and Alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Particularly preferred compounds of the formula Y are selected from the group consisting of the following sub-formulae:
wherein Alkoxy preferably denotes straight-chain alkoxy with 3, 4, or 5 C atoms.
q) LC medium which, apart from the stabilisers according to the invention, in particular of the formula I or sub-formulae thereof and the comonomers, comprises no compounds which contain a terminal vinyloxy group (—O—CH═CH2).
r) LC medium which comprises 1 to 5, preferably 1, 2 or 3, stabilisers, preferably selected from stabilisers according to the invention, in particular of the formula I or sub-formulae thereof.
s) LC medium in which the proportion of stabilisers, in particular of the formula I or sub-formulae thereof, in the mixture as a whole is 1 to 1500 ppm, preferably 100 to 1000 ppm.
t) LC medium which comprises 1 to 8, preferably 1 to 5, compounds of the formulae CY1, CY2, PY1 and/or PY2. The proportion of these compounds in the mixture as a whole is preferably 5 to 60%, particularly preferably 10 to 35%. The content of these individual compounds is preferably in each case 2 to 20%.
u) LC medium which comprises 1 to 8, preferably 1 to 5, compounds of the formulae CY9, CY10, PY9 and/or PY10. The proportion of these compounds in the mixture as a whole is preferably 5 to 60%, particularly preferably 10 to 35%. The content of these individual compounds is preferably in each case 2 to 20%.
v) LC medium which comprises 1 to 10, preferably 1 to 8, compounds of the formula ZK, in particular compounds of the formulae ZK1, ZK2 and/or ZK6. The proportion of these compounds in the mixture as a whole is preferably 3 to 25%, particularly preferably 5 to 45%. The content of these individual compounds is preferably in each case 2 to 20%.
w) LC medium in which the proportion of compounds of the formulae CY, PY and ZK in the mixture as a whole is greater than 70%, preferably greater than 80%.
x) LC medium in which the LC host mixture contains one or more compounds containing an alkenyl group, preferably selected from the group consisting of formula CY, PY and LY, wherein one or both of R1 and R2 denote straight-chain alkenyl having 2-6 C atoms, formula ZK and DK, wherein one or both of R3 and R4 or one or both of R5 and R6 denote straight-chain alkenyl having 2-6 C atoms, and formula B2 and B3, very preferably selected from formulae CY15, CY16, CY24, CY32, PY15, PY16, ZK3, ZK4, DK3, DK6, B2 and B3, most preferably selected from formulae ZK3, ZK4, B2 and B3. The concentration of these compounds in the LC host mixture is preferably from 2 to 70%, very preferably from 3 to 55%.
y) LC medium which contains one or more, preferably 1 to 5, compounds selected of formula PY1-PY8, very preferably of formula PY2. The proportion of these compounds in the mixture as a whole is preferably 1 to 30%, particularly preferably 2 to 20%. The content of these individual compounds is preferably in each case 1 to 20%.
z) LC medium which contains one or more, preferably 1, 2 or 3, compounds of formula T2. The content of these compounds in the mixture as a whole is preferably 1 to 20%.
In another preferred embodiment of the present invention the LC medium contains an LC host mixture with positive dielectric anisotropy. Preferred embodiments of such an LC medium, and the corresponding LC host mixture, are those of sections aa)-mmm) below:
aa) LC-medium, characterised in that it comprises one or more compounds selected from the group of compounds of the formulae II and III
wherein
R20 each, identically or differently, denote a halogenated or unsubstituted alkyl or alkoxy radical having 1 to 15 C atoms, where, in addition, one or more CH2 groups in these radicals may each be replaced, independently of one another, by —C≡C—, —CF2O—, —CH═CH—, —⋄—, —⋄⋄—, —O—, —CO—O— or —O—CO— in such a way that O atoms are not linked directly to one another,
X20 each, identically or differently, denote F, Cl, CN, SF5, SCN, NCS, a halogenated alkyl radical, a halogenated alkenyl radical, a halogenated alkoxy radical or a halogenated alkenyloxy radical, each having up to 6 C atoms, and
Y20-24 each, identically or differently, denote H or F;
W denotes H or methyl,
each, independently of one another, denote
The compounds of the formula II are preferably selected from the following formulae:
wherein R20 and X20 have the meanings indicated above.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F. Particular preference is given to compounds of the formulae IIa and IIb, in particular compounds of the formulae IIa and IIb wherein X denotes F.
The compounds of the formula III are preferably selected from the following formulae:
wherein R20 and X20 have the meanings indicated above.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F. Particular preference is given to compounds of the formulae IIIa and IIIe, in particular compounds of the formula IIIa;
bb) LC-medium additionally comprising one or more compounds selected from the following formulae:
wherein
R20, X20, W and Y20-23 have the meanings indicated above under formula II, and
Z20 denotes —C2H4—, —(CH2)4—, —CH═CH—,
—CF═CF, —C2F4—, —CH2CF2—, —CF2CH2—, —CH2O—, —OCH2—, —OOC— or —OCF2—, in formulae V and VI also a single bond, in formulae V and VIII also —CF2O—,
r denotes 0 or 1, and
s denotes 0 or 1;
The compounds of the formula IV are preferably selected from the following formulae:
wherein R20 and X20 have the meanings indicated above.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F or OCF3, furthermore OCF═CF2 or Cl;
The compounds of the formula V are preferably selected from the following formulae:
wherein R20 and X20 have the meanings indicated above.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F and OCF3, furthermore OCHF2, CF3, OCF═CF2 and OCH═CF2;
The compounds of the formula VI are preferably selected from the following formulae:
wherein R20 and X20 have the meanings indicated above.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F, furthermore OCF3, CF3, CF═CF2, OCHF2 and OCH═CF2;
The compounds of the formula VII are preferably selected from the following formulae:
wherein R20 and X20 have the meanings indicated above.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F, furthermore OCF3, OCHF2 and OCH═CF2.
cc) The medium additionally comprises one or more compounds selected from the formulae ZK1 to ZK10 given above. Especially preferred are compounds of formula ZK1 and ZK3. Particularly preferred compounds of formula ZK are selected from the sub-formulae ZK1a, ZK1 b, ZK1c, ZK3a, ZK3b, ZK3c and ZK3d.
dd) The medium additionally comprises one or more compounds selected from the formulae DK1 to DK12 given above. Especially preferred compounds are DK3.
ee) The medium additionally comprises one or more compounds selected from the following formulae:
wherein X20 has the meanings indicated above, and
L denotes H or F,
“alkenyl” denotes C2-6-alkenyl.
ff) The compounds of the formulae DK-3a and IX are preferably selected from the following formulae:
wherein “alkyl” denotes C1-6-alkyl, preferably n-C3H7, n-C4H9 or n-C5H11, in particular n-C3H7.
gg) The medium additionally comprises one or more compounds selected from the formulae B1, B2 and B3 given above, preferably from the formula B2. The compounds of the formulae B1 to B3 are particularly preferably selected from the formulae B1a, B2a, B2b and B2c.
hh) The medium additionally comprises one or more compounds selected from the following formula:
wherein L20 denotes H or F, and R21 and R22 each, identically or differently, denote n-alkyl, alkoxy, oxaalkyl, fluoroalkyl or alkenyl, each having up to 6 C atoms, and preferably each, identically or differently, denote alkyl having 1 to 6 C atoms.
ii) The medium comprises one or more compounds of the following formulae:
Wherein W, R20, X20 and Y20-23 have the meanings indicated in formula III, and
each, independently of one another, denote
and
denotes
The compounds of the formulae XI and XII are preferably selected from the following formulae:
wherein R20 and X20 have the meaning indicated above and preferably R20 denotes alkyl having 1 to 6 C atoms and X20 denotes F.
The mixture according to the invention particularly preferably comprises at least one compound of the formula XIIa and/or XIIe.
jj) The medium comprises one or more compounds of formula T given above, preferably selected from the group of compounds of the formulae T21 to T23 and T25 to T27.
Particular preference is given to the compounds of the formulae T21 to T23. Very particular preference is given to the compounds of the formulae
kk) The medium comprises one or more compounds selected from the group of formulae DK9, DK10 and DK11 given above.
ll) The medium additionally comprises one or more compounds selected from the following formulae:
wherein R20 and X20 each, independently of one another, have one of the meanings indicated above, and Y20-23 each, independently of one another, denote H or F. X20 is preferably F, Cl, CF3, OCF3 or OCHF2. R20 preferably denotes alkyl, alkoxy, oxaalkyl, fluoroalkyl or alkenyl, each having up to 6 C atoms.
The mixture according to the invention particularly preferably comprises one or more compounds of the formula XVIII-a,
wherein R20 has the meanings indicated above. R20 preferably denotes straight-chain alkyl, in particular ethyl, n-propyl, n-butyl and n-pentyl and very particularly preferably n-propyl. The compound(s) of the formula XVIII, in particular of the formula XVIII-a, is (are) preferably employed in the mixtures according to the invention in amounts of 0.5-20% by weight, particularly preferably 1-15% by weight.
mm) The medium additionally comprises one or more compounds of the formula XIX,
wherein R20, X20 and Y20-25 have the meanings indicated in formula I, s denotes 0 or 1, and
denotes
In the formula XIX, X20 may also denote an alkyl radical having 1-6 C atoms or an alkoxy radical having 1-6 C atoms. The alkyl or alkoxy radical is preferably straight-chain.
R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F;
The compounds of the formula XIX are preferably selected from the following formulae:
wherein R20, X20 and Y20 have the meanings indicated above. R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F, and Y20 is preferably F;
is preferably
R20 is straight-chain alkyl or alkenyl having 2 to 6 C atoms;
nn) The medium comprises one or more compounds of the formulae G1 to G4 given above, preferably selected from G1 and G2 wherein alkyl denotes C1-6-alkyl, Lx denotes H and X denotes F or Cl. In G2, X particularly preferably denotes Cl.
oo) The medium comprises one or more compounds of the following formulae:
wherein R20 and X20 have the meanings indicated above. R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F. The medium according to the invention particularly preferably comprises one or more compounds of the formula XXII wherein X20 preferably denotes F. The compound(s) of the formulae XX-XXII is (are) preferably employed in the mixtures according to the invention in amounts of 1-20% by weight, particularly preferably 1-15% by weight. Particularly preferred mixtures comprise at least one compound of the formula XXII.
pp) The medium comprises one or more compounds of the following pyrimidine or pyridine compounds of the formulae
wherein R20 and X20 have the meanings indicated above. R20 preferably denotes alkyl having 1 to 6 C atoms. X20 preferably denotes F. The medium according to the invention particularly preferably comprises one or more compounds of the formula M-1, wherein X20 preferably denotes F. The compound(s) of the formulae M-1-M-3 is (are) preferably employed in the mixtures according to the invention in amounts of 1-20% by weight, particularly preferably 1-15% by weight.
Further preferred embodiments are indicated below:
qq) The medium comprises two or more compounds of the formula XII, in particular of the formula XIIe;
rr) The medium comprises 2-30% by weight, preferably 3-20% by weight, particularly preferably 3-15% by weight, of compounds of the formula XII;
ss) Besides the compounds of the formulae XII, the medium comprises further compounds selected from the group of the compounds of the formulae II, III, IX-XIII, XVII and XVIII;
tt) The proportion of compounds of the formulae II, III, IX-XI, XIII, XVII and XVIII in the mixture as a whole is 40 to 95% by weight;
uu) The medium comprises 10-50% by weight, particularly preferably 12-40% by weight, of compounds of the formulae II and/or III;
vv) The medium comprises 20-70% by weight, particularly preferably 25-65% by weight, of compounds of the formulae IX-XIII;
ww) The medium comprises 4-30% by weight, particularly preferably 5-20% by weight, of compounds of the formula XVII;
xx) The medium comprises 1-20% by weight, particularly preferably 2-15% by weight, of compounds of the formula XVIII;
yy) The medium comprises at least two compounds of the formulae
zz) The medium comprises at least two compounds of the formulae
aaa) The medium comprises at least two compounds of the formula XIIa and at least two compounds of the formula XIIe.
bbb) The medium comprises at least one compound of the formula XIIa and at least one compound of the formula XIIe and at least one compound of the formula IIIa.
ccc) The medium comprises at least two compounds of the formula XIIa and at least two compounds of the formula XIIe and at least one compound of the formula IIIa.
ddd) The medium comprises in total ≥25% by weight, preferably ≥30% by weight, of one or more compounds of the formula XII.
eee) The medium comprises ≥20% by weight, preferably ≥24% by weight, preferably 25-60% by weight, of compounds of the formula ZK3, in particular the compound of the formula ZK3a,
fff) The medium comprises at least one compound selected from the group of compounds ZK3a, ZK3b and ZK3c, preferably ZK3a, in combination with compound ZK3d
ggg) The medium comprises at least one compound of the formula DPGU-n-F.
hhh) The medium comprises at least one compound of the formula CDUQU-n-F.
iii) The medium comprises at least one compound of the formula CPU-n-OXF.
jjj) The medium comprises at least one compound of the formula CPGU-3-OT.
kkk) The medium comprises at least one compound of the formula PPGU-n-F.
lll) The medium comprises at least one compound of the formula PGP-n-m, preferably two or three compounds.
mmm) The medium comprises at least one compound of the formula PGP-2-2V having the structure
In a preferred embodiment, the liquid crystal mixture according to the present invention further comprises a polymerizable component C) comprising one or more polymerizable compounds.
The polymerizable compounds can be selected from isotropic or mesogenic polymerizable compounds known to the skilled person in the art.
Preferably, the polymerizable component C) comprises one or more polymerizable compounds of formula P,
Pa-(Spa)s1-A2-(Za-A1)n2-(Spb)s2—Pb P
wherein the individual radicals have the following meanings:
Pa, Pb each, independently of one another, denote a polymerizable group,
Spa, Spb on each occurrence, identically or differently, denote a spacer group,
s1, s2 each, independently of one another, denote 0 or 1,
A1, A2 each, independently of one another, denote a radical selected from the following groups:
a) the group consisting of trans-1,4-cyclohexylene, 1,4-cyclohexenylene and 4,4″-bicyclohexylene, wherein, in addition, one or more non-adjacent CH2 groups may be replaced by —O— and/or —S— and wherein, in addition, one or more H atoms may be replaced by F,
b) the group consisting of 1,4-phenylene and 1,3-phenylene, wherein, in addition, one or two CH groups may be replaced by N and wherein, in addition, one or more H atoms may be replaced by L,
c) the group consisting of tetrahydropyran-2,5-diyl, 1,3-dioxane-2,5-diyl, tetrahydrofuran-2,5-diyl, cyclobutane-1,3-diyl, piperidine-1,4-diyl, thiophene-2,5-diyl and selenophene-2,5-diyl, each of which may also be mono- or polysubstituted by L,
d) the group consisting of saturated, partially unsaturated or fully unsaturated, and optionally substituted, polycyclic radicals having 5 to 20 cyclic C atoms, one or more of which may, in addition, be replaced by heteroatoms, preferably selected from the group consisting of
where, in addition, one or more H atoms in these radicals may be replaced by L, and/or one or more double bonds may be replaced by single bonds, and/or one or more CH groups may be replaced by N,
n2 denotes 0, 1, 2 or 3,
Za in each case, independently of one another, denotes —CO—O—, —O—CO—, —CH2O—, —OCH2—, —CF2O—, —OCF2—, or —(CH2)n—, where n is 2, 3 or 4, —O—, —CO—, —C(RyRz)—, —CH2CF2—, —CF2CF2— or a single bond,
L on each occurrence, identically or differently, denotes F, Cl, CN, SCN, SF5 or straight-chain or branched, in each case optionally fluorinated, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or al koxycarbonyloxy having 1 to 12 C atoms,
Ry, Rz each, independently of one another, denote H, F or straight-chain or branched alkyl having 1 to 12 C atoms, wherein, in addition, one or more H atoms may be replaced by F,
M denotes —O—, —S—, —CH2—, —CHY1— or —CY1Y2—, and
Y1 and Y2 each, independently of one another, have one of the meanings indicated above for RY or denote Cl or CN.
Preferred spacer groups Spa,b are selected from the formula Sp″-X″, so that the radicals P-Sp— and Pa/b-Spa/b— conforms to the formulae P-Sp″-X″— and Pa/b-Sp″-X″—, respectively, wherein
Sp″ denotes alkylene having 1 to 20, preferably 1 to 12, C atoms, which is optionally mono- or polysubstituted by F, Cl, Br, I or CN and wherein, in addition, one or more non-adjacent CH2 groups may each be replaced, independently of one another, by —O—, —S—, —NH—, —N(R0)—, —Si(R00R000)—, —CO—, —CO—O—, —O—CO—, —O—CO—O—, —S—CO—, —CO—S—, —N(R00)—CO—O—, —O—CO—N(R00)—, —N(R00)—CO—N(R00)—, —CH═CH— or —C≡C— in such a way that O and/or S atoms are not linked directly to one another,
X″ denotes —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O—, —CO—N(R00)—, —N(R00)—CO—, —N(R00)—CO—N(R00)—, —OCH2—, —CH2O—, —SCH2—, —CH2S—, —CF2O—, —OCF2—, —CF2S—, —SCF2—, —CF2CH2—, —CH2CF2—, —CF2CF2—, —CH═N—, —N═CH—, —N═N—, —CH═CR0—, —CY3═CY4—, —C≡C—, —CH═CH—CO—O—, —O—CO—CH═CH— or a single bond,
R0, R00
and R000 each, independently of one another, denote H or alkyl having 1 to 12 C atoms, and
Y3 and Y4 each, identically or differently, denote H, F, Cl or CN.
X″ is preferably —O—, —S—, —CO—, —C(O)O—, —OC(O)—, —O—C(O)O—, —CO—NR0—, —NR0—CO—, —NR0—CO—NR0— or a single bond.
Typical spacer groups Sp″ are, for
example, —(CH2)p1—, —(CH2CH2O)q1—CH2CH2—, —CH2CH2—S—CH2CH2—, —CH2CH2—NH—CH2CH2— or —(SiR00R000—O)p1—, wherein p1 is an integer from 1 to 12, q1 is an integer from 1 to 3, and R00 and R000 have the meanings indicated above.
Particularly preferred groups -Sp″-X″— are —(CH2)p1—, —(CH2)p1—O—, —(CH2)p1—O—CO—, —(CH2)p1—O—CO—O—, wherein p1 and q1 have the meanings indicated above.
Particularly preferred groups Sp″ are, for example, in each case straight-chain ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, octadecylene, ethyleneoxyethylene, methyleneoxybutylene, ethylenethioethylene, ethylene-N-methyliminoethylene, 1-methylalkylene, ethenylene, propenylene and butenylene.
Particularly preferred monomers of formula P are the following:
wherein the individual radicals have the following meanings:
P1 to P3 each, independently of one another, denote a polymerizable group as defined for formula P, preferably an acrylate, methacrylate, fluoroacrylate, oxetane, vinyloxy or epoxide group,
Sp1 to Spa each, independently of one another, denote a single bond or a spacer group, preferably having one of the meanings indicated above and below for Spa, and particularly preferably —(CH2)p1—, —(CH2)p1—O—, —(CH2)p1—CO—O— or —(CH2)p1—O—CO—O—, wherein p1 is an integer from 1 to 12, and where the linking to the adjacent ring in the last-mentioned groups takes place via the O atom,
where, in addition, one or more of the radicals P1-Sp1—, P2-Sp2— and P3-Sp3— may denote a radical Raa, with the proviso that at least one of the radicals P1-Sp1—, P2-Sp2— and P3-Sp3— present does not denote Raa,
Raa denotes H, F, Cl, CN or straight-chain or branched alkyl having 1 to 25 C atoms, wherein, in addition, one or more non-adjacent CH2 groups may each be replaced, independently of one another, by
C(R0)═C(R00)—, —C≡C—, —N(R0)—, —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a way that O and/or S atoms are not linked directly to one another, and wherein, in addition, one or more H atoms may be replaced by F, Cl, CN or P1-Sp1—, particularly preferably straight-chain or branched, optionally mono- or polyfluorinated alkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl or alkylcarbonyloxy having 1 to 12 C atoms (where the alkenyl and alkynyl radicals have at least two C atoms and the branched radicals have at least three C atoms),
R0, R00 each, independently of one another, denote H or alkyl having 1 to 12 C atoms,
Ry and Rz each, independently of one another, denote H, F, CH3 or CF3,
Zp1 denotes —O—, —CO—, —C(RyRz)— or —CF2CF2—,
Zp2 and Zp3 each, independently of one another, denote —CO—O—, —O—CO—, —CH2O—, —OCH2—, —CF2O—, —OCF2— or —(CH2)n3—, where n3 is 2, 3 or 4,
L on each occurrence, identically or differently, denotes F, Cl, CN, SCN, SF5 or straight-chain or branched, optionally mono- or polyfluorinated alkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having 1 to 12 C atoms, preferably F,
L′ and L″ each, independently of one another, denote H, F or Cl,
r denotes 0, 1, 2, 3 or 4,
s denotes 0, 1, 2 or 3,
t denotes 0, 1 or 2, and
x denotes 0 or 1.
In a particularly preferred embodiment of the present invention the LC mixture, or component C), comprises one or more compounds of formula P10-1.
wherein the parameters are defined as described above and P1 and P2 preferably denote acrylate or methacrylate.
Particularly preferred compounds of formula P10-1 are selected from the group of the following subformulae
wherein each n4 denote independently of each other an integer between 2 and 10, preferably 3,4,5 or 6.
The polymerizable compounds of formulae I and P are also suitable for polymerisation without an initiator, which is associated with considerable advantages, such as, for example, lower material costs and, in particular, reduced contamination of the LC medium by possible residual amounts of the initiator or degradation products thereof. The polymerisation can thus also be carried out without addition of an initiator. The LC medium thus, in a preferred embodiment, comprises no polymerisation initiator.
The polymerizable component C) or the LC medium as a whole may also comprise one or more stabilisers in order to prevent undesired spontaneous polymerisation of the RMs, for example during storage or transport. Suitable types and amounts of stabilisers are known to the person skilled in the art and are described in the literature. Particularly suitable are, for example, the commercially available stabilisers from the Irganox® series (BASF SE), such as, for example, Irganox® 1076. If stabilisers are employed, their proportion, based on the total amount of the RMs or the polymerizable component, is preferably 10-10,000 ppm, particularly preferably 50-1000 ppm.
The media according to the invention preferably comprise from 0.01 to 10%, particularly preferably from 0.05 to 7.5% and most preferably from 0.1 to 5% of the compounds of component C) comprising compounds of formula P according to the invention. The media preferably comprise one, two or three, more preferably one or two and most preferably one compound of the formula P according to the invention.
By means of suitable additives, the liquid-crystalline phases of the present invention can be modified in such a way that they can be used in all types of liquid-crystal display element that have been disclosed hitherto. Additives of this type are known to the person skilled in the art and are described in detail in the literature (H. Kelker/R. Hatz, Handbook of Liquid Crystals, Verlag Chemie, Weinheim, 1980). For example, pleochroic dyes can be added for the production of coloured guest-host systems or substances can be added in order to modify the dielectric anisotropy, the viscosity and/or the alignment of the nematic phases.
The media according to the invention are prepared in a manner conventional per se. In general, the components are dissolved in one another, preferably at elevated temperature.
Accordingly the present invention relates further to method for the production of an LC medium according to the present invention, comprising the step of mixing one or more compounds of formula I with a liquid-crystalline component B) comprising one or more mesogenic or liquid-crystalline compounds as described above.
The present invention further relates to a process for the fabrication of liquid crystal displays comprising at least the steps of:
providing a first substrate which includes a pixel electrode and a common electrode for generating an electric field substantially parallel to a surface of the first substrate in the pixel region;
providing a second substrate, the second substrate being disposed opposite to the first substrate;
interposing a liquid crystal mixture between the first substrate and the second substrate, the liquid crystal mixture comprising one or more compounds of formula I, component B) and optionally component C);
irradiating the liquid crystal mixture with linearly polarised light causing photoalignment of the liquid crystal;
curing the polymerizable compounds of the liquid crystal mixture by irradiation with ultraviolet light or visible light having a wavelength of 450 nm or below.
The present invention further relates to the use of the liquid crystal mixtures according to the invention for the fabrication of a liquid crystal display.
The present invention further relates to liquid crystal displays fabricated by the process described above.
In the following, the production process according to the present invention is described in greater detail.
The first substrate includes a pixel electrode and a common electrode for generating an electric field substantially parallel to a surface of the first substrate in the pixel region. Various kinds of displays having at least two electrodes on one substrate are known to the skilled person wherein the most significant difference is that either both the pixel electrode and the common electrode are structured, as it is typical for IPS displays, or only the pixel electrode is structured and the common electrode is unstructured, which is the case for FFS displays.
It has to be understood that the present invention refers to any kind of electrode configurations suitable for generating an electric field substantially parallel to a surface of the first substrate in the pixel region; mentioned above, i.e. IPS as well as FFS displays.
The process according to the present invention is independent of the kind of substrate or material of the surface which is in contact with the liquid crystal mixture according to the invention, during and after this process. Examples of materials used for the substrates or surfaces are organic polymers including polyimide, indium tin oxide (ITO), indium zinc oxide (IZO), silicon nitride (SiNx) and silicon dioxide (SiO2). The process is especially suitable for the use in displays containing substrates that do not have a polyimide layer on one or more of the surfaces that are in contact with the liquid crystal.
In case one or more substrates contain a polyimide layer, the polyimide can be rubbed or not rubbed, preferably not rubbed.
Hence, the invention relates to a display produced by the process according to the invention in which the substrates contain a rubbed or unrubbed polyimide layer, preferably an unrubbed polyimide layer.
The invention further relates to a display produced by the process according to the invention in which none or only one of the top and bottom substrates contains a polyimide layer.
In one embodiment of the present invention the liquid crystal composition is injected between the first and second substrates or is filled into the cell by capillary force after combining the first and second substrates. In an alternative embodiment, the liquid crystal composition may be interposed between the first and second substrates by combining the second substrate to the first substrate after loading the liquid crystal composition on the first substrate. Preferably, the liquid crystal is dispensed dropwise onto a first substrate in a process known as “one drop filling” (ODF) process, as disclosed in for example JPS63-179323 and JPH10-239694, or using the Ink Jet Printing (IJP) method.
In a preferred embodiment, the process according to the invention contains a process step where the liquid crystal inside the display panel is allowed to rest for a period of time in order to evenly redistribute the liquid crystal medium inside the panel (herein referred to as “annealing”).
However it is likewise preferred that the annealing step is combined with a previous step, such as edge sealant pre-curing. In which case a ‘separate’ annealing step may not be necessary at all.
For the production of the displays according to the present invention, the photoreactive mesogen of formula I is preferably allowed to redistribute in the panel. After filling and assembly, the display panel is annealed for a time between 1 min and 3 h, preferably between 2 min and 1 h and most preferably between 5 min and 30 min. The annealing is preferably performed at room temperature.
In an alternative embodiment, the annealing is performed at elevated temperature, preferably at above 20° C. and below 140° C., more preferably above 40° C. and below 100° C. and most preferably above 50° C. and below 80° C.
In a preferred embodiment, one or more of the process steps of filling the display, annealing, photoalignment and curing of the polymerizable compound is performed at a temperature above the clearing point of the liquid crystal host mixture.
During the photoalignment of the liquid crystal inside the liquid crystal panel, anisotropy is induced by exposing the display or the liquid crystal layer to linearly polarised light.
In a preferred embodiment of the present invention the photoreactive component A) comprising one or more compounds of formula I, is photoaligned in a first step using linearly polarised light and in a second step further cured using linearly polarized or unpolarised UV light. In the second step the optional component C) is also further cured.
In another preferred embodiment, the linearly polarised light applied according to the inventive process is ultraviolet light which enables simultaneous photoalignment and photocuring of the photoreactive component A) comprising one or more compounds of formula I, and, if present, photocuring of the polymerizable component C).
Photoalignment of the photoreactive compounds of formula I and curing of the polymerizable groups of compounds of formula I and the curing of the optional polymerizable compounds of formula P can be performed simultaneously or stepwise. In case the process is split into different steps, the individual steps can be performed at the same temperature or at different temperatures.
After the photoalignment and curing step(s) a so-called “post-curing” step can optionally be performed by irradiation with UV-light and/or visible light (both either linearly or unpolarised) at reduced temperature in order to remove unreacted polymerizable compounds. The post-curing is preferably performed at above 0° C. and below the clearing point of the utilized LC mixture, preferably 20° C. and below 60° C.° C., and most preferably above 20° C. and below 40° C.
The polymerizable compounds are optionally polymerised or crosslinked (if a polymerizable compound contains two or more polymerizable groups) with the application of an electrical field. The polymerisation can be carried out in one or more steps.
Suitable and preferred polymerisation methods for component C) are, for example, thermal or photopolymerization, preferably photopolymerization, in particular UV photopolymerization. One or more initiators can optionally also be added here. Suitable conditions for the polymerisation and suitable types and amounts of initiators are known to the person skilled in the art and are described in the literature. Suitable for free-radical polymerisation are, for example, the commercially available photoinitiators Irgacure651®, Irgacure184®, Irgacure907®, Irgacure369® or Darocure1173® (BASF SE). If an initiator is employed, its proportion is preferably 0.001 to 5% by weight, particularly preferably 0.001 to 1% by weight.
The present invention also relates to electro-optical liquid-crystal display elements containing a liquid-crystalline medium according to the invention, which is preferably homogeneously aligned. In a preferred embodiment the liquid crystal display is of the IPS or FFS mode.
Further combinations of the embodiments and variants of the invention in accordance with the description arise from the claims.
The invention is explained in greater detail below with reference to working examples, but without intending to be restricted thereby. The person skilled in the art will be able to glean from the examples working details that are not given in detail in the general description, generalise them in accordance with general expert knowledge and apply them to a specific problem.
Besides the usual and well-known abbreviations, the following abbreviations are used:
C: crystalline phase; N: nematic phase; Sm: smectic phase; I: isotropic phase. The numbers between these symbols show the transition temperatures of the substance concerned.
Temperature data are in ° C., unless indicated otherwise.
Physical, physicochemical or electro-optical parameters are determined by generally known methods, as described, inter alia, in the brochure “Merck Liquid Crystals—Licristal®—Physical Properties of Liquid Crystals—Description of the Measurement Methods”, 1998, Merck KGaA, Darmstadt.
Above and below, Δn denotes the optical anisotropy (589 nm, 20° C.) and Δε denotes the dielectric anisotropy (1 kHz, 20° C.). The dielectric anisotropy Δε is determined at 20° C. and 1 kHz. The optical anisotropy Δn is determined at 20° C. and a wavelength of 589.3 nm.
The Δε and Δn values and the rotational viscosity (γ1) of the compounds according to the invention are obtained by linear extrapolation from liquid-crystalline mixtures consisting of 5 to 10% of the respective compound according to the invention and 90-95% of the commercially available liquid-crystal mixture ZLI-2857 (for Δε) or ZLI-4792 (for Δn, γ1) (mixtures, Merck KGaA, Darmstadt).
The compounds used in the present invention are prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se, which are not mentioned here in greater detail.
In the present invention and especially in the following examples, the structures of the mesogenic compounds are indicated by means of abbreviations, also called acronyms. In these acronyms, the chemical formulae are abbreviated as follows using Tables A to C below. All groups CnH2n+1, CmH2m+1 and C1H2l+1 or CnH2n−1, CmH2m−1 and C1H2l−1 denote straight-chain alkyl or alkenyl, preferably 1E-alkenyl, each having n, m and l C atoms respectively. Table A lists the codes used for the ring elements of the core structures of the compounds, while Table B shows the linking groups. Table C gives the meanings of the codes for the left-hand or right-hand end groups. The acronyms are composed of the codes for the ring elements with optional linking groups, followed by a first hyphen and the codes for the left-hand end group, and a second hyphen and the codes for the right-hand end group. Table D shows illustrative structures of compounds together with their respective abbreviations.
TABLE A
Ring elements
C
P
D
DI
A
AI
G
GI
U
UI
Y
M
MI
N
NI
Np
dH
N3f
N3fl
tH
tHI
tH2f
tH2fl
K
KI
L
LI
F
FI
Nf
Nfl
TABLE B
Linking groups
E
—CH2CH2—
Z
—CO—O—
V
—CH═CH—
ZI
—O—CO—
X
—CF═CH—
O
—CH2—O—
XI
—CH═CF—
OI
—O—CH2—
B
—CF═CF—
Q
—CF2—O—
T
—C≡C—
QI
—O—CF2—
W
—CF2CF2—
T
—C≡O—
TABLE C
End groups
Left-hand side
Right-hand side
Use alone
-n-
CnH2n+1—
-n
—CnH2n+1
—nO—
CnH2n+1—O—
—nO
—O—CnH2n+1
—V—
CH2═CH—
—V
—CH═CH2
—nV—
CnH2n+1—CH═CH—
—nV
—CnH2n—CH═CH2
—Vn—
CH2═CH—CnH2n+1—
—Vn
—CH═CH—CnH2n+1
—nVm—
CnH2n+1—CH═CH—CmH2m—
—nVm
—CnH2n—CH═CH—CmH2m+1
—N—
N≡C—
—N
—C≡N
—S—
S═C═N—
—S
—N═C═S
—F—
F—
—F
—F
—CL—
Cl—
—CL
—Cl
—M—
CFH2—
—M
—CFH2
—D—
CF2H—
—D
—CF2H
—T—
CF3—
—T
—CF3
—MO—
CFH2O—
—OM
—OCFH2
—DO—
CF2HO—
—OD
—OCF2H
—TO—
CF3O—
—OT
—OCF3
—FXO—
CF2═CH—O—
—OXF
—O—CH═CF2
—A—
H—C≡C—
—A
—C≡C—H
—nA—
CnH2n+1—C≡C—
—An
—C≡C—CnH2n+1
—NA—
N≡C—C≡C—
—AN
—C≡C—C≡N
Use together with one another and with others
— . . . A . . . —
—C≡—
— . . . A . . .
—C≡—
— . . . V . . . —
CH═CH—
— . . . V . . .
—CH═CH—
— . . . Z . . . —
—CO—O—
— . . . Z . . .
—CO—O—
— . . . ZI . . . —
—O—CO—
— . . . ZI . . .
—O—CO—
— . . . K . . . —
—CO—
— . . . K . . .
—CO—
— . . . W . . . —
—CF═CF—
— . . . W . . .
—CF═CF—
wherein n and m each denote integers, and the three dots “ . . . ” are placeholders for other abbreviations from this table.
The following table shows illustrative structures together with their respective abbreviations. These are shown in order to illustrate the meaning of the rules for the abbreviations. They furthermore represent compounds which are preferably used.
TABLE D
Illustrative structures
CC-n-m
CC-n-Om
CC-n-V
CC-n-Vm
CC-n-mV
CC-n-mVI
CC-V-V
CC-V-mV
CC-V-Vm
CC-Vn-mV
CC-nV-mV
CC-nV-Vm
CP-n-m
CP-nO-m
CP-n-Om
CP-V-m
CP-Vn-m
CP-nV-m
CP-V-V
CP-V-mV
CP-V-Vm
CP-Vn-mV
CP-nV-mV
CP-nV-Vm
PP-n-m
PP-nO-m
PP-n-Om
PP-n-V
PP-n-Vm
PP-n-mV
PP-n-mVI
CCP-n-m
CCP-nO-m
CCP-n-Om
CCP-n-V
CCP-n-Vm
CCP-n-mV
CCP-n-mVI
CCP-V-m
CCP-nV-m
CCP-Vn-m
CCP-nVm-I
CPP-n-m
CPG-n-m
CGP-n-m
CPP-nO-m
CPP-n-Om
CPP-V-m
CPP-nV-m
CPP-Vn-m
CPP-nVm-I
PGP-n-m
PGP-n-V
PGP-n-Vm
PGP-n-mV
PGP-n-mVI
CCEC-n-m
CCEC-n-Om
CCEP-n-m
CCEP-n-Om
CPPC-n-m
CGPC-n-m
CCPC-n-m
CCZPC-n-m
CPGP-n-m
CPGP-n-mV
CPGP-n-mVI
PGIGP-n-m
CP-n-F
CP-n-CL
GP-n-F
GP-n-CL
CCP-n-OT
CCG-n-OT
CCP-n-T
CCG-n-F
CCG-V-F
CCG-V-F
CCU-n-F
CDU-n-F
CPG-n-F
CPU-n-F
CGU-n-F
PGU-n-F
GGP-n-F
GGP-n-CL
PGIGI-n-F
PGIGI-n-CL
CCPU-n-F
CCGU-n-F
CPGU-n-F
CPGU-n-OT
DPGU-n-F
PPGU-n-F
CCZU-n-F
CCQP-n-F
CCQG-n-F
CCQU-n-F
PPQG-n-F
PPQU-n-F
PGQU-n-F
GGQU-n-F
PUQU-n-F
MUQU-n-F
NUQU-n-F
CDUQU-n-F
CPUQU-n-F
CGUQU-n-F
PGPQP-n-F
PGPQG-n-F
PGPQU-n-F
PGUQU-n-F
APUQU-n-F
DGUQU-n-F
CY-n-Om
CY-n-m
CY-V-Om
CY-nV-(O)m
CVC-n-m
CVY-V-m
CEY-V-m
PY-n-(O)m
CCY-n-m
CCY-n-Om
CCY-V-m
CCY-Vn-m
CCY-V-Om
CCY-n-OmV
CCY-n-zOm
CCOC-n-m
CPY-n-(O)m
CPY-V-Om
CQY-n-(O)m
CQIY-n-(O)m
CCQY-n-(O)m
CCQIY-n-(O)m
CPQY-n-(O)m
CPQIY-n-Om
CLY-n-(O)m
CYLI-n-m
LYLI-n-m
LY-n-(O)m
PGIGI-n-F
PGP-n-m
PYP-n-(O)m
PYP-n-mV
YPY-n-m
YPY-n-mV
BCH-nm
BCH-nmF
CPYP-n-(O)m
CPGP-n-m
CPYC-n-m
CYYC-n-m
CCYY-n-m
CPYG-n-(O)m
CBC-nm
CBC-nmF
CNap-n-Om
CCNap-n-Om
CENap-n-Om
CTNap-n-Om
CETNap-n-Om
CK-n-F
DFDBC-n(O)-(O)m
C-DFDBF-n-(O)m
wherein n, m and l preferably, independently of one another, denote 1 to 7.
The following table, Table E, shows illustrative compounds which can be used as additional stabilisers in the mesogenic media according to the present invention.
TABLE E
Table E shows possible stabilisers which can
be added to the LC media according to the invention.
(n here denotes an integer from 1 to 12,
preferably 1, 2, 3, 4, 5, 6, 7 or 8,
terminal methyl groups are not shown).
The LC media preferably comprise 0 to 10% by weight, in particular 1 ppm to 5% by weight, particularly preferably 1 ppm to 1% by weight, of stabilisers.
Table F below shows illustrative compounds which can preferably be used as chiral dopants in the mesogenic media according to the present invention.
TABLE F
In a preferred embodiment of the present invention, the mesogenic media comprise one or more compounds selected from the group of the compounds from Table F.
The mesogenic media according to the present application preferably comprise two or more, preferably four or more, compounds selected from the group consisting of the compounds from the above tables.
The liquid-crystal media according to the present invention preferably comprise
seven or more, preferably eight or more, individual compounds, preferably of three or more, particularly preferably of four or more, different formulae, selected from the group of the compounds from Table D.
Hereinafter, the present invention is described in more detail and specifically with reference to the Examples, which however are not intended to limit the present invention.
EXAMPLES
Compound Examples
1.1 Synthesis of diethyl 3-(2-benzyloxyethyl)pentanedioate (1)
Under reflux 13.8 ml (90 mmol) of the diethyl malonate are added to mixture of 34.5 ml of a solution of sodium methylate in ethanol (20%, 50 mmol) and 40 ml ethanol. After 2h 10 g (50 mmol) of 2-bromoethoxymethylbenzene are added and heating was continued overnight. Water and MTB ether are poured into the cooled reaction mixture. The aqueous layer is extracted with MTB ether. The combined organic layers are washed with brine and dried over sodium sulfate. The solvent is evaporated. The residue is purified by silica chromatography (toluene; toluene/MTB ether 9:1). The isolated material is distilled under vacuum (0.1 mbar, 116-121° C.).
1.2 Synthesis of 2-(2-benzyloxyethyl)propane-1,3-diol (2)
A solution of 5 g (20 mmol) of the malonate 1 in 60 ml toluene is added to a suspension of 930 mg (24 mmol) Lithium aluminum hydride in 8 ml Toluene. After 3h reflux the cooled reaction mixture is quenched with ethyl acetate. The mixture is acidified with 2 mol/l hydrochloric acid (pH 3-4). The aqueous layer is extracted with MTB ether. The combined organic layers are washed with water and dried over sodium sulfate. The solvent is evaporated. The residue is purified by silica chromatography (ethyl acetate.
1.3 Synthesis of [4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]butoxy]-tert-butyl-dimethyl-silane (3)
At room temperature 3.4 ml (25 mmol) triethyl amine are added to a mixture of 2.1 g (10 mmol) of the diol 2 and 120 mg DMAP dissolved in 30 ml dichloro methane. Afterwards a solution of 4.5 g (30 mmol) TBDMS-Cl in 15 ml dichloro methane are added to the reaction mixture at 3-4° C. After stirring 16h at room temperature the mixture is quenched with water. The combined organic layers are washed with brine and dried over sodium sulfate. The solvent is evaporated. The residue is purified by silica chromatography (n-heptane/ethyl acetate 19:1).
1.4 Synthesis of 4-[tert-butyl(dimethyl)silyl]oxy-3-[[tert-butyl(dimethyl)silyl]oxy-methyl]-butan-1-ol (4)
A solution of 500 mg (1 mmol) of 3 in 13 ml ethyl acetate is hydrogenated using Pd/C-5% at room temperature. The solvent is evaporated. The residue is purified by silica chromatography (n-heptane/ethyl acetate (gradient)).
1.5 Synthesis of [4-[(6-bromo-2-naphthyl)oxy]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]butoxy]-tert-butyl-dimethyl-silane (5)
A solution of 10 g (43 mmol) 2-hydroxy-6-bromo naphthalene, 17.1 g (49 mmol) 5 and 13.1 g triphenylphosphine in 80 ml THF is treated with 10.2 ml (52 mmol) diisopropyl carboxylate at room temperature. The mixture is stirred overnight. The solvent is evaporated. The residue is purified by silica chromatography (toluene).
1.6 Synthesis of butyl (E)-3-[6-[4-[tert-butyl(dimethyl)silyl]oxy-3-[[tert-butyl(dimethyl)silyl]oxymethyl]butoxy]-2-naphthyl]prop-2-enoate (6)
A solution of 24.8 g (84% pure, 38 mmol) 5, 6.4 ml (45 mmol) butyl acrylate and 10.5 ml triethyl amine in 150 ml acetonitrile is treated with 250 mg Palladium(II)acetate and 570 mg tri-(o-tolyl) phosphine and refluxed overnight. The solvent is evaporated. The residue is filtrated through silica gel (n-heptane/toluene 1:1; toluene).
1.7 Synthesis of (E)-3-[6-[4-[tert-butyl(dimethyl)silyl]oxy-3-[[tert-butyl(dimethyl)silyl]oxymethyl]butoxy]-2-naphthyl]prop-2-enoic acid (7)
A solution of 20.5 g (33 mmol) 6 in 100 ml THF and 16 ml methanol is treated with 34 ml 2N sodium hydroxide and stirred at 30° C. overnight. The mixture is added to 1.5 l aqueous saturated ammonia hydrochloride solution and acidified with 1N hydrochloric acid (pH 5). The aqueous layer is extracted with MTB ether. The organic layer is dried with sodium sulfate. The solvent is evaporated. The residue is dried under low pressure.
1.8 Synthesis of 1-[4-(benzyloxy)-3-methylphenyl]ethan-1-one 8
12.7 g (85.0 mmol) of 1-(4-hydroxy-3-methyl-phenyl)-ethanone, 12.7 mL (107 mmol) benzyl bromide and 7.62 g (55.0 mmol) potassium carbonate are dissolved/suspended in methyl(ethyl)ketone and stirred for 18 h under reflux. The reaction mixture is cooled down to room temperature (RT) and the precipitating solid is filtered and washed with methyl tertiary-butyl ether (MTB-E). The product is further crystallized out of heptane at 5° C. and is directly used in the next synthesis step.
1.9 Synthesis of 4-(benzyloxy)-3-methylphenyl acetate 9
39.1 mL (0.165 mmol) m-chloroperbenzoic acid are suspended in in 102 mL methylene chloride and a solution of 19.3 g (80.0 mmol) of ketone 8 in 72 mL methylene chloride is added dropwise to the reaction mixture. The yellow reaction mixture is then stepwise heated up to reflux and stirred for 16 h. The reaction mixture is cooled to room temperature (RT) and poured onto ice water. The phases are separated and the organic layer is filtered off from precipitated 3-chlorobenzoic acid, washed with sodium hydrogen carbonate, tested for peroxide remnants (with ammonia iron(II) sulfate solution), dried over sodium sulfate, filtered and evaporated under vacuum. The crude product is filtered through 900 g silica gel with toluene and ethyl acetate (95:5) to give the product as a yellow oil.
1.10 Synthesis of 4-(benzyloxy)-3-methylphenol 10
23.4 g (91.0 mmol) acetate 9 are solved in 181.0 mL ethanol and 5.84 mL (197.0 mmol) sodium hydroxide solution (32%) are added dropwise to the solution (the reaction solution turned to red color). The reaction mixture is stirred for 2h at ambient temperature and then poured onto ice water and treated with HCl solution till a pH value of 1 is achieved. The reaction mixture is extracted with methyl tertiary-butyl ether (MTB-E), the organic layer dried over sodium sulfate, filtered and evaporated under vacuum. The black oil is filtered over silica gel with methylene chloride and the obtained solid is then crystallized out of heptane at −25° C. to give slightly brown colored crystals.
1H NMR (500 MHz, DMSO-d6)
δ=2.13 ppm (s, 3H, CH3), 4.99 (s, 2H, CH2—O), 6.51 (dd, J=2.86, 8.62 Hz, 1H), 6.58 (d, J=2.49 Hz, 1H), 6.81 (d, J=8.70 Hz, 1H), 7.32 (d, J=7.23 Hz, 1H), 7.39 (t, J=7.71 Hz, 2H), 7.44 (d, J=8.70 Hz, 2H).
1.11 Synthesis of benzyl 4-triisopropylsilyloxybenzoate (11)
A mixture of 400 ml DMF, 75 g (328 mmol) benzyl-4-hydroxybenzoate and 45 g (661 mmol) imidazole was treated with a solution of 77.5 ml (361 mmol) chloro triisopropyl silane in 200 ml DMF at room temperature. After 5h stirring the reaction mixture is diluted with toluene and n-heptane and poured ice cold water. The aqueous layer is extracted with toluene, the combined organic layers are dried with sodium sulfate and filtrated through silica gel (n-heptane/toluene 1:1). The solvent of the product containing fractions is evaporated. Yield: 116 g 11
1.12 Synthesis of 4-triisopropylsilyloxybenzoic acid (12)
A solution of 116 g (296 mmol) 11 in ethanol is hydrogenated with Pd-C5% (51.4% water) at room temperature. The reaction mixture is diluted with MTB ether. Silica gel and Celite® are added. The obtained mixture is filtrated through silica gel/Celite® (MTB ether). The solvent of the product containing fraction is evaporated. The residue is crystallized from n-heptane (6° C.).
1.13 Synthesis of (4-benzyloxy-3-methyl-phenyl) 4-triisopropylsilyloxybenzoate (13)
A solution of 21.1 g (98 mmol) 10 and 29 g (98 mmol) 12 in 900 ml dichloro methane is treated with 600 mg DMAP and 22.6 g (118 mmol) N-(3-dimethylamino propyl)-N′-ethyl carbodiimide hydrochloride and stirred overnight at room temperature. The mixture was filtered through silica gel (dichloromethane). The solvent of the product containing fraction is evaporated.
1.14 Synthesis of (4-hydroxy-3-methyl-phenyl) 4-triisopropylsilyloxybenzoate (14)
A solution of 35 g (71 mmol) 13 in 350 ml THF is hydrogenated with Pd-C5% (51.4% water) at room temperature. The solvent is evaporated.
1.15 Synthesis of [4-[(E)-3-[6-[4-[tert-butyl(dimethyl)silyl]oxy-3-[[tert-butyl(dimethyl)silyl]oxymethyl]butoxy]-2-naphthyl]prop-2-enoyl]oxy-3-methyl-phenyl] 4-triisopropylsilyloxybenzoate (15)
A solution of 3.9 g (6.9 mmol) 7 and 2.7 g (6.7 mmol) 14 in 40 ml dichloro methane is treated with 40 mg DMAP and 1.5 g (7.8 mmol) N-(3-dimethylamino propyl)-N′-ethyl carbodiimide hydrochloride and stirred overnight at room temperature. The mixture was filtered through silica gel (dichloro methane). The solvent of the product containing fraction is evaporated. Yield 5.4 g 15
1.18 Synthesis of [4-[(E)-3-[6-[4-hydroxy-3-(hydroxymethyl)butoxy]-2-naphthyl]prop-2-enoyl]oxy-3-methyl-phenyl] 4-hydroxybenzoate (16)
A solution of 4.9 g (5.3 mmol) 15 in 60 ml THF is treated with 6.5 ml (40 mmol) triethylamine trishydrofluoride at a temperature below 5° C. The reaction mixture is stirred overnight at room temperature, and filtered through silica gel collecting fractions (THF). The product containing fraction are combined and the solvent is evaporated. The residue is suspended in 12 ml acetonitrile and heated to reflux. The mixture is cooled to 6° C. The precipitate is isolated.
1.17 Synthesis of [3-methyl-4-[(E)-3-[6-[4-(2-methylprop-2-enoyloxy)-3-(2-methylprop-2-enoyloxymethyl)butoxy]-2-naphthyl]prop-2-enoyl]oxy-phenyl] 4-(2-methylprop-2-enoyloxy)benzoate (17)
A mixture of 1.3 g (2.4 mmol) 16 and 15 ml dichloro methane is treated with 1.0 ml (12 mmol) methacrylic acid and 30 mg DMAP. At 5° C. 2.4 ml (14 mmol) N-(3-dimethylamino propyl)-N′-ethyl are added. After 1 h stirring at this temperature stirring is continued at room temperature overnight. The reaction mixture is purified by silica chromatography (dichloro methane/THF gradient 2%). Further purification by chromatography on reversed phase silica gel (acetonitrile) and crystallization from acetonitrile.
1H NMR (700 MHz, Chloroform-d) δ=8.25 (d, J=8.4 Hz, 2H), 8.03 (d, J=15.9 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.77-7.70 (m, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.19-7.08 (m, 5H), 6.73 (d, J=15.9 Hz, 1H), 6.40 (s, 1H), 6.12 (s, 2H), 5.85-5.79 (m, 1H), 5.60-5.54 (m, 2H), 4.30 (d, J=5.7 Hz, 4H), 4.23 (t, J=6.2 Hz, 2H), 2.51 (p, J=6.2 Hz, 1H), 2.27 (s, 3H), 2.09 (s, 3H), 2.02 (q, J=6.4 Hz, 2H), 1.95 (s, 6H).
In accordance or in analogy to the above described procedures, the following compounds are obtained:
No.
Structure
RM-1
RM-2
RM-3
RM-4
RM-5
Comparative Compounds
Nematic Host Mixtures
The nematic LC host mixture are prepared as indicated in the following tables:
Mixture N—1:
Composition [%-w/w]
Physical properties
CC-3-V
36.00
Clearing Point [° C.]:
78
CC-3-V1
5.00
ne [589 nm, 20° C.]:
1.5907
CCP-V-1
8.00
Δn [589 nm, 20° C.]:
0.1095
PGP-2-2V
3.00
ε∥ [1 kHz, 20° C.]:
16.6
CCQU-3-F
9.5
ε⊥ [1 kHz, 20° C.]:
3.7
PUQU-3-F
8.5
Δε [1 kHz, 20° C.]:
12.9
APUQU-2-F
5.00
K1 [pN, 20° C.]:
12.1
APUQU-3-F
8.00
K3 [pN, 20° C.]:
13.4
PGUQU-3-F
4.00
K3/K1 [pN, 20° C.]:
1.11
PGUQU-4-F
8.00
V0 [V, 20° C.]:
1.01
PGUQU-5-F
5.00
LTS bulk [h, −20° C.]:
1000
Σ
100.0
Mixture N—2:
Composition [%-w/w]
Physical properties
CC-3-V
44.00
Clearing Point [° C.]:
80.5
CC-3-V1
12.00
ne [589 nm, 20° C.]:
1.5865
CCP-V-1
11.00
Δn [589 nm, 20° C.]:
0.0991
CCP-V2-1
9.00
ε∥ [1 kHz, 20° C.]:
5.3
PGP-2-3
6.00
ε⊥ [1 kHz, 20° C.]:
2.6
PGUQU-3-F
6.00
Δε [1 kHz, 20° C.]:
2.7
APUQU-3-F
4.5
K1 [pN, 20° C.]:
14.6
PP-1-2V1
7.00
K3 [pN, 20° C.]:
15.9
PPGU-3-F
0.5
K3/K1 [pN, 20° C.]:
1.09
Σ
100.0
V0 [V, 20° C.]:
2.46
LTS bulk [h, −20° C.]:
1000
Mixture N—3:
Composition [%-w/w]
Physical properties
CY-3-O2
12.00
Clearing Point [° C.]:
85.2
CY-5-O2
10.5
ne [589 nm, 20° C.]:
1.5956
CCY-3-O1
6.00
Δn [589 nm, 20° C.]:
0.1120
CCY-3-O2
7.00
ε∥ [1 kHz, 20° C.]:
3.7
CCY-5-O2
5.00
ε⊥ [1 kHz, 20° C.]:
7.9
CPY-2-O2
12.00
Δε [1 kHz, 20° C.]:
−4.2
CPY-3-O2
12.00
PYP-2-3
7.5
CC-3-V1
4.00
CC-3-V
24.00
Σ
100.0
Mixture N—4:
Composition [%-w/w]
Physical properties
CC-3-V
50.00
Clearing Point [° C.]:
79.4
CC-3-V1
4.5
ne [589 nm, 20° C.]:
1.5981
CCP-V-1
13.5
Δn [589 nm, 20° C.]:
0.1094
CPGU-3-OT
6.00
ε∥ [1 kHz, 20° C.]:
8.1
PGP-2-2V
6.5
ε⊥ [1 kHz, 20° C.]:
2.9
PGU-2-F
10.00
Δε [1 kHz, 20° C.]:
5.2
PGUQU-3-F
7.00
K1 [pN, 20° C.]:
12.6
PPGU-3-F
1.00
K3 [pN, 20° C.]:
14.2
PUQU-2-F
1.5
K3/K1 [pN, 20° C.]:
1.13
Σ
100.0
V0 [V, 20° C.]:
1.64
LTS bulk [h, −20° C.]:
240
Mixture N—5:
Composition [%-w/w]
Physical properties
CC-3-V
30.00
Clearing Point [° C.]:
87
CC-3-V1
10.00
ne [589 nm, 20° C.]:
1.5829
CCH-34
2.5
Δn [589 nm, 20° C.]:
0.1019
CCP-V-1
1.5
ε∥ [1 kHz, 20° C.]:
3.5
PGIY-2-O4
4.00
ε⊥ [1 kHz, 20° C.]:
7.1
CCY-3-O2
10.00
Δε [1 kHz, 20° C.]:
−3.7
CCY-5-O2
2.00
K1 [pN, 20° C.]:
15.2
CLY-3-O2
8.00
K3 [pN, 20° C.]:
18.0
CPY-2-O2
6.00
K3/K1 [pN, 20° C.]:
1.19
CPY-3-O2
10.00
V0 [V, 20° C.]:
2.35
CY-3-O2
12.00
LTS bulk [h, −20° C.]:
0
B-2O-O5
4.00
Σ
100.0
Mixture N—6:
Composition [%-w/w]
Physical properties
CC-3-V
21.75
Clearing Point [° C.]:
91
CC-3-V1
10.45
ne [589 nm, 20° C.]:
1.5970
CPP-V-3
9.52
no [589 nm, 20° C.]:
1.4865
BCH-32
4.74
Δn [589 nm, 20° C.]:
0.1105
BCH-52
3.55
ε∥ [1 kHz, 20° C.]:
3.8
PYP-2-3
9.76
ε⊥ [1 kHz, 20° C.]:
8.1
COY-3-O1
3.19
Δε [1 kHz, 20° C.]:
−4.3
COY-3-O2
6.53
K1 [pN, 20° C.]:
15.8
COY-1V-O2
3.22
K3 [pN, 20° C.]:
19.0
CCOY-3-O2
8.74
K3/K1 [pN, 20° C.]:
1.20
CCOY-2-O2
8.89
V0 [V, 20° C.]:
2.21
CCOY-V-O2
2.67
CCOY-V-O3
2.64
CCOY-1V-O2
4.35
Σ
100.0
Mixture N—7:
Composition [%-w/w]
Physical properties
CC-3-V
29.0
Clearing Point [° C.]:
70
CC-3-V1
10.0
ne [589 nm, 20° C.]:
1.5976
CCP-V-1
12.0
no [589 nm, 20° C.]:
1.4894
CCP-V2-1
4.0
Δn [589 nm, 20° C.]:
0.1082
CCY-V-O2
8.0
ε∥ [1 kHz, 20° C.]:
3.4
COY-3-O2
2.0
ε⊥ [1 kHz, 20° C.]:
5.5
CCOY-3-O2
4.0
Δε [1 kHz, 20° C.]:
−2.2
PY-3-O2
8.0
K1 [pN, 20° C.]:
12.7
PY-V2-O2
14.0
K3 [pN, 20° C.]:
14.5
PYP-2-3
9.0
K3/K1 [pN, 20° C.]:
1.14
Σ
100.0
V0 [V, 20° C.]:
2.73
γ1 [mPa s, 20° C.]:
66
LTS bulk [h, −20° C.]:
0
Mixture N—8:
Composition [%-w/w]
Physical properties
CC-3-V
29.0
Clearing Point [° C.]:
70.5
CC-3-V1
9.0
ne [589 nm, 20° C.]:
1.5976
CCP-V-1
13.0
no [589 nm, 20° C.]:
1.4889
CCY-V-O2
10.0
Δn [589 nm, 20° C.]:
0.1087
COY-3-O2
2.0
ε∥ [1 kHz, 20° C.]:
3.5
CCOY-3-O2
6.0
ε⊥ [1 kHz, 20° C.]:
6.0
PY-3-O2
8.0
Δε [1 kHz, 20° C.]:
−2.5
PY-V2-O2
14.0
K1 [pN, 20° C.]:
12.6
PYP-2-3
9.0
K3 [pN, 20° C.]:
14.6
Σ
100.0
K3/K1 [pN, 20° C.]:
1.16
V0 [V, 20° C.]:
2.55
γ1 [mPa s, 20° C.]:
70
LTS bulk [h, −20° C.]:
96
Mixture N—9:
Composition [%-w/w]
Physical properties
CC-3-V
29.0
Clearing Point [° C.]:
81
PP-1-3
2.0
ne [589 nm, 20° C.]:
1.5909
CC-3-V1
4.0
no [589 nm, 20° C.]:
1.4840
CEY-3-O2
4.0
Δn [589 nm, 20° C.]:
0.1069
COY-3-O2
7.0
ε∥ [1 kHz, 20° C.]:
3.8
CAIY-3-O2
10.0
ε⊥ [1 kHz, 20° C.]:
8.4
PYP-2-3
17.0
Δε [1 kHz, 20° C.]:
−4.6
CCOY-2-O2
16.0
K1 [pN, 20° C.]:
14.4
CCOY-3-O2
11.0
K3 [pN, 20° C.]:
16.8
Σ
100.0
K3/K1 [pN, 20° C.]:
1.17
V0 [V, 20° C.]:
2.03
γ1 [mPa s, 20° C.]:
134
LTS bulk [h, −20° C.]:
264
Fabrication of Display Cells
Unless explicitly stated otherwise, the display cells are made with Corning AF glass of 0.7 mm thickness using 6.4 μm spacer beads and XN-1500T sealant.
For measurement of electro-optics 3 μm thick PI-free IPS cells are made of substrates commercially available from SD-tech and constructed into cells using ITO electrodes having 5 μm electrode spacing and a 3 μm electrode width.
The cells are assembled by hand and then cured using a Omnicure 2000 Mercury lamp with with 35 mW/cm2 the irradiation power is thereby measured by an Opsytec UV pad-e spectroradiometer.
Mixture Examples
Nematic LC mixtures M-1 to M-24 according to the invention are prepared from the nematic host mixtures N-1 to N-9 listed above and photoalignment additives of formula I, according to the compositions given in the following table.
c [%] of
Photoalignment
Mixture
Host
Host
additive
example
Mixture
Mixture
Compound
c [%]
M-1
N-1
99.70
RM-1
0.30
M-2
N-1
99.50
RM-1
0.50
M-3
N-1
99.00
RM-1
1.00
M-4
N-1
99.50
RM-2
0.50
M-5
N-1
99.00
RM-2
1.00
M-6
N-1
99.70
RM-3
0.30
M-7
N-1
99.50
RM-3
0.50
M-8
N-1
99.00
RM-3
1.00
M-9
N-2
99.50
RM-2
0.50
M-10
N-2
99.00
RM-2
1.00
M-11
N-3
99.50
RM-2
0.50
M-12
N-3
99.00
RM-2
1.00
M-13
N-4
99.50
RM-2
0.50
M-14
N-4
99.00
RM-2
1.00
M-15
N-5
99.70
RM-1
0.30
M-16
N-5
99.50
RM-1
0.50
M-17
N-6
99.70
RM-1
0.30
M-18
N-6
99.50
RM-1
0.50
M-19
N-7
99.70
RM-1
0.30
M-20
N-7
99.50
RM-1
0.50
M-21
N-8
99.70
RM-1
0.30
M-22
N-8
99.50
RM-1
0.50
M-23
N-9
99.70
RM-1
0.30
M-24
N-9
99.50
RM-1
0.50
Additionally comparable nematic LC mixtures CM-1 to CM-6 to the invention are prepared from the nematic host mixtures N-1 listed above and photoalignment additives according to the prior art. The compositions are given in the following table.
Comparative
c [%] of
Photoalignment
Mixture
Host
Host
additive
example
Mixture
Mixture
Compound
c [%]
CM-1
N-1
99.70
CRM-1
0.30
CM-2
N-1
99.50
CRM-1
0.50
CM-3
N-1
99.00
CRM-1
1.00
CM-4
N-1
99.70
CRM-2
0.30
CM-5
N-1
99.50
CRM-2
0.50
CM-6
N-1
99.00
CRM-2
1.00
Cell Filling and Curing
Unless explicitly stated otherwise, the selected LC mixtures are capillary filled using capillary action at room temp., annealed for 1 h at 100° C. and then irradiated at the same temperature with linearly polarised UV light (35 mW/cm2) for the given time. The cells are then cooled to room temperature. Next, the alignment quality is studied between crossed polarisers on a light box.
Curing
Host mixture
Compound
time
Example
[%]
[%]
[s]
Alignment
M-1
N-1
99.70
RM-1
0.30
300
++
M-2
N-1
99.50
RM-1
0.50
180
++
M-3
N-1
99.00
RM-1
1.00
60
++
M-6
N-1
99.70
RM-3
0.30
180
+
M-7
N-1
99.50
RM-3
0.50
120
+
M-8
N-1
99.00
RM-3
1.00
60
++
M-9
N-2
99.50
RM-2
0.50
180
++
M-10
N-2
99.00
RM-2
1.00
60
++
M-11
N-3
99.50
RM-2
0.50
180
+
M-12
N-3
99.00
RM-2
1.00
120
++
M-13
N-4
99.50
RM-2
0.50
180
+
M-14
N-4
99.00
RM-2
1.00
120
++
M-15
N-5
99.70
RM-1
0.30
300
+
M-16
N-5
99.50
RM-1
0.50
180
+
CM-2
N-1
99.50
CRM-1
0.50
120
+
CM-3
N-1
99.00
CRM-1
1.00
120
++
CM-5
N-1
99.50
CRM-2
0.50
120
++
CM-6
N-1
99.00
CRM-2
1.00
60
++
CM-7
N-1
100.00
−
−
−
−
Alignment quality: (++) excellent, (+) good, (o) acceptable, (−) poor
At least good uniform planar alignment is achieved with all mixtures despite from comparison mixture example CM-7. With mixtures comprising CRM-1 is it not possible to reach the optimum dark state level at below 1% concentration.
VHR Measurements
Unless explicitly stated otherwise, the selected LC mixtures are capillary filled using capillary action at room temp., annealed for 1 h at 100° C. and then irradiated at the same temperature with linearly polarised UV light (35 mW/cm2) from an Omnicure S2000 mercury lamp with a built in 320-500 nm filter either utilizing an additional 360 nm long pass filter (cuts off shorter wavelengths from 320-360 nm) or without such filter. The cells are then cooled to room temperature. Next, the VHR is studied using Toyo LCM-1 LC Material Characteristics Measurement System. Unless described otherwise, the measurement of the VHR is carried out as described in T. Jacob, U. Finkenzeller in “Merck Liquid Crystals—Physical Properties of Liquid Crystals”, 1997.
VHR measured at 100° C., 60 Hz and 1 V after curing without 360 nm cut off filter
Host mixture
Photoalignment compound
VHR
Example
[%]
[%]
[%]
M-1
N-1
99.70
RM-1
0.30
18.5
M-4
N-1
99.50
RM-2
0.50
23.5
VHR measured at 100° C., 60 Hz and 1 V after curing without 360 nm cut off filter
Host mixture
Photoalignment compound
VHR
Example
[%]
[%]
[%]
M-1
N-1
99.70
RM-1
0.30
92.6
M-4
N-1
99.50
RM-2
0.50
93.8
Host mixture
Photoalignment compound
Example
[%]
[%]
Alignment
CM-1
N-1
99.70
CRM-1
0.30
No alignment
CM-2
N-1
99.50
CRM-1
0.50
No alignment
CM-3
N-1
99.00
CRM-1
1.00
No alignment
CM-4
N-1
99.70
CRM-2
0.30
No alignment
CM-5
N-1
99.50
CRM-2
0.50
No alignment
CM-6
N-1
99.00
CRM-2
1.00
No alignment
As can be seen from the above-given tables the VHR of test cells in accordance with the present invention can be significantly improved by utilizing a 360 nm cut off filter while irradiating the test cells. In comparison to the test cells according to the present invention, the test cells utilizing the comparative mixtures CM-1 to CM-6 do not show any uniform alignment after curing utilizing a 360 nm cut off filter.
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17050017
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merck patent gmbh
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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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Apr 27th, 2022 09:11AM
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Apr 27th, 2022 09:11AM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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Oct 28th, 2016 12:00AM
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https://www.uspto.gov?id=US11312909-20220426
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Polymerizable compounds and the use thereof in liquid-crystal displays
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Polymerizable compounds, to processes and intermediates for the preparation thereof, liquid-crystal (LC) media comprising them, and the use of the polymerizable compounds and LC media for optical, electro-optical and electronic purposes, in particular in LC displays, especially in LC displays of the polymer sustained alignment type, or a stabilizers in LC media and LC displays.
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11312909
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1. A compound of formula I
P-Sp-A1-(Z1-A2)z-R I
wherein individual radicals, independently of each other and on each occurrence identically or differently, have the following meanings
P a polymerizable acrylate or methacrylate group,
Sp a spacer group that is optionally substituted by one or more groups P or La, or a single bond,
-A1-(Z1-A2)z is
wherein the benzene rings are optionally substituted by one or more groups L, P-Sp-, La or La-Sp-
R P-Sp-,
L F, Cl, —CN, P-Sp-, La, La-Sp-, or straight chain alkyl having 1 to 25 C atoms or branched or cyclic alkyl having 3 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by P, F, Cl or La-,
La —C(Raa)(Rbb)OH,
Raa, Rbb straight-chain alkyl with 1 to 20 C atoms, branched alkyl with 3 to 20 C atoms, or cyclic alkyl with 3 to 12 C atoms, or Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12 C atoms, wherein in Raa and Rbb one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F or Cl,
wherein the compound of formula I contains at least one group La or La-Sp-.
2. The compound according to claim 1, wherein Raa and Rbb denote straight-chain alkyl with 1 to 12 C atoms or branched alkyl with 3 to 12 C atoms, or Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12 C atoms.
3. The compound according to claim 1, wherein all groups P that are present in the compound have the same meaning.
4. The compound according to claim 1, containing a group P-Sp- of the following formulae
P—CHLa- SL1
P—(CH2)cc—O-CHLa- SL2
P—(CH2)cc—CO—O-CHLa- SL3
P—(CH2)cc—CHLa- SL4
cc is 1, 2, 3, 4, 5 or 6 and
La is as defined in claim 1.
5. The compound according to claim 1, wherein A1-(Z1-A2)z- is
wherein the benzene rings are optionally substituted by one or more groups L, P-Sp-, La or La-Sp-.
6. The compound according to claim 1, of the following subformulae:
wherein
r1, r3, r7 are independently of each other 0, 1, 2 or 3,
r2 is 0, 1, 2, 3 or 4,
r4, r5, r6 are independently of each other 0, 1 or 2,
wherein r1+r7≥1, r1+r2+r3≥1, r4+r5≥1, r1+r3+r4≥1 and at least one of L denotes La or La-Sp-, and/or
wherein the compounds contain at least one group Sp that is substituted by La.
7. A compound of the formula:
or a compound of formula I8-1 or I8-2 wherein P is replaced by Pg
Sp a spacer group that is optionally substituted by one or more groups P or La, or a single bond,
P a polymerizable acrylate or methacrylate group,
Pg is —OH, a protected hydroxy group or a masked hydroxy group,
L F, Cl, —CN, P-Sp-, La, La-Sp-, or straight chain alkyl having 1 to 25 C atoms, or branched or cyclic alkyl having 3 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by P, F, Cl or La-,
La —C(Raa)(Rbb)OH,
Raa, Rbb straight-chain alkyl with 1 to 20 C atoms, branched alkyl with 3 to 20 C atoms, or cyclic alkyl with 3 to 12 C atoms, or Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12 C atoms, wherein in Raa and Rbb one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F or Cl,
r1, r3, r7 are independently of each other 0, 1, 2 or 3,
r2 is 0, 1, 2, 3 or 4,
r4, r5, r6 are independently of each other 0, 1 or 2,
wherein R denotes H or Pg-Sp,
wherein r1+r7≥1, r1+r2+r3≥1, r4+r5≥1, r1+r3+r4≥1 and at least one of L denotes La or La-Sp-, and/or
wherein the compounds contain at least one group Sp that is substituted by La.
8. A liquid crystal (LC) medium comprising one or more compounds formula I as defined in claim 1.
9. The LC medium of claim 8, comprising
a polymerizable component A) comprising one or more compounds of formula I, and
a liquid-crystalline LC component B) comprising one or more mesogenic or liquid-crystalline compounds.
10. The LC medium of claim 9, wherein component B) comprises one or more compounds of formulae CY and/or PY:
in which
a denotes 1 or 2,
b denotes 0 or 1,
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —O—CO— or
—CO—O— in such a way that O atoms are not linked directly to one another,
Zx denotes —CH═CH—, —CH2O—, —OCH2—, —CF2O—, —OCF2—, —O—, —CH2—, —CH2CH2— or a single bond,
L1-4 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
11. The LC medium according to claim 9 wherein component B) comprises one or more compounds of the following formulae:
in which the individual radicals, on each occurrence identically or differently, each, independently of one another, have the following meaning:
RA1 alkenyl having 2 to 9 C atoms or, if at least one of the rings X, Y and Z denotes cyclohexenyl, also one of the meanings of RA2,
RA2 alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another,
Zx —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O—, or a single bond,
L1-4 each, independently of one another, H, F, Cl, OCF3, CF3, CH3, CH2F or CHF2H,
x 1 or 2,
z 0 or 1.
12. The LC medium according to claim 9, wherein component B) comprises one or more compounds of the following formula:
in which the individual radicals have the following meanings:
R3 and R4 each, independently of one another, denote alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —O—CO— or —CO—O— in such a way that O atoms are not linked directly to one another,
Zy denotes —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —COO—, —OCO—, —C2F4—, —CF═CF— or a single bond.
13. The LC medium according to claim 8, wherein the compounds of formula I are polymerized.
14. The LC medium according to claim 8, containing from 50 to 1000 ppm of one or more compounds of formula I.
15. A process of preparing an LC medium according to claim 8, comprising mixing one or more mesogenic or liquid-crystalline compounds, with one or more compounds of formula I and optionally with further liquid-crystalline compounds and/or additives.
16. An LC display comprising one or more compounds of formula I comprising an LC medium as defined in claim 8.
17. The LC display of claim 16, which is a VA, IPS, UB-FFS, TN, OCB, FFS or poli-VA display.
18. The LC display of claim 16, which is a PSA display.
19. The LC display of claim 18, which is a PS-VA, PS-OCB, PS-IPS, PS-FFS, PS-UB-FFS, PS-poli-VA or PS-TN display.
20. The LC display of claim 18, comprising two substrates, at least one which is transparent to light, an electrode provided on each substrate or two electrodes provided on only one of the substrates, and located between the substrates a layer of an LC medium, comprising one or more compounds of formula I and optionally one or more additional compounds that are polymerizable, wherein the compounds of formula I and the additional polymerizable compounds are polymerized between the substrates of the display.
21. A process for the production of an LC display according to claim 20, comprising providing an LC medium, comprising one or more compounds of formula I and optionally one or more additional compounds that are polymerizable, between the substrates of the display, and polymerizing the compounds of formula I and the additional polymerizable compounds.
22. A compound of the following formulae
Sp a spacer group that is optionally substituted by one or more groups P or La, or a single bond,
P is a polymerizable group,
and at least one group Pg-Sp is a spacer group substituted by La,
L F, Cl, —CN, P-Sp-, La, La-Sp-, or straight chain alkyl having 1 to 25 C atoms or branched or cyclic alkyl having 3 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by P, F, Cl or La,
La —C(Raa)(Rbb)OH,
Raa, Rbb straight-chain alkyl with 1 to 20 C atoms, branched alkyl with 3 to 20 C atoms, or cyclic alkyl with 3 to 12 C atoms, or Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12 C atoms, wherein in Raa and Rbb one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F or Cl,
r1, r3, r7 are independently of each other 0, 1, 2 or 3,
r2 is 0, 1, 2, 3 or 4,
r4, r5, r6 are independently of each other 0, 1 or 2,
wherein r1+r7≥1, r1+r2+r3≥1, r4+r5≥1, r1+r3+r4≥1,
wherein R denotes H or Pg-Sp, and Pg denotes OH, a protected hydroxyl group or a masked hydroxyl group, wherein the compounds contain at least one group La or La-Sp.
23. A process for preparing a compound of formula I of claim 1, by esterification of a compound
wherein P is replaced by Pg
Sp a spacer group that is optionally substituted by one or more groups P or La, or a single bond,
P is a polymerizable group,
L F, Cl, —CN, P-Sp-, La, La-Sp-, or straight chain alkyl having 1 to 25 carbon atoms or branched or cyclic alkyl having 3 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by P, F, Cl or La-,
La —C(Raa)(Rbb)OH,
Raa, Rbb straight-chain alkyl with 1 to 20 C atoms, branched alkyl with 3 to 20 C atoms, or cyclic alkyl with 3 to 12 C atoms, or Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12 C atoms, wherein in Raa and Rbb one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F or Cl,
r1, r3, r7 are independently of each other 0, 1, 2 or 3,
r2 is 0, 1, 2, 3 or 4,
r4, r5, r6 are independently of each other 0, 1 or 2,
wherein r1+r7≥1, r1+r2+r3≥1, r4+r5≥1, r1+r3+r4≥1,
wherein R denotes H or Pg-Sp, and
wherein Pg denotes OH, using corresponding acids, acid derivatives, or halogenated compounds containing a group P, in the presence of a dehydrating reagent, and the compounds 111-119 contain at least one group La or La-Sp.
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23
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The present invention relates to polymerizable compounds, to processes and intermediates for the preparation thereof, to liquid-crystal (LC) media comprising them, and to the use of the polymerizable compounds and LC media for optical, electro-optical and electronic purposes, in particular in LC displays, especially in LC displays of the polymer sustained alignment type or as stabilizers in LC media and LC displays.
BACKGROUND OF THE INVENTION
One of the liquid-crystal display (LCD) modes used at present is the TN (“twisted nematic”) mode. However, TN LCDs have the disadvantage of a strong viewing-angle dependence of the contrast.
In addition, so-called VA (“vertically aligned”) displays are known which have a broader viewing angle. The LC cell of a VA display contains a layer of an LC medium between two transparent electrodes, where the LC medium usually has a negative dielectric anisotropy. In the switched-off state, the molecules of the LC layer are aligned perpendicular to the electrode surfaces (homeotropically) or have a tilted homeotropic alignment. On application of an electrical voltage to the two electrodes, a realignment of the LC molecules parallel to the electrode surfaces takes place.
Furthermore, OCB (“optically compensated bend”) displays are known which are based on a birefringence effect and have an LC layer with a so-called “bend” alignment and usually positive dielectric anisotropy. On application of an electrical voltage, a realignment of the LC molecules perpendicular to the electrode surfaces takes place. In addition, OCB displays normally contain one or more birefringent optical retardation films in order to prevent undesired transparency to light of the bend cell in the dark state. OCB displays have a broader viewing angle and shorter response times compared with TN displays.
Also known are so-called IPS (“in-plane switching”) displays, which contain an LC layer between two substrates, where the two electrodes are arranged on only one of the two substrates and preferably have intermeshed, comb-shaped structures. On application of a voltage to the electrodes, an electric field which has a significant component parallel to the LC layer is thereby generated between them. This causes realignment of the LC molecules in the layer plane.
Furthermore, so-called FFS (“fringe-field switching”) displays have been reported (see, inter alia, S. H. Jung et al., Jpn. J. Appl. Phys., Volume 43, No. 3, 2004, 1028), which contain two electrodes on the same substrate, one of which structured in a comb-shaped manner and the other is unstructured. A strong, so-called “fringe field” is thereby generated, i.e. a strong electric field close to the edge of the electrodes, and, throughout the cell, an electric field which has both a strong vertical component and also a strong horizontal component. FFS displays have a low viewing-angle dependence of the contrast. FFS displays usually contain an LC medium with positive dielectric anisotropy, and an alignment layer, usually of polyimide, which provides planar alignment to the molecules of the LC medium.
FFS displays can be operated as active-matrix or passive-matrix displays. In the case of active-matrix displays, individual pixels are usually addressed by integrated, non-linear active elements, such as, for example, transistors (for example thin-film transistors (“TFTs”)), while in the case of passive-matrix displays, individual pixels are usually addressed by the multiplex method, as known from the prior art.
Furthermore, FFS displays have been disclosed (see S. H. Lee et al., Appl. Phys. Lett. 73(20), 1998, 2882-2883 and S. H. Lee et al., Liquid Crystals 39(9), 2012, 1141-1148), which have similar electrode design and layer thickness as FFS displays, but comprise a layer of an LC medium with negative dielectric anisotropy instead of an LC medium with positive dielectric anisotropy. The LC medium with negative dielectric ansiotropy shows a more favorable director orientation that has less tilt and more twist orientation compared to the LC medium with positive dielectric anisotropy, as a result of which these displays have a higher transmission. The displays further comprise an alignment layer, preferably of polyimide provided on at least one of the substrates that is in contact with the LC medium and induces planar alignment of the LC molecules of the LC medium. These displays are also known as “Ultra Brightness FFS (UB-FFS)” mode displays. These displays require an LC medium with high reliability.
The term “reliability” as used hereinafter means the quality of the performance of the display during time and with different stress loads, such as light load, temperature, humidity, voltage, and comprises display effects such as image sticking (area and line image sticking), mura (i.e., clouding), yogore (i.e., stains) etc. which are known to the skilled person in the field of LC displays. As a standard parameter for categorizing the reliability usually the voltage holding ration (VHR) value is used, which is a measure for maintaining a constant electrical voltage in a test display. The higher the VHR value, the better the reliability of the LC medium.
In VA displays of the more recent type, uniform alignment of the LC molecules is restricted to a plurality of relatively small domains within the LC cell. Disclinations may exist between these domains, also known as tilt domains. VA displays having tilt domains have, compared with conventional VA displays, a greater viewing-angle independence of the contrast and the grey shades. In addition, displays of this type are simpler to produce since additional treatment of the electrode surface for uniform alignment of the molecules in the switched-on state, such as, for example, by rubbing, is no longer necessary. Instead, the preferential direction of the tilt or pretilt angle is controlled by a special design of the electrodes.
In so-called MVA (“multidomain vertical alignment”) displays, this is usually achieved by the electrodes having protrusions which cause a local pretilt. As a consequence, the LC molecules are aligned parallel to the electrode surfaces in different directions in different, defined regions of the cell on application of a voltage. “Controlled” switching is thereby achieved, and the formation of interfering disclination lines is prevented. Although this arrangement improves the viewing angle of the display, it results, however, in a reduction in its transparency to light. A further development of MVA uses protrusions on only one electrode side, while the opposite electrode has slits, which improves the transparency to light. The slitted electrodes generate an inhomogeneous electric field in the LC cell on application of a voltage, meaning that controlled switching is still achieved. For further improvement of the transparency to light, the separations between the slits and protrusions can be increased, but this in turn results in a lengthening of the response times. In so-called PVA (“patterned VA”) displays, protrusions are rendered completely superfluous in that both electrodes are structured by means of slits on the opposite sides, which results in increased contrast and improved transparency to light, but is technologically difficult and makes the display more sensitive to mechanical influences (“tapping”, etc.). For many applications, such as, for example, monitors and especially TV screens, however, a shortening of the response times and an improvement in the contrast and luminance (transmission) of the display are demanded.
A further development are displays of the so-called PS (“polymer sustained”) or PSA (“polymer sustained alignment”) type, for which the term “polymer stabilized” is also occasionally used. In these, a small amount (for example 0.3% by weight, typically <1% by weight) of one or more polymerizable, compound(s), preferably polymerizable monomeric compound(s), is added to the LC medium and, after filling the LC medium into the display, is polymerized or crosslinked in situ, usually by UV photopolymerization, optionally while a voltage is applied to the electrodes of the display. The polymerization is carried out at a temperature where the LC medium exhibits a liquid crystal phase, usually at room temperature. The addition of polymerizable mesogenic or liquid-crystalline compounds, also known as reactive mesogens or “RMs”, to the LC mixture has proven particularly suitable.
Unless indicated otherwise, the term “PSA” is used hereinafter when referring to displays of the polymer sustained alignment type in general, and the term “PS” is used when referring to specific display modes, like PS-VA, PS-TN and the like.
Also, unless indicated otherwise, the term “RM” is used hereinafter when referring to a polymerizable mesogenic or liquid-crystalline compound.
In the meantime, the PS(A) principle is being used in various conventional LC display modes. Thus, for example, PS-VA, PS-OCB, PS-IPS, PS-FFS, PS-UB-FFS and PS-TN displays are known. The polymerization of the RMs preferably takes place with an applied voltage in the case of PS-VA and PS-OCB displays, and with or without, preferably without, an applied voltage in the case of PS-IPS displays. As can be demonstrated in test cells, the PS(A) method results in a pretilt in the cell. In the case of PS-OCB displays, for example, it is possible for the bend structure to be stabilized so that an offset voltage is unnecessary or can be reduced. In the case of PS-VA displays, the pretilt has a positive effect on response times. For PS-VA displays, a standard MVA or PVA pixel and electrode layout can be used. In addition, however, it is also possible, for example, to manage with only one structured electrode side and no protrusions, which significantly simplifies production and at the same time results in very good contrast at the same time as very good transparency to light.
Furthermore, the so-called posi-VA displays (“positive VA”) have proven to be a particularly suitable mode. Like in classical VA displays, the initial orientation of the LC molecules in posi-VA displays is homeotropic, i.e. substantially perpendicular to the substrates, in the initial state when no voltage is applied. However, in contrast to classical VA displays, in posi-VA displays LC media with positive dielectric anisotropy are used. Like in the usually used IPS displays, the two electrodes in posi-VA displays are arranged on only one of the two substrates, and preferably exhibit intermeshed and comb-shaped (interdigital) structures. By application of a voltage to the interdigital electrodes, which create an electrical field that is substantially parallel to the layer of the LC medium, the LC molecules are transferred into an orientation that is substantially parallel to the substrates. In posi-VA displays polymer stabilization, by addition of RMs to the LC medium which are polymerized in the display, has also proven to be advantageous, as a significant reduction of the switching times could thereby be realized.
PS-VA displays are described, for example, in EP 1 170 626 A2, U.S. Pat. Nos. 6,861,107, 7,169,449, US 2004/0191428 A1, US 2006/0066793 A1 and US 2006/0103804 A1. PS-OCB displays are described, for example, in T.-J-Chen et al., Jpn. J. Appl. Phys. 45, 2006, 2702-2704 and S. H. Kim, L.-C-Chien, Jpn. J. Appl. Phys. 43, 2004, 7643-7647. PS-IPS displays are described, for example, in U.S. Pat. No. 6,177,972 and Appl. Phys. Lett. 1999, 75(21), 3264. PS-TN displays are described, for example, in Optics Express 2004, 12(7), 1221.
Like the conventional LC displays described above, PSA displays can be operated as active-matrix or passive-matrix displays. In the case of active-matrix displays, individual pixels are usually addressed by integrated, non-linear active elements, such as, for example, transistors (for example thin-film transistors (“TFTs”)), while in the case of passive-matrix displays, individual pixels are usually addressed by the multiplex method, as known from the prior art.
The PSA display may also comprise an alignment layer on one or both of the substrates forming the display cell. The alignment layer is usually applied on the electrodes (where such electrodes are present) such that it is in contact with the LC medium and induces initial alignment of the LC molecules. The alignment layer may comprise or consist of, for example, a polyimide, which may also be rubbed, or may be prepared by a photoalignment method.
In particular for monitor and especially TV applications, optimisation of the response times, but also of the contrast and luminance (thus also transmission) of the LC display continues to be demanded. The PSA method can provide significant advantages here. In particular in the case of PS-VA, PS-IPS, PS-FFS and PS-posi-VA displays, a shortening of the response times, which correlate with a measurable pretilt in test cells, can be achieved without significant adverse effects on other parameters.
Prior art has suggested biphenyl diacrylates or dimethacrylates, which are optionally fluorinated as RMs for use in PSA displays
However, the problem arises that not all combinations consisting of an LC mixture and one or more RMs are suitable for use in PSA displays because, for example, an inadequate tilt or none at all becomes established or since, for example, the so-called “voltage holding ratio” (VHR or HR) is inadequate for TFT display applications. In addition, it has been found that, on use in PSA displays, the LC mixtures and RMs known from the prior art do still have some disadvantages. Thus, not every known RM which is soluble in LC mixtures is suitable for use in PSA displays. In addition, it is often difficult to find a suitable selection criterion for the RM besides direct measurement of the pretilt in the PSA display. The choice of suitable RMs becomes even smaller if polymerization by means of UV light without the addition of photoinitiators is desired, which may be advantageous for certain applications.
In addition, the selected combination of LC host mixture/RM should have the lowest possible rotational viscosity and the best possible electrical properties. In particular, it should have the highest possible VHR. In PSA displays, a high VHR after irradiation with UV light is particularly necessary since UV exposure is a requisite part of the display production process, but also occurs as normal exposure during operation of the finished display.
In particular, it would be desirable to have available novel materials for PSA displays which produce a particularly small pretilt angle. Preferred materials here are those which produce a lower pretilt angle during polymerization for the same exposure time than the materials known to date, and/or through the use of which the (higher) pretilt angle that can be achieved with known materials can already be achieved after a shorter exposure time. The production time (“tact time”) of the display could thus be shortened and the costs of the production process reduced.
A further problem in the production of PSA displays is the presence or removal of residual amounts of unpolymerized RMs, in particular after the polymerization step for production of the pretilt angle in the display. For example, unreacted RMs of this type may adversely affect the properties of the display by, for example, polymerizing in an uncontrolled manner during operation after finishing of the display.
Thus, the PSA displays known from the prior art often exhibit the undesired effect of so-called “image sticking” or “image burn”, i.e. the image produced in the LC display by temporary addressing of individual pixels still remains visible even after the electric field in these pixels has been switched off or after other pixels have been addressed.
This “image sticking” can occur on the one hand if LC host mixtures having a low VHR are used. The UV component of daylight or the backlighting can cause undesired decomposition reactions of the LC molecules therein and thus initiate the production of ionic or free-radical impurities. These may accumulate, in particular, at the electrodes or the alignment layers, where they may reduce the effective applied voltage. This effect can also be observed in conventional LC displays without a polymer component.
In addition, an additional “image sticking” effect caused by the presence of unpolymerized RMs is often observed in PSA displays. Uncontrolled polymerization of the residual RMs is initiated here by UV light from the environment or by the backlighting. In the switched display areas, this changes the tilt angle after a number of addressing cycles. As a result, a change in transmission in the switched areas may occur, while it remains unchanged in the unswitched areas.
It is therefore desirable for the polymerization of the RMs to proceed as completely as possible during production of the PSA display and for the presence of unpolymerized RMs in the display to be excluded as far as possible or reduced to a minimum. Thus, RMs and LC mixtures are required which enable or support highly effective and complete polymerization of the RMs. In addition, controlled reaction of the residual RM amounts would be desirable. This would be simpler if the RM polymerized more rapidly and effectively than the compounds known to date.
A further problem that has been observed in the operation of PSA displays is the stability of the pretilt angle. Thus, it was observed that the pretilt angle, which was generated during display manufacture by polymerizing the RM as described above, does not remain constant but can deteriorate after the display was subjected to voltage stress during its operation. This can negatively affect the display performance, e.g. by increasing the black state transmission and hence lowering the contrast.
Another problem to be solved is that the RMs of prior art do often have high melting points, and do only show limited solubility in many currently common LC mixtures, and therefore frequently tend to spontaneously crystallize out of the mixture. In addition, the risk of spontaneous polymerization prevents the LC host mixture being warmed in order to dissolve the polymerizable component, meaning that the best possible solubility even at room temperature is necessary. In addition, there is a risk of separation, for example on introduction of the LC medium into the LC display (chromatography effect), which may greatly impair the homogeneity of the display. This is further increased by the fact that the LC media are usually introduced at low temperatures in order to reduce the risk of spontaneous polymerization (see above), which in turn has an adverse effect on the solubility.
Another problem observed in prior art is that the use of conventional LC media in LC displays, including but not limited to displays of the PSA type, often leads to the occurrence of mura in the display, especially when the LC medium is filled in the display cell manufactured using the one drop filling (ODF) method. This phenomenon is also known as “ODF mura”. It is therefore desirable to provide LC media which lead to reduced ODF mura.
Another problem observed in prior art is that LC media for use in PSA displays, including but not limited to displays of the PSA type, do often exhibit high viscosities and, as a consequence, high switching times. In order to reduce the viscosity and switching time of the LC medium, it has been suggested in prior art to add LC compounds with an alkenyl group. However, it was observed that LC media containing alkenyl compounds often show a decrease of the reliability and stability, and a decrease of the VHR especially after exposure to UV radiation. Especially for use in PSA displays this is a considerable disadvantage, because the photo-polymerization of the RMs in the PSA display is usually carried out by exposure to UV radiation, which may cause a VHR drop in the LC medium.
There is thus still a great demand for PSA displays and LC media and polymerizable compounds for use in such displays, which do not show the drawbacks as described above, or only do so to a small extent, and have improved properties.
In particular, there is a great demand for PSA displays, and LC media and polymerizable compounds for use in such PSA displays, which enable a high specific resistance at the same time as a large working-temperature range, short response times, even at low temperatures, and a low threshold voltage, a low pretilt angle, a multiplicity of grey shades, high contrast and a broad viewing angle, have high reliability and high values for the “voltage holding ratio” (VHR) after UV exposure, and, in case of the polymerizable compounds, have low melting points and a high solubility in the LC host mixtures. In PSA displays for mobile applications, it is especially desired to have available LC media that show low threshold voltage and high birefringence.
The invention provides novel suitable materials, in particular RMs and LC media comprising the same, for use in PSA displays, which do not have the disadvantages indicated above or do so to a reduced extent.
In particular, the invention provides RMs, and LC media comprising them, for use in PSA displays, which enable very high specific resistance values, high VHR values, high reliability, low threshold voltages, short response times, high birefringence, show good UV absorption especially at longer wavelengths, enable quick and complete polymerization of the RMs, allow the generation of a low pretilt angle as quickly as possible, enable a high stability of the pretilt even after longer time and/or after UV exposure, reduce or prevent the occurrence of “image sticking” and “ODF mura” in the display, and in case of the RMs polymerize as rapidly and completely as possible and show a high solubility in the LC media which are typically used as host mixtures in PSA displays.
The invention further provides novel RMs, in particular for optical, electro-optical and electronic applications, and of suitable processes and intermediates for the preparation thereof.
In particular, it has been found, surprisingly, that, the use of compounds of formula I as described and claimed hereinafter in LC media allows achieving the advantageous effects as mentioned above. These compounds are characterized in that they contain a mesogenic core with one or more polymerizable reactive groups and one or more tertiary hydroxy substituents attached thereto.
It was surprisingly found that the use of these compounds, and of LC media comprising them, in PSA displays facilitates a quick and complete UV-photopolymerization reaction in particular at longer UV wavelengths in the range from 300-380 nm, preferably from 320 to 360 nm, even without the addition of photoinitiator, leads to a fast generation of a large and stable pretilt angle, reduces image sticking and ODF mura in the display, leads to a high reliability and a high VHR value after UV photopolymerization, especially in case of LC host mixtures containing LC compounds with an alkenyl group, and enables to achieve fast response times, a low threshold voltage and a high birefringence.
In addition, the compounds of formula I have low melting points, good solubility in a wide range of LC media, especially in commercially available LC host mixtures for PSA use, and a low tendency to crystallization. Besides, they show good absorption at longer UV wavelengths, in particular in the range from 300-380 nm, preferably from 320 to 360 nm, and enable a quick and complete polymerization with small amounts of residual, unreacted monomers in the cell.
The compounds of formula I have not been disclosed in prior art so far. Other compounds with tertiary hydroxy groups have been described in prior art for use as radical scavengers, for example in P. M. Cullis, S. Langman, I. D. Podmore and M. C. R. Symons, J. Chem. Sci. Trans. 1990, 86, 3267. Therefore, it was surprising that compounds comprising a tertiary hydroxy group as as disclosed and claimed hereinafter can be used as Polymerizable monomers for quick and complete UV photopolymerization in LC media and generation of a pretilt angle in PSA displays.
Another aspect of the present invention is related to the use of the compounds of formula I as disclosed and claimed hereinafter as stabilizers for LC media and LC displays. Thus, it was observed that in LC media as used in prior art, often do not have a sufficiently high reliability.
The term “reliability” as used hereinafter means the quality of the performance of the display during time and with different stress loads, such as light load, temperature, humidity, or voltage which cause display defects such as image sticking (area and line image sticking), mura, yogore etc. and which are known to the skilled person in the field of LC displays. As a standard parameter for categorizing the reliability usually the voltage holding ration (VHR) value is used, which is a measure for maintaining a constant electrical voltage in a test display. The higher the VHR value, the better the reliability of the medium.
For example, in case of UB-FFS displays using LC media with negative dielectric anisotropy, the reduced reliability can be explained by an interaction of the LC molecules with the polyimide of the alignment layer, as a result of which ions are extracted from the polyimide alignment layer, and wherein LC molecules with negative dielectric anisotropy do more effectively extract such ions.
This results in new requirements for LC media to be used in UB-FFS displays. In particular, the LC medium has to show a high reliability and a high VHR value after UV exposure. Further requirements are a high specific resistance, a large working-temperature range, short response times even at low temperatures, a low threshold voltage, a multiplicity of grey levels, high contrast and a broad viewing angle, and reduced image sticking.
Another problem observed in prior art is that LC media for use in displays, including but not limited to UB-FFS displays, do often exhibit high viscosities and, as a consequence, high switching times. In order to reduce the viscosity and switching time of the LC medium, it has been suggested in prior art to add LC compounds with an alkenyl group. However, it was observed that LC media containing alkenyl compounds often show a decrease of the reliability and stability, and a decrease of the VHR especially after exposure to UV radiation but also to visible light from the backlight of a display, that usually does not emit UV light.
In order to reduce the decrease of the reliability and stability, the use of stabilizers was proposed, such as for example compounds of the HALS-(hindered amine light stabilizer) type, as disclosed in e.g. EP 2 514 800 B1 and WO 2009/129911 A1. A typical example is Tinuvin 770, a compound of the formula
Nevertheless, these LC mixtures can still exhibit insufficient reliability during the operation of a display, e.g. upon irradiation with the typical CCFL-(Cold Cathode Fluorescent Lamp) backlight.
A different class of compound used for the stabilization of liquid crystals are antioxidants derived from phenol, such as for example the compound
as described in DE 19539141 A1. Such stabilizers can be used to stabilize LC mixtures against heat or the influence of oxygen but typically do not show advantages under light stress.
Because of the complex modes of action of the different kinds of stabilizers and minute effects in a display, where the liquid crystal, a complex mixture of many different types of compounds itself, interacts with different kinds of species, including the polyimide, it is a challenging task also for the skilled person to choose the right stabilizer in order to identify the best material combination. Hence, there is still great demand for new types of stabilizers with different properties in order to broaden the range of applicable materials.
The present invention therefore also provides a process for providing improved LC media for use in LC displays, in particular in VA-, IPS- or UB-FFS displays, which do not exhibit the disadvantages described above or only do so to a small extent and have improved properties. A further object of the invention is to provide LC displays with good transmission, high reliability, high VHR value especially after backlight exposure, a high specific resistance, a large working-temperature range, short response times even at low temperatures, a low threshold voltage, a multiplicity of grey levels, high contrast and a broad viewing angle, and reduced image sticking.
The present invention provides a process for the stabilization of LC mixtures for the use in LC displays, in particular in VA-, IPS- or UB-FFS displays comprising an LC medium with negative dielectric anisotropy as described and claimed hereinafter. In particular, the inventors of the present invention have found that the above objects can be achieved by using an LC medium comprising one or more compounds of formula I as disclosed and claimed hereinafter as stabilizer, and preferably comprising one or more alkenyl compounds, in a VA-, IPS or UB-FFS display. It has also been found that when using such stabilizers in an LC medium for use in an UB-FFS display, surprisingly the reliability and the VHR value after backlight load are higher, compared to an LC medium without a stabilizer according to the present invention.
As described above, the compounds according to the present invention are also suitable for use as RMs in PSA display modes like for example PS-VA. Surprisingly it was found that such compounds, which contain one or more polymerizable groups, are, quite contrary to being harmful in terms of reliability of the LC, also suitable to stabilize LC mixtures under light stress.
Also, the use of an LC medium comprising a stabilizer as described hereinafter allows to exploit the known advantages of alkenyl-containing LC media, like reduced viscosity and faster switching time, and at the same time leads to improved reliability and high VHR value especially after backlight exposure.
SUMMARY OF THE INVENTION
The invention relates to compounds of formula I
P-Sp-A1-(Z1-A2)z-R I
wherein the individual radicals, independently of each other and on each occurrence identically or differently, have the following meanings
P a polymerizable group,
Sp a spacer group that is optionally substituted by one or more groups P or La, or a single bond,
A1, A2 an alicyclic, heterocyclic, aromatic or heteroaromatic group with 4 to 30 ring atoms, which may also contain fused rings, and is optionally substituted by one or more groups L or R,
Z1 —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O—, —OCH2—, —CH2O—, —SCH2—, —CH2S—, —CF2O—, —OCF2—, —CF2S—, —SCF2—, —(CH2)n1—, —CF2CH2—, —CH2CF2—, —(CF2)n1—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CC—, —CH═CH—CO—O—, —O—CO—CH═CH—, —CH2—CH2—CO—O—, —O—CO—CH2—CH2—, —C(R0)(R00)—, or a single bond,
R0, R00 H or alkyl having 1 to 12 C atoms,
R H, L, P-Sp- or La-Sp-,
L F, Cl, —CN, P-Sp-, La, La-Sp-, or straight chain, branched or cyclic alkyl having 1 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by P, F, Cl or La,
La —C(Raa)(Rbb)OH,
Raa, Rbb straight-chain alkyl with 1 to 20 C atoms, branched alkyl with 3 to 20 C atoms, or cyclic alkyl with 3 to 12, preferably 4 to 6, C atoms, or Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12, preferably 4 to 6, C atoms, wherein in all aforementioned groups one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F or Cl,
z 0, 1, 2 or 3,
n1 1, 2, 3 or 4,
characterized in that the compounds contain at least one group La or La-Sp-.
The invention further relates to the use of compounds of formula I as polymerizable compounds or RMs in LC media and LC displays, especially in the LC medium, active layer or alignment layer of an LC display, wherein the LC displays are preferably PSA displays.
The invention further relates to the use of compounds of formula I as stabilizers in LC media and LC displays, especially in the LC medium, active layer or alignment layer of an LC display.
The invention further relates to methods for preparing compounds of formula I, and to novel intermediates used or obtained in these methods.
The invention furthermore relates to an LC medium comprising one or more compounds of formula I.
The invention furthermore relates to an LC medium comprising one or more stabilizers, at least one of which is a compound of formula I.
The invention furthermore relates to an LC medium comprising one or more polymerizable compounds, at least one of which is a compound of formula I.
The invention furthermore relates to an LC medium comprising
a polymerizable component A) comprising, preferably consisting of, one or more polymerizable compounds, at least one of which is a compound of formula I, and
a liquid-crystalline component B), hereinafter also referred to as “LC host mixture”, comprising, preferably consisting of, one or more mesogenic or liquid-crystalline compounds.
The liquid-crystalline component B) of an LC medium according to the present invention is hereinafter also referred to as “LC host mixture”, and preferably comprises one or more, preferably at least two mesogenic or LC compounds selected from low-molecular-weight compounds which are unpolymerizable.
The invention furthermore relates to an LC medium as described above and below, wherein the LC host mixture or component B) comprises at least one mesogenic or LC compound comprising an alkenyl group.
The invention furthermore relates to an LC medium or LC display as described above, wherein the compounds of formula I, or the polymerizable compounds of component A), are polymerized.
The invention furthermore relates to a process for preparing an LC medium as described above and below, comprising the steps of mixing one or more mesogenic or LC compounds, or an LC host mixture or LC component B) as described above and below, with one or more compounds of formula I, and optionally with further LC compounds and/or additives.
The invention furthermore relates to the use of compounds of formula I and LC media according to the invention in PSA displays, in particular the use in PSA displays containing an LC medium, for the production of a tilt angle in the LC medium by in-situ polymerization of the compound(s) of the formula I in the PSA display, preferably in an electric or magnetic field.
The invention furthermore relates to an LC display comprising one or more compounds of formula I or an LC medium according to the invention, in particular a PSA display, particularly preferably a PS-VA, PS-OCB, PS-IPS, PS-FFS, PS-UB-FFS, PS-posi-VA or PS-TN display.
The invention furthermore relates to an LC display comprising a polymer obtainable by polymerization of one or more compounds of formula I or of a polymerizable component A) as described above, or comprising an LC medium according to the invention, which is preferably a PSA display, very preferably a PS-VA, PS-OCB, PS-IPS, PS-FFS, PS-UB-FFS, PS-posi-VA or PS-TN display.
The invention furthermore relates to an LC display of the PSA type comprising two substrates, at least one which is transparent to light, an electrode provided on each substrate or two electrodes provided on only one of the substrates, and located between the substrates a layer of an LC medium that comprises one or more polymerizable compounds and an LC component as described above and below, wherein the polymerizable compounds are polymerized between the substrates of the display.
The invention furthermore relates to a process for manufacturing an LC display as described above and below, comprising the steps of filling or otherwise providing an LC medium, which comprises one or more polymerizable compounds as described above and below, between the substrates of the display, and polymerizing the polymerizable compounds.
The PSA displays according to the invention have two electrodes, preferably in the form of transparent layers, which are applied to one or both of the substrates. In some displays, for example in PS-VA, PS-OCB or PS-TN displays, one electrode is applied to each of the two substrates. In other displays, for example in PS-posi-VA, PS-IPS or PS-FFS or PS-UB-FFS displays, both electrodes are applied to only one of the two substrates.
In a preferred embodiment the polymerizable component is polymerized in the LC display while a voltage is applied to the electrodes of the display.
The polymerizable compounds of the polymerizable component are preferably polymerized by photo-polymerization, very preferably by UV photo-polymerization.
The invention furthermore relates to the use of compounds of formula I and LC media according to the invention as stabilizer in LC displays, in particular the use in LC displays containing an LC medium, for stabilising the LC medium against unwanted chemical reactions or degradation caused by ionic impurities and/or oxygen and/or humidity.
The invention furthermore relates to an LC display comprising one or more compounds of formula I as stabilizer, or an LC medium according to the invention, in particular a VA, IPS or UB-FFS display, or a TN, OCB, FFS or posi-VA display.
DETAILED DESCRIPTION OF THE INVENTION
Unless stated otherwise, the term “ultraviolet (UV) light” means light in the wavelength region of 310-400 nm of the electromagnetic spectrum.
Unless stated otherwise, the compounds of formula I are preferably selected from achiral compounds.
As used herein, the terms “active layer” and “switchable layer” mean a layer in an electrooptical display, for example an LC display, that comprises one or more molecules having structural and optical anisotropy, like for example LC molecules, which change their orientation upon an external stimulus like an electric or magnetic field, resulting in a change of the transmission of the layer for polarized or unpolarized light.
As used herein, the terms “tilt” and “tilt angle” will be understood to mean a tilted alignment of the LC molecules of an LC medium relative to the surfaces of the cell in an LC display (here preferably a PSA display). The tilt angle here denotes the average angle (<90°) between the longitudinal molecular axes of the LC molecules (LC director) and the surface of the plane-parallel outer plates which form the LC cell. A low value for the tilt angle (i.e. a large deviation from the 90° angle) corresponds to a large tilt here. A suitable method for measurement of the tilt angle is given in the examples. Unless indicated otherwise, tilt angle values disclosed above and below relate to this measurement method.
As used herein, the terms “reactive mesogen” and “RM” will be understood to mean a compound containing a mesogenic or liquid crystalline skeleton, and one or more functional groups attached thereto which are suitable for polymerization and are also referred to as “polymerizable group” or “P”.
Unless stated otherwise, the term “polymerizable compound” as used herein will be understood to mean a polymerizable monomeric compound.
As used herein, the term “low-molecular-weight compound” will be understood to mean to a compound that is monomeric and/or is not prepared by a polymerization reaction, as opposed to a “polymeric compound” or a “polymer”.
As used herein, the term “unpolymerizable compound” will be understood to mean a compound that does not contain a functional group that is suitable for polymerization under the conditions usually applied for the polymerization of the RMs.
The term “mesogenic group” as used herein is known to the person skilled in the art and described in the literature, and means a group which, due to the anisotropy of its attracting and repelling interactions, essentially contributes to causing a liquid-crystal (LC) phase in low-molecular-weight or polymeric substances. Compounds containing mesogenic groups (mesogenic compounds) do not necessarily have to have an LC phase themselves. It is also possible for mesogenic compounds to exhibit LC phase behaviour only after mixing with other compounds and/or after polymerization. Typical mesogenic groups are, for example, rigid rod- or disc-shaped units. An overview of the terms and definitions used in connection with mesogenic or LC compounds is given in Pure Appl. Chem. 2001, 73(5), 888 and C. Tschierske, G. PeIzl, S. Diele, Angew. Chem. 2004, 116, 6340-6368.
The term “spacer group”, hereinafter also referred to as “Sp”, as used herein is known to the person skilled in the art and is described in the literature, see, for example, Pure Appl. Chem. 2001, 73(5), 888 and C. Tschierske, G. PeIzl, S. Diele, Angew. Chem. 2004, 116, 6340-6368. As used herein, the terms “spacer group” or “spacer” mean a flexible group, for example an alkylene group, which connects the mesogenic group and the polymerizable group(s) in a polymerizable mesogenic compound.
Above and below,
denote a trans-1,4-cyclohexylene ring, and
denote a 1,4-phenylene ring.
In a group
the single bond shown between the two ring atoms can be attached to any free position of the benzene ring.
Above and below “organic group” denotes a carbon or hydrocarbon group.
“Carbon group” denotes a mono- or polyvalent organic group containing at least one carbon atom, where this either contains no further atoms (such as, for example, —C≡C—) or optionally contains one or more further atoms, such as, for example, N, O, S, B, P, Si, Se, As, Te or Ge (for example carbonyl, etc.). The term “hydrocarbon group” denotes a carbon group which additionally contains one or more H atoms and optionally one or more heteroatoms, such as, for example, N, O, S, B, P, Si, Se, As, Te or Ge.
“Halogen” denotes F, Cl, Br or I.
—CO—, —C(═O)— and —C(O)— denote a carbonyl group, i.e.
“O.” denotes an oxygen free radical.
A carbon or hydrocarbon group can be a saturated or unsaturated group. Unsaturated groups are, for example, aryl, alkenyl or alkynyl groups. A carbon or hydrocarbon radical having more than 3 C atoms can be straight-chain, branched and/or cyclic and may also contain spiro links or condensed rings.
The terms “alkyl”, “aryl”, “heteroaryl”, etc., also encompass polyvalent groups, for example alkylene, arylene, heteroarylene, etc.
The term “aryl” denotes an aromatic carbon group or a group derived therefrom. The term “heteroaryl” denotes “aryl” as defined above, containing one or more heteroatoms, preferably selected from N, O, S, Se, Te, Si and Ge.
Preferred carbon and hydrocarbon groups are optionally substituted, straight-chain, branched or cyclic, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy and alkoxycarbonyloxy having 1 to 40, preferably 1 to 20, very preferably 1 to 12, C atoms, optionally substituted aryl or aryloxy having 5 to 30, preferably 6 to 25, C atoms, or optionally substituted alkylaryl, arylalkyl, alkylaryloxy, arylalkyloxy, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy and aryloxycarbonyloxy having 5 to 30, preferably 6 to 25, C atoms, wherein one or more C atoms may also be replaced by hetero atoms, preferably selected from N, O, S, Se, Te, Si and Ge.
Further preferred carbon and hydrocarbon groups are C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C20 allyl, C4-C20 alkyldienyl, C4-C20 polyenyl, C6-C20 cycloalkyl, C4-C15 cycloalkenyl, C6-C30 aryl, C6-C30 alkylaryl, C6-C30 arylalkyl, C6-C30 alkylaryloxy, C6-C30 arylalkyloxy, C2-C30 heteroaryl, C2-C30 heteroaryloxy.
Particular preference is given to C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C25 aryl and C2-C25 heteroaryl.
Further preferred carbon and hydrocarbon groups are straight-chain, branched or cyclic alkyl having 1 to 20, preferably 1 to 12, C atoms, which are unsubstituted or mono- or polysubstituted by F, Cl, Br, I or CN and in which one or more non-adjacent CH2 groups may each be replaced, independently of one another, by —C(Rx)═C(Rx)—, —CC—, —N(Rx)—, —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a way that O and/or S atoms are not linked directly to one another.
Rx preferably denotes H, F, Cl, CN, a straight-chain, branched or cyclic alkyl chain having 1 to 25 C atoms, in which, in addition, one or more non-adjacent C atoms may be replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— and in which one or more H atoms may be replaced by F or Cl, or denotes an optionally substituted aryl or aryloxy group with 6 to 30 C atoms, or an optionally substituted heteroaryl or heteroaryloxy group with 2 to 30 C atoms.
Preferred alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, 2-methylbutyl, n-pentyl, s-pentyl, cyclopentyl, n-hexyl, cyclohexyl, 2-ethylhexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, dodecanyl, trifluoromethyl, perfluoro-n-butyl, 2,2,2-trifluoroethyl, perfluorooctyl, perfluorohexyl, etc.
Preferred alkenyl groups are, for example, ethenyl, propenyl, butenyl, pentenyl, cyclopentenyl, hexenyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl, etc.
Preferred alkynyl groups are, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, octynyl, etc.
Preferred alkoxy groups are, for example, methoxy, ethoxy, 2-methoxy-ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 2-methylbutoxy, n-pentoxy, n-hexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecoxy, n-dodecoxy, etc.
Preferred amino groups are, for example, dimethylamino, methylamino, methylphenylamino, phenylamino, etc.
Aryl and heteroaryl groups can be monocyclic or polycyclic, i.e. they can contain one ring (such as, for example, phenyl) or two or more rings, which may also be fused (such as, for example, naphthyl) or covalently bonded (such as, for example, biphenyl), or contain a combination of fused and linked rings. Heteroaryl groups contain one or more heteroatoms, preferably selected from O, N, S and Se.
Particular preference is given to mono-, bi- or tricyclic aryl groups having 6 to 25 C atoms and mono-, bi- or tricyclic heteroaryl groups having 5 to 25 ring atoms, which optionally contain fused rings and are optionally substituted. Preference is furthermore given to 5-, 6- or 7-membered aryl and heteroaryl groups, in which, in addition, one or more CH groups may be replaced by N, S or O in such a way that O atoms and/or S atoms are not linked directly to one another.
Preferred aryl groups are, for example, phenyl, biphenyl, terphenyl, [1,1′:3′,1″]terphenyl-2′-yl, naphthyl, anthracene, binaphthyl, phenanthrene, 9,10-dihydro-phenanthrene, pyrene, dihydropyrene, chrysene, perylene, tetracene, pentacene, benzopyrene, fluorene, indene, indenofluorene, spirobifluorene, etc.
Preferred heteroaryl groups are, for example, 5-membered rings, such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 6-membered rings, such as pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, or condensed groups, such as indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran, dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline, benzo-6,7-quinoline, benzo-7,8-quinoline, benzoisoquin-oline, acridine, phenothiazine, phenoxazine, benzopyridazine, benzopyrimi-dine, quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline, phenanthridine, phenanthroline, thieno[2,3b]thiophene, thieno[3,2b]thiophene, dithienothiophene, isobenzothiophene, dibenzothiophene, benzothiadiazo-thiophene, or combinations of these groups.
The aryl and heteroaryl groups mentioned above and below may also be substituted by alkyl, alkoxy, thioalkyl, fluorine, nitro, nitrile, fluoroalkyl or further aryl or heteroaryl groups.
The (non-aromatic) alicyclic and heterocyclic groups encompass both saturated rings, i.e. those containing exclusively single bonds, and also partially unsaturated rings, i.e. those which may also contain multiple bonds.
Heterocyclic rings contain one or more heteroatoms, preferably selected from Si, O, N, S and Se.
The (non-aromatic) alicyclic and heterocyclic groups can be monocyclic, i.e. contain only one ring (such as, for example, cyclohexane), or polycyclic, i.e. contain a plurality of rings (such as, for example, decahydronaphthalene or bicyclooctane). Particular preference is given to saturated groups. Preference is furthermore given to mono-, bi- or tricyclic groups having 5 to 25 ring atoms, which optionally contain fused rings and are optionally substituted. Preference is furthermore given to 5-, 6-, 7- or 8-membered carbocyclic groups, in which, in addition, one or more C atoms may be replaced by Si and/or one or more CH groups may be replaced by N and/or one or more non-adjacent CH2 groups may be replaced by —O— and/or —S—.
Preferred alicyclic and heterocyclic groups are, for example, 5-membered groups, such as cyclopentane, tetrahydrofuran, tetrahydrothiofuran, pyrroli-dine, 6-membered groups, such as cyclohexane, silinane, cyclohexene, tetrahydropyran, tetrahydrothiopyran, 1,3-dioxane, 1,3-dithiane, piperidine, 7-membered groups, such as cycloheptane, and fused groups, such as tetrahydronaphthalene, decahydronaphthalene, indane, bicyclo[1.1.1]-pentane-1,3-diyl, bicyclo[2.2.2]octane-1,4-diyl, spiro[3.3]heptane-2,6-diyl, octahydro-4,7-methanoindane-2,5-diyl.
Preferred substituents for the abovementioned aryl and heteroaryl groups are, for example, solubility-promoting groups, such as alkyl or alkoxy, electron-withdrawing groups, such as fluorine, nitro or nitrile, or substituents for increasing the glass transition temperature (Tg) in the polymer, in particular bulky groups, such as, for example, t-butyl or optionally substituted aryl groups.
Preferred substituents are, for example, F, Cl, Br, I, —CN, —NO2, —NCO, —NCS, —OCN, —SCN, —C(═O)N(Rx)2, —C(═O)Y1, —C(═O)Rx, —N(Rx)2, straight-chain or branched alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy each having 1 to 25 C atoms, in which one or more H atoms may optionally be replaced by F or Cl, optionally substituted silyl having 1 to 20 Si atoms, or optionally substituted aryl having 6 to 25, preferably 6 to 15, C atoms,
wherein Rx denotes H, F, Cl, CN, or straight chain, branched or cyclic alkyl having 1 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F, Cl, P— or P-Sp-, and
Y1 denotes halogen.
“Substituted silyl or aryl” preferably means substituted by halogen, —CN, R0, —OR0, —CO—R0, —CO—O—R0, —O—CO—R0 or —O—CO—O—R0, wherein R0 denotes H or alkyl with 1 to 20 C atoms.
Particularly preferred substituents are, for example, F, Cl, CN, NO2, CH3, C2H5, OCH3, OC2H5, COCH3, COC2H5, COOCH3, COOC2H5, CF3, OCF3, OCHF2, OC2F5, furthermore phenyl.
is preferably
in which L has one of the meanings indicated above.
The polymerizable group P is a group which is suitable for a polymerization reaction, such as, for example, free-radical or ionic chain polymerization, polyaddition or polycondensation, or for a polymer-analogous reaction, for example addition or condensation onto a main polymer chain. Particular preference is given to groups for chain polymerization, in particular those containing a C═C double bond or —C≡C— triple bond, and groups which are suitable for polymerization with ring opening, such as, for example, oxetane or epoxide groups.
Preferred groups P are selected from the group consisting of CH2═CW1—CO—O—, CH2═CW1—CO—,
CH2═CW2—(O)k3—, CW1═CH—CO—(O)k3—, CW1═CH—CO—NH—, CH2═CW1—CO—NH—, CH3—CH═CH—O—, (CH2═CH)2CH—OCO—, (CH2═CH—CH2)2CH—OCO—, (CH2═CH)2CH—O—, (CH2═CH—CH2)2N—, (CH2═CH—CH2)2N—CO—, HO—CW2W3—, HS—CW2W3—, HW2N—, HO—CW2W3—NH—, CH2═CW1—CO—NH—, CH2═CH—(COO)k1-Phe-(O)k2—, CH2═CH—(CO)k1-Phe-(O)k2—, Phe-CH═CH—, HOOC—, OCN— and W4W5W6Si—, in which W1 denotes H, F, Cl, CN, CF3, phenyl or alkyl having 1 to 5 C atoms, in particular H, F, Cl or CH3, W2 and W3 each, independently of one another, denote H or alkyl having 1 to 5 C atoms, in particular H, methyl, ethyl or n-propyl, W4, W5 and W6 each, independently of one another, denote Cl, oxaalkyl or oxacarbonylalkyl having 1 to 5 C atoms, W7 and W8 each, independently of one another, denote H, Cl or alkyl having 1 to 5 C atoms, Phe denotes 1,4-phenylene, which is optionally substituted by one or more radicals L as defined above which are other than P-Sp-, k1, k2 and k3 each, independently of one another, denote 0 or 1, k3 preferably denotes 1, and k4 denotes an integer from 1 to 10.
Very preferred groups P are selected from the group consisting of CH2═CW1—CO—O—, CH2═CW1—CO—,
CH2═CW2—O—, CH2═CW2—, CW1═CH—CO—(O)k3—, CW1═CH—CO—NH—, CH2═CW1—CO—NH—, (CH2═CH)2CH—OCO—, (CH2═CH—CH2)2CH—OCO—, (CH2═CH)2CH—O—, (CH2═CH—CH2)2N—, (CH2═CH—CH2)2N—CO—, CH2═CW1—CO—NH—, CH2═CH—(COO)k1-Phe-(O)k2—, CH2═CH—(CO)k1-Phe-(O)k2—, Phe-CH═CH— and W4W5W6Si—, in which W1 denotes H, F, Cl, CN, CF3, phenyl or alkyl having 1 to 5 C atoms, in particular H, F, Cl or CH3, W2 and W3 each, independently of one another, denote H or alkyl having 1 to 5 C atoms, in particular H, methyl, ethyl or n-propyl, W4, W5 and W6 each, independently of one another, denote Cl, oxaalkyl or oxacarbonylalkyl having 1 to 5 C atoms, W7 and W8 each, independently of one another, denote H, Cl or alkyl having 1 to 5 C atoms, Phe denotes 1,4-phenylene, k1, k2 and k3 each, independently of one another, denote 0 or 1, k3 preferably denotes 1, and k4 denotes an integer from 1 to 10.
Very particularly preferred groups P are selected from the group consisting of CH2═CW1—CO—O—, in particular CH2═CH—CO—O—, CH2═C(CH3)—CO—O— and CH2═CF—CO—O—, furthermore CH2═CH—O—, (CH2═CH)2CH—O—CO—, (CH2═CH)2CH—O—,
Further preferred polymerizable groups P are selected from the group consisting of vinyloxy, acrylate, methacrylate, fluoroacrylate, chloroacrylate, oxetane and epoxide, most preferably from acrylate and methacrylate.
If the spacer group Sp is different from a single bond, it is preferably of the formula Sp″-X″, so that the respective radical P-Sp- conforms to the formula P-Sp″-X″—, wherein
Sp″ denotes linear or branched alkylene having 1 to 20, preferably 1 to 12, C atoms, which is optionally mono- or polysubstituted by F, Cl, Br, I or CN and in which, in addition, one or more non-adjacent CH2 groups may each be replaced, independently of one another, by —O—, —S—, —NH—, —N(R0)—, —Si(R0R00)—, —CO—, —CO—O—, —O—CO—, —O—CO—O—, —S—CO—, —CO—S—, —N(R00)—CO—O—, —O—CO—N(R0)—, —N(R0)—CO—N(R00)—, —CH═CH— or —C≡C— in such a way that O and/or S atoms are not linked directly to one another,
X″ denotes —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O—, —CO—N(R0)—, —N(R0)—CO—, —N(R0)—CO—N(R00)—, —OCH2—, —CH2O—, —SCH2—, —CH2S—, —CF2O—, —OCF2—, —CF2S—, —SCF2—, —CF2CH2—, —CH2CF2—, —CF2CF2—, —CH═N—, —N═CH—, —N═N—, —CH═CR0—, —CY2═CY3—, —C≡C—, —CH═CH—CO—O—, —O—CO—CH═CH— or a single bond,
R0 and R00 each, independently of one another, denote H or alkyl having 1 to 20 C atoms, and
Y2 and Y3 each, independently of one another, denote H, F, Cl or CN.
X″ is preferably —O—, —S—, —CO—, —COO—, —OCO—, —O—COO—, —CO—NR0—, —NR0—CO—, —NR0—CO—NR00— or a single bond.
Typical spacer groups Sp and -Sp″-X″— are, for example, —(CH2)p1—, —(CH2)p1—O—, —(CH2)p1—O—CO—, —(CH2)p1—CO—O—, —(CH2)p1—O—CO—O—, —(CH2CH2O)q1—CH2CH2—, —CH2CH2—S—CH2CH2—, —CH2CH2—NH—CH2CH2— or —(SiR0R00—O)p1—, in which p1 is an integer from 1 to 12, q1 is an integer from 1 to 3, and R0 and R00 have the meanings indicated above.
Particularly preferred groups Sp and -Sp″-X″— are —(CH2)p1—, —(CH2)p1—O—, —(CH2)p1—O—CO—, —(CH2)p1—CO—O—, —(CH2)p1—O—CO—O—, in which p1 and q1 have the meanings indicated above.
Particularly preferred groups Sp″ are, in each case straight-chain, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, octadecylene, ethyleneoxyethylene, methyleneoxybutylene, ethylenethioethylene, ethylene-N-methylimino-ethylene, 1-methylalkylene, ethenylene, propenylene and butenylene.
In a preferred embodiment of the invention the compounds of formula I and its subformulae contain a spacer group Sp that is substituted by one or more polymerizable groups P, so that the group Sp-P corresponds to Sp(P)s, with s being (branched polymerizable groups).
Preferred compounds of formula I according to this preferred embodiment are those wherein s is 2, i.e. compounds which contain a group Sp(P)2. Very preferred compounds of formula I according to this preferred embodiment contain a group selected from the following formulae:
—X-alkyl-CHPP S1
—X-alkyl-CH((CH2)aaP)((CH2)bbP) S2
—X—N((CH2)aaP)((CH2)bbP) S3
—X-alkyl-CH P—CH2—CH2P S4
—X-alkyl-C(CH2P)(CH2P)—CaaH2aa+1 S5
—X-alkyl-CHP—CH2P S6
—X-alkyl-CPP—CaaH2aa+1 S7
—X-alkyl-CHPCHP—CaaH2aa+1 S8
in which P is as defined in formula I,
alkyl denotes a single bond or straight-chain or branched alkylene having 1 to 12 C atoms which is unsubstituted or mono- or polysubstituted by F, Cl or CN and in which one or more non-adjacent CH2 groups may each, independently of one another, be replaced by —C(R0)═C(R0)—, —C≡C—, —N(R0)—, —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a way that O and/or S atoms are not linked directly to one another, where R0 has the meaning indicated above, aa and bb each, independently of one another, denote 0, 1, 2, 3, 4, 5 or 6,
X has one of the meanings indicated for X″, and is preferably O, CO, SO2, O—CO—, CO—O or a single bond.
Preferred spacer groups Sp(P)2 are selected from formulae S1, S2 and S3.
Very preferred spacer groups Sp(P)2 are selected from the following subformulae:
—CHPP S1a
—O—CHPP S1b
—CH2—CHPP S1c
—OCH2—CHPP S1d
—CH(CH2—P)(CH2—P) S2a
—OCH(CH2—P)(CH2—P) S2b
—CH2—CH(CH2—P)(CH2—P) S2c
—OCH2—CH(CH2—P)(CH2—P) S2d
—CO—NH((CH2)2P)((CH2P) S3a
In the compounds of formula I and its subformulae as described above and below, P is preferably selected from the group consisting of vinyloxy, acrylate, methacrylate, fluoroacrylate, chloroacrylate, oxetane and epoxide, most preferably from acrylate and methacrylate.
Further preferred are compounds of formula I and its subformulae as described above and below, wherein all polymerizable groups P that are present in the compound have the same meaning, and very preferably denote acrylate or methacrylate, most preferably methacrylate.
In the compounds of formula I and its subformulae as described above and below, Raa and Rbb preferably denote straight chain alkyl with 1 to 12 C atoms or branched alkyl with 3 to 12 C atoms. More preferably Raa and Rbb denote, independently of each other, methyl, ethyl, propyl and butyl, very preferably methyl or ethyl, most preferably methyl.
Further preferred are compounds of formula I and its subformulae as described above and below, wherein Raa and Rbb together with the C atom to which they are attached form a cyclic alkyl group with 3 to 12 C atoms, very preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
Very preferably the compounds of formula I contain a group La or -Sp-La selected from the following formulae
wherein the asterisk denotes the linkage to the adjacent group in the compound of formula I.
In another preferred embodiment of the invention the compounds of formula I and its subformulae contain a linear or branched alkylene spacer group Sp that is substituted by one or more groups La. Preferred compounds of formula I according to this preferred embodiment contain a group P-Sp- selected from the following formulae:
P—CHLa- SL1
P—(CH2)cc—O-CHLa- SL2
P—(CH2)cc—CO—O-CHLa- SL3
P—(CH2)cc—CHLa- SL4
in which P and La are as defined in formula I or have one of the meanings given above and below, and cc is 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3.
Preferred compounds of formula I contain one or more groups P-Sp- selected from formulae SL1, SL2 and SL3, very preferably of formula SL1.
In the compounds of formula I, Z1 is preferably a single bond.
In the compounds of formula I, A1 and A2 preferably denote benzene, naphthalene, phenanthrene or anthracene, which is optionally substituted by one or more groups L, P-Sp-, La or La-Sp-.
Preferably -A1-(Z1-A2)z- in formula I denotes benzene, biphenylene, p-terphenylene (1,4-diphenylbenzene), m-terphenylene (1,3-diphenylbenzene), naphthylene, 2-phenyl-naphthylene, phenanthrene, anthracene, dibenzofuran or dibenzothiophene, all of which are optionally substituted by one or more groups L, P-Sp-, La or La-Sp-.
Very preferred groups -A1-(Z1-A2)z-, in formula I are selected from the following formulae
wherein the benzene rings are optionally substituted by one or more groups L, P-Sp-, La or La-Sp-.
In the compounds of formula I and its subformulae as described above and below, -A1-(Z1-A2)z- is preferably selected from formulae A1, A2, A5, A8 and A9, very preferably from formulae A1, A2 and A5.
Preferred compounds of formula I are selected from the following subformulae
wherein P, Sp, R and L have the meanings given in formula I,
r1, r3, r7 are independently of each other 0, 1, 2 or 3,
r2 is 0, 1, 2, 3 or 4,
r4, r5, r6 are independently of each other 0, 1 or 2,
wherein r1+r7≥1, r1+r2+r3≥1, r4+r5≥1, r1+r3+r4≥1, and at least one of L denotes La or La-Sp-, with La being as defined in formula I, and/or
wherein the compounds contain at least one group Sp that is substituted by La.
Preferred are compounds of formula I1-I7 wherein one of the two groups R is H and the other is P-Sp.
Further preferred are compounds of formula I1-I7 wherein both groups R denote H.
Further preferred are compounds of formula I1-I7 wherein both groups R denote P-Sp.
Very preferred are compounds of formula I1, I2 and I5.
Further preferred compounds of formula I and I1-I7 are selected from the following subformulae
wherein P, Sp, P(Sp)2, L, r1-r7 have the meanings given in formula I or one of the preferred meanings as given above and below, and
r1+r7≥1, r1+r2+r3≥1, r4+r5≥1, r1+r3+r4≥1 and at least one of L denotes La or La-Sp-, with La being as defined in formula I, and/or
the compounds contain at least one group Sp that is substituted by La.
Preferably in formulae I1-2, I2-2, I3-2, I4-2, I5-2, I6-2, I6-4 and I7-2 the group -Sp(P)2 is selected from formulae S1 to S8 or S1a to S3a as defined above.
Very preferred compounds of formula I are selected from the following subformulae:
wherein P, Sp, Sp(P)2 and La have the meanings given above or below, with Sp preferably being different from a single bond, Sp′ is a spacer group that is substituted by a group La, and is preferably selected from formulae SL1-SL4, and L′ has one of the meanings given for L above or below that is preferably different from La.
Very preferred compounds of subformulae I1-1-1 to I9-1-1 are those wherein all groups P are identical and denote acrylate or methacrylate, preferably methacrylate, furthermore those wherein Sp is, —(CH2)p1—, —(CH2)p1—O—, —(CH2)p1—O—CO— or —(CH2)p1—CO—O—, in which p1 is an integer from 1 to 12, preferably 1 to 6, and the O- or CO-group is connected to the benzene ring, furthermore those wherein Sp(P)2 is selected from formulae S1-S8, very preferably from subformulae S1a-S3a, furthermore those wherein Sp′ is selected from formula SL1, furthermore those wherein L′ is F or denotes La-Sp-, preferably F, furthermore those wherein La is selected from formulae 1-5, most preferably of formula 1.
Further preferred compounds of formula I and its subformulae are selected from the following preferred embodiments, including any combination thereof:
All groups Pin the compound have the same meaning,
-A1-(Z1-A2)z- is selected from formulae A1, A2, A5, A8 and A9, very preferably form formulae A1, A2 and A5,
the compounds contain exactly two polymerizable groups (represented by the groups P),
the compounds contain exactly three polymerizable groups (represented by the groups P),
P is selected from the group consisting of acrylate, methacrylate and oxetane, very preferably acrylate or methacrylate,
the compounds contain at least one, preferably exactly one, group P-Sp- wherein Sp is substituted by La, and which is preferably selected from formulae SL1-SL4, very preferably from formulae SL1, SL2 and SL3,
Sp, when being different from a single bond, is —(CH2)p2—, —(CH2)p2—O—, —(CH2)p2—CO—O—, —(CH2)p2—O—CO—, wherein p2 is 2, 3, 4, 5 or 6, and the O-atom or the CO-group, respectively, is connected to the benzene ring,
Sp(P)2 is selected from subformulae S11-S31,
Sp′ is selected from formula SL1,
R denotes P-Sp-,
R does not denote or contain a polymerizable group,
R does not denote or contain a polymerizable group and denotes straight chain, branched or cyclic alkyl having 1 to 25 C atoms, wherein one or more non-adjacent CH2-groups are optionally replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a manner that O- and/or S-atoms are not directly connected with each other, and wherein one or more H atoms are each optionally replaced by F, Cl or La,
L, when being different from La-Sp-, denotes F, Cl or CN,
L′ is F,
La denotes —C(CH3)2—OH, —C(C2H5)2—OH or —C(CH3)(C2H5)OH, very preferably —C(CH3)2—OH,
La is selected from formulae 1-5,
r1, r2 and r3 denote 0 or 1,
r1, r2, r3, r4, r5 and r6 denote 0 or 1,
one of r1 and r7 is 0 and the other is 1,
r1 is 1, and r2 and r3 are 0,
r3 is 1 and r1 and r2 are 0,
one of r4 and r5 is 0 and the other is 1,
r4 and r6 are 0 and r5 is 1,
r1 and r4 are 0 and r3 is 1,
r1 and r3 are 0 and r4 is 1,
r3 and r4 are 0 and r1 is 1,
Very preferred compounds of formula I and its subformulae are selected from the following list:
wherein “Met” is methyl and “Et” is ethyl.
The invention furthermore relates to compounds of formula II1-II9
wherein Sp, L, r1-6 and q are as defined in formula I1-I9, R denotes H or Pg-Sp, and Pg denotes OH, a protected hydroxyl group or a masked hydroxyl group.
Preferred compounds of formula II1-II9 are selected from subformulae I1-1 to I9-2 and I1-1-1 to I9-1-1 as defined above, wherein P is replaced by Pg.
Suitable protected hydroxyl groups Pg are known to the person skilled in the art. Preferred protecting groups for hydroxyl groups are alkyl, alkoxyalkyl, acyl, alkylsilyl, arylsilyl and arylmethyl groups, especially 2-tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl, acetyl, triisopropylsilyl, tert-butyl-dimethylsilyl or benzyl.
The term “masked hydroxyl group” is understood to mean any functional group that can be chemically converted into a hydroxyl group. Suitable masked hydroxyl groups Pg are known to the person skilled in the art.
The compounds of formula II are suitable as intermediates for the preparation of compounds of the formula I and its subformulae.
The invention further relates to the use of the compounds of formula II as intermediates for the preparation of compounds of the formula I and its subformulae.
The compounds and intermediates of the formulae I and II and sub-formulae thereof can be prepared analogously to processes known to the person skilled in the art and described in standard works of organic chemistry, such as, for example, in Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Thieme-Verlag, Stuttgart.
For example, compounds of formula I can be synthesised by esterification or etherification of the intermediates of formula II, wherein Pg denotes OH, using corresponding acids, acid derivatives, or halogenated compounds containing a polymerizable group P.
For example, acrylic or methacrylic esters can be prepared by esterification of the corresponding alcohols with acid derivatives like, for example, (meth)acryloyl chloride or (meth)acrylic anhydride in the presence of a base like pyridine or triethyl amine, and 4-(N,N-dimethylamino)pyridine (DMAP).
Alternatively the esters can be prepared by esterification of the alcohols with (meth)acrylic acid in the presence of a dehydrating reagent, for example according to Steglich with dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and DMAP.
Further suitable methods are shown in the examples.
For the production of PSA displays, the polymerizable compounds contained in the LC medium are polymerized or crosslinked (if one compound contains two or more polymerizable groups) by in-situ polymerization in the LC medium between the substrates of the LC display, optionally while a voltage is applied to the electrodes.
The structure of the PSA displays according to the invention corresponds to the usual geometry for PSA displays, as described in the prior art cited at the outset. Geometries without protrusions are preferred, in particular those in which, in addition, the electrode on the colour filter side is unstructured and only the electrode on the TFT side has slots. Particularly suitable and preferred electrode structures for PS-VA displays are described, for example, in US 2006/0066793 A1.
A preferred PSA type LC display of the present invention comprises:
a first substrate including a pixel electrode defining pixel areas, the pixel electrode being connected to a switching element disposed in each pixel area and optionally including a micro-slit pattern, and optionally a first alignment layer disposed on the pixel electrode,
a second substrate including a common electrode layer, which may be disposed on the entire portion of the second substrate facing the first substrate, and optionally a second alignment layer,
an LC layer disposed between the first and second substrates and including an LC medium comprising a polymerizable component A and a liquid crystal component B as described above and below, wherein the polymerizable component A may also be polymerized.
The first and/or second alignment layer controls the alignment direction of the LC molecules of the LC layer. For example, in PS-VA displays the alignment layer is selected such that it imparts to the LC molecules homeotropic (or vertical) alignment (i.e. perpendicular to the surface) or tilted alignment. Such an alignment layer may for example comprise a polyimide, which may also be rubbed, or may be prepared by a photoalignment method.
The LC layer with the LC medium can be deposited between the substrates of the display by methods that are conventionally used by display manufacturers, for example the so-called one-drop-filling (ODF) method. The polymerizable component of the LC medium is then polymerized for example by UV photopolymerization. The polymerization can be carried out in one step or in two or more steps.
The PSA display may comprise further elements, like a colour filter, a black matrix, a passivation layer, optical retardation layers, transistor elements for addressing the individual pixels, etc., all of which are well known to the person skilled in the art and can be employed without inventive skill.
The electrode structure can be designed by the skilled person depending on the individual display type. For example for PS-VA displays a multi-domain orientation of the LC molecules can be induced by providing electrodes having slits and/or bumps or protrusions in order to create two, four or more different tilt alignment directions.
Upon polymerization the polymerizable compounds form a crosslinked polymer, which causes a certain pretilt of the LC molecules in the LC medium. Without wishing to be bound to a specific theory, it is believed that at least a part of the crosslinked polymer, which is formed by the polymerizable compounds, will phase-separate or precipitate from the LC medium and form a polymer layer on the substrates or electrodes, or the alignment layer provided thereon. Microscopic measurement data (like SEM and AFM) have confirmed that at least a part of the formed polymer accumulates at the LC/substrate interface.
The polymerization can be carried out in one step. It is also possible firstly to carry out the polymerization, optionally while applying a voltage, in a first step in order to produce a pretilt angle, and subsequently, in a second polymerization step without an applied voltage, to polymerize or crosslink the compounds which have not reacted in the first step (“end curing”).
Suitable and preferred polymerization methods are, for example, thermal or photopolymerization, preferably photopolymerization, in particular UV induced photopolymerization, which can be achieved by exposure of the polymerizable compounds to UV radiation.
Optionally one or more polymerization initiators are added to the LC medium. Suitable conditions for the polymerization and suitable types and amounts of initiators are known to the person skilled in the art and are described in the literature. Suitable for free-radical polymerization are, for example, the commercially available photoinitiators Irgacure651®, Irgacure184®, Irgacure907®, Irgacure369® or Darocure1173® (Ciba AG). If a polymerization initiator is employed, its proportion is preferably 0.001 to 5% by weight, particularly preferably 0.001 to 1% by weight.
The polymerizable compounds according to the invention are also suitable for polymerization without an initiator, which is accompanied by considerable advantages, such, for example, lower material costs and in particular less contamination of the LC medium by possible residual amounts of the initiator or degradation products thereof. The polymerization can thus also be carried out without the addition of an initiator. In a preferred embodiment, the LC medium thus does not contain a polymerization initiator.
The LC medium may also comprise one or more stabilizers in order to prevent undesired spontaneous polymerization of the RMs, for example during storage or transport. Suitable types and amounts of stabilizers are known to the person skilled in the art and are described in the literature. Particularly suitable are, for example, the commercially available stabilizers from the Irganox® series (Ciba AG), such as, for example, Irganox® 1076. If stabilizers are employed, their proportion, based on the total amount of RMs or the polymerizable component (component A), is preferably 10-500,000 ppm, particularly preferably 50-50,000 ppm.
The compounds of formula I do in particular show good UV absorption in, and are therefore especially suitable for, a process of preparing a PSA display including one or more of the following features:
the polymerizable medium is exposed to UV light in the display in a 2-step process, including a first UV exposure step (“UV-1 step”) to generate the tilt angle, and a second UV exposure step (“UV-2 step”) to finish polymerization,
the polymerizable medium is exposed to UV light in the display generated by an energy-saving UV lamp (also known as “green UV lamps”). These lamps are characterized by a relative low intensity (1/100-1/10 of a conventional UV1 lamp) in their absorption spectra from 300-380 nm, and are preferably used in the UV2 step, but are optionally also used in the UV1 step when avoiding high intensity is necessary for the process.
the polymerizable medium is exposed to UV light in the display generated by a UV lamp with a radiation spectrum that is shifted to longer wavelengths, preferably 340 nm or more, to avoid short UV light exposure in the PS-VA process.
Both using lower intensity and a UV shift to longer wavelengths protect the organic layer against damage that may be caused by the UV light.
A preferred embodiment of the present invention relates to a process for preparing a PSA display as described above and below, comprising one or more of the following features:
the polymerizable LC medium is exposed to UV light in a 2-step process, including a first UV exposure step (“UV-1 step”) to generate the tilt angle, and a second UV exposure step (“UV-2 step”) to finish polymerization,
the polymerizable LC medium is exposed to UV light generated by a UV lamp having an intensity of from 0.5 mW/cm2 to 10 mW/cm2 in the wavelength range from 300-380 nm, preferably used in the UV2 step, and optionally also in the UV1 step,
the polymerizable LC medium is exposed to UV light having a wavelength of 340 nm or more, and preferably 400 nm or less.
This preferred process can be carried out for example by using the desired UV lamps or by using a band pass filter and/or a cut-off filter, which are substantially transmissive for UV light with the respective desired wavelength(s) and are substantially blocking light with the respective undesired wavelengths. For example, when irradiation with UV light of wavelengths λ of 300-400 nm is desired, UV exposure can be carried out using a wide band pass filter being substantially transmissive for wavelengths 300 nm<λ<400 nm. When irradiation with UV light of wavelength λ of more than 340 nm is desired, UV exposure can be carried out using a cut-off filter being substantially transmissive for wavelengths λ>340 nm.
“Substantially transmissive” means that the filter transmits a substantial part, preferably at least 50% of the intensity, of incident light of the desired wavelength(s). “Substantially blocking” means that the filter does not transmit a substantial part, preferably at least 50% of the intensity, of incident light of the undesired wavelengths. “Desired (undesired) wavelength” e.g. in case of a band pass filter means the wavelengths inside (outside) the given range of λ, and in case of a cut-off filter means the wavelengths above (below) the given value of λ.
This preferred process enables the manufacture of displays by using longer UV wavelengths, thereby reducing or even avoiding the hazardous and damaging effects of short UV light components.
UV radiation energy is in general from 6 to 100 J, depending on the production process conditions.
Preferably an LC medium according to the present invention for use in PSA displays does essentially consist of a polymerizable component A), or one or more compounds of formula I, and an LC component B), or LC host mixture, as described above and below. However, the LC medium may additionally comprise one or more further components or additives, preferably selected from the list including but not limited to co-monomers, chiral dopants, polymerization initiators, inhibitors, stabilizers, surfactants, wetting agents, lubricating agents, dispersing agents, hydrophobing agents, adhesive agents, flow improvers, defoaming agents, deaerators, diluents, reactive diluents, auxiliaries, colourants, dyes, pigments and nanoparticles.
Particular preference is given to LC media comprising one, two or three compounds of formula I.
Preference is furthermore given to LC media in which the polymerizable component A) comprises exclusively compounds of formula I.
Preference is furthermore given to LC media in which the liquid-crystalline component B) or the LC host mixture has a nematic LC phase, and preferably has no chiral liquid crystal phase.
The LC component B), or LC host mixture, is preferably a nematic LC mixture.
Preference is furthermore given to achiral compounds of formula I, and to LC media in which the compounds of component A and/or B are selected exclusively from the group consisting of achiral compounds.
Preferably the proportion of the polymerizable component A) in the LC medium is from >0 to <5%, very preferably from >0 to <1%, most preferably from 0.01 to 0.5%.
Preferably the proportion of compounds of formula I in the LC medium is from >0 to <5%, very preferably from >0 to <1%, most preferably from 0.01 to 0.5%.
Preferably the proportion of the LC component B) in the LC medium is from 95 to <100%, very preferably from 99 to <100%.
In a preferred embodiment the polymerizable compounds of the polymerizable component B) are exclusively selected from formula I.
In another preferred embodiment the polymerizable component B) comprises, in addition to the compounds of formula I, one or more further polymerizable compounds (“co-monomers”), preferably selected from RMs.
Suitable and preferred mesogenic comonomers are selected from the following formulae:
in which the individual radicals have the following meanings:
P1, P2 and P3 each, independently of one another, denote an acrylate or methacrylate group,
Sp1, Sp2 and Spa each, independently of one another, denote a single bond or a spacer group having one of the meanings indicated above and below for Sp, and particularly preferably denote —(CH2)p1—, —(CH2)p1—O—, —(CH2)p1—CO—O—, —(CH2)p1—O—CO— or —(CH2)p1—O—CO—O—, in which p1 is an integer from 1 to 12, where, in addition, one or more of the radicals P1-Sp′-, P1—Sp2- and P3—Sp3- may denote Raa, with the proviso that at least one of the radicals P1-Sp1-, P2-Sp2 and P3-Sp3- present is different from Raa,
Raa denotes H, F, Cl, CN or straight-chain or branched alkyl having 1 to 25 C atoms, in which, in addition, one or more non-adjacent CH2 groups may each be replaced, independently of one another, by C(R0)═C(R00)—, —C≡C—, —N(R0)—, —N(R0)—, —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a way that O and/or S atoms are not linked directly to one another, and in which, in addition, one or more H atoms may be replaced by F, Cl, CN or P1-Sp1-, particularly preferably straight-chain or branched, optionally mono- or polyfluorinated alkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having 1 to 12 C atoms (where the alkenyl and alkynyl radicals have at least two C atoms and the branched radicals have at least three C atoms),
R0, R00 each, independently of one another and identically or differently on each occurrence, denote H or alkyl having 1 to 12 C atoms,
Ry and Rz each, independently of one another, denote H, F, CH3 or CF3,
X1, X2 and X3 each, independently of one another, denote —CO—O—, —O—CO— or a single bond,
Z1 denotes —O—, —CO—, —C(RyRz)— or —CF2CF2—,
Z2 and Z3 each, independently of one another, denote —CO—O—, —O—CO—, —CH2O—, —OCH2—, —CF2O—, —OCF2— or —(CH2)n—, where n is 2, 3 or 4,
L*on each occurrence, identically or differently, denotes F, Cl, CN or straight-chain or branched, optionally mono- or polyfluorinated alkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy or alkoxycarbonyloxy having 1 to 12 C atoms, preferably F,
L′ and L″ each, independently of one another, denote H, F or Cl,
r denotes 0, 1, 2, 3 or 4,
s denotes 0, 1, 2 or 3,
t denotes 0, 1 or 2,
x denotes 0 or 1.
Especially preferred are compounds of formulae M2, M13, M17, M22, M23, M24 and M30.
Further preferred are trireactive compounds M15 to M30, in particular M17, M18, M19, M22, M23, M24, M25, M26, M30 and M31.
In the compounds of formulae M1 to M31 the group
is preferably
wherein L on each occurrence, identically or differently, has one of the meanings given above or below, and is preferably F, Cl, CN, CH3, C2H5, C(CH3)3, CH(CH3)2, CH2CH(CH3)C2H5, OCH3, OC2H5, COCH3, COC2H5, COOCH3, COOC2H5, CF3, OCF3, OCHF2, OC2F5 or P-Sp-, very preferably F, Cl, CN, CH3, C2H5, OCH3, COCH3, OCF3 or P-Sp-, more preferably F, Cl, CH3, OCH3, COCH3 or OCF3, especially F or CH3.
In another preferred embodiment of the invention the LC medium does not contain any polymerizable compounds other than the compounds of formula I.
If the compounds of formula I are used as stabilizers, their proportion in the LC medium according to the invention is preferably from >0 to 1000 ppm, particularly preferably from 100 to 750 ppm, very particularly preferably from 300 to 600 ppm.
Further to the compounds of formula I the LC medium may also comprise one or more additional stabilizers. Suitable additional stabilizers are, for example, the commercially available stabilizers from the Irganox® series (Ciba AG), like, for example, Irganox® 1076, or the stabilizers selected from Table C below. If additional stabilizers are employed, their proportion in the LC medium is preferably 10-1000 ppm, particularly preferably 50-500 ppm.
Besides the compounds of formula I and the optional further polymerizable compounds described above, the LC media for use in the LC displays according to the invention comprise an LC mixture (“host mixture”) comprising one or more, preferably two or more LC compounds which are selected from low-molecular-weight compounds that are unpolymerizable. These LC compounds are selected such that they stable and/or unreactive to a polymerization reaction under the conditions applied to the polymerization of the polymerizable compounds.
In principle, any LC mixture which is suitable for use in conventional displays is suitable as host mixture. Suitable LC mixtures are known to the person skilled in the art and are described in the literature, for example mixtures in VA displays in EP 1 378 557 A1 and mixtures for OCB displays in EP 1 306 418 A1 and DE 102 24 046 A1.
The compounds of formula I are especially suitable for use in an LC host mixture that comprises one or more mesogenic or LC compounds comprising an alkenyl group (hereinafter also referred to as “alkenyl compounds”), wherein said alkenyl group is stable to a polymerization reaction under the conditions used for polymerization of the compounds of formula I and of the other polymerizable compounds contained in the LC medium. Compared to RMs known from prior art the compounds of formula I do in such an LC host mixture exhibit improved properties, like solubility, reactivity or capability of generating a tilt angle.
Thus, in addition to the compounds of formula I, the LC medium according to the present invention comprises one or more mesogenic or liquid crystalline compounds comprising an alkenyl group, (“alkenyl compound”), where this alkenyl group is preferably stable to a polymerization reaction under the conditions used for the polymerization of the compounds of formula I or of the other polymerizable compounds contained in the LC medium.
The alkenyl groups in the alkenyl compounds are preferably selected from straight-chain, branched or cyclic alkenyl, in particular having 2 to 25 C atoms, particularly preferably having 2 to 12 C atoms, in which, in addition, one or more non-adjacent CH2 groups may be replaced by —O—, —S—, —CO—, —CO—O—, —O—CO—, —O—CO—O— in such a way that O and/or S atoms are not linked directly to one another, and in which, in addition, one or more H atoms may be replaced by F and/or Cl.
Preferred alkenyl groups are straight-chain alkenyl having 2 to 7 C atoms and cyclohexenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, 1,4-cyclohexen-1-yl and 1,4-cyclohexen-3-yl.
The concentration of compounds containing an alkenyl group in the LC host mixture (i.e. without any polymerizable compounds) is preferably from 5% to 100%, very preferably from 20% to 60%.
Especially preferred are LC mixtures containing 1 to 5, preferably 1, 2 or 3 compounds having an alkenyl group.
The mesogenic and LC compounds containing an alkenyl group are preferably selected from formulae AN and AY as defined below.
Besides the compounds of formula I or the polymerizable component A) as described above, the LC media according to the present invention comprise an LC component B), or LC host mixture, comprising one or more, preferably two or more LC compounds which are selected from low-molecular-weight compounds that are unpolymerizable. These LC compounds are selected such that they stable and/or unreactive to a polymerization reaction under the conditions applied to the polymerization of the polymerizable compounds.
In a first preferred embodiment the LC medium contains an LC component B), or LC host mixture, based on compounds with negative dielectric anisotropy. Such LC media are especially suitable for use in VA, IPS, UB-FFS, PS-VA, PS-IPS and PS-UB-FFS displays. Particularly preferred embodiments of such an LC medium are those of sections a)-z3) below:
a) LC medium wherein the component B) or LC host mixture comprises one or more compounds selected from formulae CY and PY:
wherein
a denotes 1 or 2,
b denotes 0 or 1,
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
Zx and Zy each, independently of one another, denote —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond, preferably a single bond,
L1-4 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
Preferably, both L1 and L2 denote F or one of L1 and L2 denotes F and the other denotes Cl, or both L3 and L4 denote F or one of L3 and L4 denotes F and the other denotes Cl.
The compounds of the formula CY are preferably selected from the group consisting of the following sub-formulae:
in which a denotes 1 or 2, alkyl and alkyl*each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms, and (0) denotes an oxygen atom or a single bond. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
The compounds of the formula PY are preferably selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl*each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms, and (O) denotes an oxygen atom or a single bond. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
b) LC medium wherein the component B) or LC host mixture comprises one or more mesogenic or LC compounds comprising an alkenyl group (hereinafter also referred to as “alkenyl compounds”), wherein said alkenyl group is stable to a polymerization reaction under the conditions used for polymerization of the polymerizable compounds contained in the LC medium.
Preferably the component B) or LC host mixture comprises one or more alkenyl compounds selected from formulae AN and AY
in which the individual radicals, on each occurrence identically or differently, and each, independently of one another, have the following meaning:
RA1 alkenyl having 2 to 9 C atoms or, if at least one of the rings X, Y and Z denotes cyclohexenyl, also one of the meanings of RA2,
RA2 alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another,
Zx —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O—, or a single bond, preferably a single bond,
L1,2 H, F, Cl, OCF3, CF3, CH3, CH2F or CHF2H, preferably H, F or Cl,
x 1 or 2,
z 0 or 1.
Preferred compounds of formula AN and AY are those wherein RA2 is selected from ethenyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl.
In a preferred embodiment the component B) or LC host mixture comprises one or more compounds of formula AN selected from the following sub-formulae:
in which alkyl and alkyl*each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl and alkenyl*each, independently of one another, denote a straight-chain alkenyl radical having 2-7 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Preferably the component B) or LC host mixture comprises one or more compounds selected from formulae AN1, AN2, AN3 and AN6, very preferably one or more compounds of formula AN1.
In another preferred embodiment the component B) or LC host mixture comprises one or more compounds of formula AN selected from the following sub-formulae:
in which m denotes 1, 2, 3, 4, 5 or 6, i denotes 0, 1, 2 or 3, and Rb1 denotes H, CH3 or C2H5.
In another preferred embodiment the component B) or LC host mixture comprises one or more compounds selected from the following sub-formulae:
Most preferred are compounds of formula AN1a2 and AN1a5.
In another preferred embodiment the component B) or LC host mixture comprises one or more compounds of formula AY selected from the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, “(0)” denotes an 0-atom or a single bond, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-7 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
In another preferred embodiment the component B) or LC host mixture comprises one or more compounds of formula AY selected from the following sub-formulae:
in which m and n each, independently of one another, denote 1, 2, 3, 4, 5 or 6, and alkenyl denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Preferably the proportion of compounds of formula AN and AY in the LC medium is from 2 to 70% by weight, very preferably from 5 to 60% by weight, most preferably from 10 to 50% by weight.
Preferably the LC medium or LC host mixture contains 1 to 5, preferably 1, 2 or 3 compounds selected from formulae AN and AY.
In another preferred embodiment of the present invention the LC medium comprises one or more compounds of formula AY14, very preferably of AY14a. The proportion of compounds of formula AY14 or AY14a in the LC medium is preferably 3 to 20% by weight.
The addition of alkenyl compounds of formula AN and/or AY enables a reduction of the viscosity and response time of the LC medium.
c) LC medium wherein the component B) or LC host mixture comprises one or more compounds of the following formula:
in which the individual radicals have the following meanings:
R3 and R4 each, independently of one another, denote alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —O—CO— or —CO—O— in such a way that O atoms are not linked directly to one another,
Zy denotes —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond, preferably a single bond.
The compounds of the formula ZK are preferably selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Especially preferred are compounds of formula ZK1.
Particularly preferred compounds of formula ZK are selected from the following sub-formulae:
wherein the propyl, butyl and pentyl groups are straight-chain groups.
Most preferred are compounds of formula ZK1a.
d) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds of the following formula:
in which the individual radicals on each occurrence, identically or differently, have the following meanings:
R5 and R6 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
and
e denotes 1 or 2.
The compounds of the formula DK are preferably selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl denotes a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
e) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds of the following formula:
in which the individual radicals have the following meanings:
with at least one ring F being different from cyclohexylene,
f denotes 1 or 2,
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another,
Zx denotes —CH2CH2—, —CH═CH—, —CF2O—, —OCF2—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CH═CH—CH2O— or a single bond, preferably a single bond,
L1 and L2 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
Preferably, both radicals L1 and L2 denote F or one of the radicals L1 and L2 denotes F and the other denotes Cl.
The compounds of the formula LY are preferably selected from the group consisting of the following sub-formulae:
in which R1 has the meaning indicated above, alkyl denotes a straight-chain alkyl radical having 1-6 C atoms, (0) denotes an oxygen atom or a single bond, and v denotes an integer from 1 to 6. R1 preferably denotes straight-chain alkyl having 1 to 6 C atoms or straight-chain alkenyl having 2 to 6 C atoms, in particular CH3, C2H5, n-C3H7, n-C4H9, n-C5H11, CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
f) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which alkyl denotes C1-6-alkyl, Lx denotes H or F, and X denotes F, Cl, OCF3, OCHF2 or OCH═CF2. Particular preference is given to compounds of the formula G1 in which X denotes F.
g) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which R5 has one of the meanings indicated above for R1, alkyl denotes C1-6-alkyl, d denotes 0 or 1, and z and m each, independently of one another, denote an integer from 1 to 6. R5 in these compounds is particularly preferably C1-6-alkyl or -alkoxy or C2-6-alkenyl, d is preferably 1. The LC medium according to the invention preferably comprises one or more compounds of the above-mentioned formulae in amounts of 5% by weight.
h) LC medium wherein component B) or the LC host mixture additionally comprises one or more biphenyl compounds selected from the group consisting of the following formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
The proportion of the biphenyls of the formulae B1 to B3 in the LC host mixture is preferably at least 3% by weight, in particular ≥5% by weight.
The compounds of the formula B2 are particularly preferred.
The compounds of the formulae B1 to B3 are preferably selected from the group consisting of the following sub-formulae:
in which alkyl* denotes an alkyl radical having 1-6 C atoms. The medium according to the invention particularly preferably comprises one or more compounds of the formulae B1a and/or B2c.
i) LC medium wherein component B) or the LC host mixture additionally comprises one or more terphenyl compounds of the following formula:
in which R5 and R6 each, independently of one another, have one of the meanings indicated above, and
each, independently of one another, denote
in which L5 denotes F or Cl, preferably F, and L6 denotes F, Cl, OCF3, CF3, CH3, CH2F or CHF2, preferably F.
The compounds of the formula T are preferably selected from the group consisting of the following sub-formulae:
in which R denotes a straight-chain alkyl or alkoxy radical having 1-7 C atoms, R* denotes a straight-chain alkenyl radical having 2-7 C atoms, (0) denotes an oxygen atom or a single bond, and m denotes an integer from 1 to 6. R* preferably denotes CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
R preferably denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy or pentoxy.
The LC host mixture according to the invention preferably comprises the terphenyls of the formula T and the preferred sub-formulae thereof in an amount of 0.5-30% by weight, in particular 1-20% by weight.
Particular preference is given to compounds of the formulae T1, T2, T3 and T21. In these compounds, R preferably denotes alkyl, furthermore alkoxy, each having 1-5 C atoms.
The terphenyls are preferably employed in LC media according to the invention if the Δn value of the mixture is to be ≥0.1. Preferred LC media comprise 2-20% by weight of one or more terphenyl compounds of the formula T, preferably selected from the group of compounds T1 to T22.
k) LC medium wherein component B) or the LC host mixture additionally comprises one or more quaterphenyl compounds selected from the group consisting of the following formulae:
wherein
RQ is alkyl, alkoxy, oxaalkyl or alkoxyalkyl having 1 to 9 C atoms or alkenyl or alkenyloxy having 2 to 9 C atoms, all of which are optionally fluorinated,
XQ is F, Cl, halogenated alkyl or alkoxy having 1 to 6 C atoms or halogenated alkenyl or alkenyloxy having 2 to 6 C atoms,
LQ1 to LQ6 independently of each other are H or F, with at least one of LQ1 to LQ6 being F.
Preferred compounds of formula Q are those wherein RQ denotes straight-chain alkyl with 2 to 6 C-atoms, very preferably ethyl, n-propyl or n-butyl.
Preferred compounds of formula Q are those wherein LQ3 and LQ4 are F. Further preferred compounds of formula Q are those wherein LQ3, LQ4 and one or two of LQ1 and LQ2 are F.
Preferred compounds of formula Q are those wherein XQ denotes F or OCF3, very preferably F.
The compounds of formula Q are preferably selected from the following subformulae
wherein RQ has one of the meanings of formula Q or one of its preferred meanings given above and below, and is preferably ethyl, n-propyl or n-butyl.
Especially preferred are compounds of formula Q1, in particular those wherein RQ is n-propyl.
Preferably the proportion of compounds of formula Q in the LC host mixture is from >0 to 5% by weight, very preferably from 0.1 to 2% by weight, most preferably from 0.2 to 1.5% by weight.
Preferably the LC host mixture contains 1 to 5, preferably 1 or 2 compounds of formula Q.
The addition of quaterphenyl compounds of formula Q to the LC host mixture enables to reduce ODF mura, whilst maintaining high UV absorption, enabling quick and complete polymerization, enabling strong and quick tilt angle generation, and increasing the UV stability of the LC medium.
Besides, the addition of compounds of formula Q, which have positive dielectric anisotropy, to the LC medium with negative dielectric anisotropy allows a better control of the values of the dielectric constants ∈∥ and ∈⊥, and in particular enables to achieve a high value of the dielectric constant ∈∥ while keeping the dielectric anisotropy Δ∈ constant, thereby reducing the kick-back voltage and reducing image sticking.
l) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds of formula C:
wherein
RC denotes alkyl, alkoxy, oxaalkyl or alkoxyalkyl having 1 to 9 C atoms or alkenyl or alkenyloxy having 2 to 9 C atoms, all of which are optionally fluorinated,
XC denotes F, Cl, halogenated alkyl or alkoxy having 1 to 6 C atoms or halogenated alkenyl or alkenyloxy having 2 to 6 C atoms,
LC1, LC2 independently of each other denote H or F, with at least one of LC1 and LC2 being F.
Preferred compounds of formula C are those wherein RC denotes straight-chain alkyl with 2 to 6 C-atoms, very preferably ethyl, n-propyl or n-butyl.
Preferred compounds of formula C are those wherein LC1 and LC2 are F.
Preferred compounds of formula C are those wherein XC denotes F or OCF3, very preferably F.
Preferred compounds of formula C are selected from the following formula
wherein RC has one of the meanings of formula C or one of its preferred meanings given above and below, and is preferably ethyl, n-propyl or n-butyl, very preferably n-propyl.
Preferably the proportion of compounds of formula C in the LC host mixture is from >0 to ≤10% by weight, very preferably from 0.1 to 8% by weight, most preferably from 0.2 to 5% by weight.
Preferably the LC host mixture contains 1 to 5, preferably 1, 2 or 3 compounds of formula C.
The addition of compounds of formula C, which have positive dielectric anisotropy, to the LC medium with negative dielectric anisotropy allows a better control of the values of the dielectric constants ∈∥ and ∈⊥, and in particular enables to achieve a high value of the dielectric constant ∈∥ while keeping the dielectric anisotropy Δ∈ constant, thereby reducing the kick-back voltage and reducing image sticking. Besides, the addition of compounds of formula C enables to reduce the viscosity and the response time of the LC medium.
m) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which R1 and R2 have the meanings indicated above and preferably each, independently of one another, denote straight-chain alkyl having 1 to 6 C atoms or straight-chain alkenyl having 2 to 6 C atoms.
Preferred media comprise one or more compounds selected from the formulae 01, 03 and 04.
n) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds of the following formula:
in which
R9 denotes H, CH3, C2H5 or n-C3H7, (F) denotes an optional fluorine substituent, and q denotes 1, 2 or 3, and R7 has one of the meanings indicated for R1, preferably in amounts of >3% by weight, in particular 5% by weight and very particularly preferably 5-30% by weight.
Particularly preferred compounds of the formula FI are selected from the group consisting of the following sub-formulae:
in which R7 preferably denotes straight-chain alkyl, and R9 denotes CH3, C2H5 or n-C3H7. Particular preference is given to the compounds of the formulae FI1, FI2 and FI3.
o) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds selected from the group consisting of the following formulae:
in which R8 has the meaning indicated for R1, and alkyl denotes a straight-chain alkyl radical having 1-6 C atoms.
p) LC medium wherein component B) or the LC host mixture additionally comprises one or more compounds which contain a tetrahydronaphthyl or naphthyl unit, such as, for example, the compounds selected from the group consisting of the following formulae:
in which
R10 and R11 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
and R10 and R11 preferably denote straight-chain alkyl or alkoxy having 1 to 6 C atoms or straight-chain alkenyl having 2 to 6 C atoms, and
Z1 and Z2 each, independently of one another, denote —C2H4—, —CH═CH—, —(CH2)4—, —(CH2)3O—, —O(CH2)3—, —CH═CH—CH2CH2—, —CH2CH2CH═CH—, —CH2O—, —OCH2—, —CO—O—, —O—CO—, —C2F4—, —CF═CF—, —CF═CH—, —CH═CF—, —CH2— or a single bond.
q) LC medium wherein component B) or the LC host mixture additionally comprises one or more difluorodibenzochromans and/or chromans of the following formulae:
in which
R11 and R12 each, independently of one another, have one of the meanings indicated above for R11,
ring M is trans-1,4-cyclohexylene or 1,4-phenylene,
Zm —C2H4—, —CH2O—, —OCH2—, —CO—O— or —O—CO—,
c is 0, 1 or 2,
preferably in amounts of 3 to 20% by weight, in particular in amounts of 3 to 15% by weight.
Particularly preferred compounds of the formulae BC, CR and RC are selected from the group consisting of the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, (0) denotes an oxygen atom or a single bond, c is 1 or 2, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Very particular preference is given to LC host mixtures comprising one, two or three compounds of the formula BC-2.
r) LC medium wherein component B) or the LC host mixture additionally comprises one or more fluorinated phenanthrenes and/or dibenzofurans of the following formulae:
in which R11 and R12 each, independently of one another, have one of the meanings indicated above for R11, b denotes 0 or 1, L denotes F, and r denotes 1, 2 or 3.
Particularly preferred compounds of the formulae PH and BF are selected from the group consisting of the following sub-formulae:
in which R and R′ each, independently of one another, denote a straight-chain alkyl or alkoxy radical having 1-7 C atoms.
s) LC medium wherein component B) or the LC host mixture additionally comprises one or more monocyclic compounds of the following formula
wherein
R1 and R2 each, independently of one another, denote alkyl having 1 to 12 C atoms, where, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another, preferably alkyl or alkoxy having 1 to 6 C atoms,
L1 and L2 each, independently of one another, denote F, Cl, OCF3, CF3, CH3, CH2F, CHF2.
Preferably, both L1 and L2 denote F or one of L1 and L2 denotes F and the other denotes Cl,
The compounds of the formula Y are preferably selected from the group consisting of the following sub-formulae:
in which, Alkyl and Alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, Alkoxy denotes a straight-chain alkoxy radical having 1-6 C atoms, Alkenyl and Alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-6 C atoms. Alkenyl and Alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Particularly preferred compounds of the formula Y are selected from the group consisting of the following sub-formulae:
wherein Alkoxy preferably denotes straight-chain alkoxy with 3, 4, or 5 C atoms.
t) LC medium which, apart from the polymerizable compounds as described above and below, does not contain a compound which contains a terminal vinyloxy group (—O—CH═CH2).
u) LC medium wherein component B) or the LC host mixture comprises 1 to 8, preferably 1 to 5, compounds of the formulae CY1, CY2, PY1 and/or PY2. The proportion of these compounds in the LC host mixture as a whole is preferably 5 to 60%, particularly preferably 10 to 35%. The content of these individual compounds is preferably in each case 2 to 20%.
v) LC medium wherein component B) or the LC host mixture comprises 1 to 8, preferably 1 to 5, compounds of the formulae CY9, CY10, PY9 and/or PY10. The proportion of these compounds in the LC host mixture as a whole is preferably 5 to 60%, particularly preferably 10 to 35%. The content of these individual compounds is preferably in each case 2 to 20%.
w) LC medium wherein component B) or the LC host mixture comprises 1 to 10, preferably 1 to 8, compounds of the formula ZK, in particular compounds of the formulae ZK1, ZK2 and/or ZK6. The proportion of these compounds in the LC host mixture as a whole is preferably 3 to 25%, particularly preferably 5 to 45%. The content of these individual compounds is preferably in each case 2 to 20%.
x) LC medium in which the proportion of compounds of the formulae CY, PY and ZK in the LC host mixture as a whole is greater than 70%, preferably greater than 80%.
y) LC medium in which the LC host mixture contains one or more compounds containing an alkenyl group, preferably selected from formulae AN and AY, very preferably selected from formulae AN1, AN3, AN6 and AY14, most preferably from formulae AN1a, AN3a, AN6a and AY14. The concentration of these compounds in the LC host mixture is preferably from 2 to 70%, very preferably from 3 to 55%.
z) LC medium wherein component B) or the LC host mixture contains one or more, preferably 1 to 5, compounds selected of formula PY1-PY8, very preferably of formula PY2. The proportion of these compounds in the LC host mixture as a whole is preferably 1 to 30%, particularly preferably 2 to 20%. The content of these individual compounds is preferably in each case 1 to 20%.
z1) LC medium wherein component B) or the LC host mixture contains one or more, preferably 1, 2 or 3, compounds selected from formulae T1, T2 and T5, very preferably from formula T2. The content of these compounds in the LC host mixture as a whole is preferably 1 to 20%.
z2) LC medium in which the LC host mixture contains one or more compounds selected from formulae CY and PY, one or more compounds selected from formulae AN and AY, and one or more compounds selected from formulae T and Q.
z3) LC medium in which the LC host mixture contains one or more, preferably 1, 2 or 3, compounds of formula BF1, and one or more, preferably 1, 2 or 3, compounds selected from formulae AY14, AY15 and AY16, very preferably of formula AY14. The proportion of the compounds of formula AY14-AY16 in the LC host mixture is preferably from 2 to 35%, very preferably from 3 to 30%. The proportion of the compounds of formula BF1 in the LC host mixture is preferably from 0.5 to 20%, very preferably from 1 to 15%. Further preferably the LC host mixture according to this preferred embodiment contains one or more, preferably 1, 2 or 3 compounds of formula T, preferably selected from formula T1, T2 and T5, very preferably from formula T2 or T5. The proportion of the compounds of formula T in the LC host mixture medium is preferably from 0.5 to 15%, very preferably from 1 to 10%.
In a second preferred embodiment the LC medium contains an LC host mixture based on compounds with positive dielectric anisotropy. Such LC media are especially suitable for use in TN, OCB, Posi-VA, IPS, FFS, PS-OCB-, PS-TN-, PS-Posi-VA-, PS-IPS- or PS-FFS-displays.
in which the individual radicals have, independently of each other and on each occurrence identically or differently, the following meanings:
each, independently of one another, and on each occurrence, identically or differently
R21, R31 each, independently of one another, alkyl, alkoxy, oxaalkyl or alkoxyalkyl having 1 to 9 C atoms or alkenyl or alkenyloxy having 2 to 9 C atoms, all of which are optionally fluorinated,
X0 F, Cl, halogenated alkyl or alkoxy having 1 to 6 C atoms or halogenated alkenyl or alkenyloxy having 2 to 6 C atoms,
Z31 —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O— or a single bond, preferably —CH2CH2—, —COO—, trans-CH═CH— or a single bond, particularly preferably —COO—, trans-CH═CH— or a single bond,
L21, L22, L31, L32 each, independently of one another, H or F,
g 0, 1, 2 or 3.
In the compounds of formula A and B, X0 is preferably F, Cl, CF3, CHF2, OCF3, OCHF2, OCFHCF3, OCFHCHF2, OCFHCHF2, OCF2CH3, OCF2CHF2, OCF2CHF2, OCF2CF2CHF2, OCF2CF2CHF2, OCFHCF2CF3, OCFHCF2CHF2, OCF2CF2CF3, OCF2CF2CClF2, OCClFCF2CF3 or CH═CF2, very preferably F or OCF3, most preferably F.
In the compounds of formula A and B, R21 and R31 are preferably selected from straight-chain alkyl or alkoxy with 1, 2, 3, 4, 5 or 6 C atoms, and straight-chain alkenyl with 2, 3, 4, 5, 6 or 7 C atoms.
In the compounds of formula A and B, g is preferably 1 or 2.
In the compounds of formula B, Z31 is preferably COO, trans-CH═CH or a single bond, very preferably COO or a single bond.
Preferably component B) of the LC medium comprises one or more compounds of formula A selected from the group consisting of the following formulae:
in which A21, R21, X0, L21 and L22 have the meanings given in formula A, L23 and L24 each, independently of one another, are H or F, and X0 is preferably F. Particularly preferred are compounds of formulae A1 and A2.
Particularly preferred compounds of formula A1 are selected from the group consisting of the following subformulae:
in which R21, X0, L21 and L22 have the meaning given in formula A1, L23, L24, L25 and L26 are each, independently of one another, H or F, and X0 is preferably F.
Very particularly preferred compounds of formula A1 are selected from the group consisting of the following subformulae:
In which R21 is as defined in formula A1.
Particularly preferred compounds of formula A2 are selected from the group consisting of the following subformulae:
in which R21, X0, L21 and L22 have the meaning given in formula A2, L23, L24, L25 and L26 each, independently of one another, are H or F, and X0 is preferably F.
Very particularly preferred compounds of formula A2 are selected from the group consisting of the following subformulae:
in which R21 and X0 are as defined in formula A2.
Particularly preferred compounds of formula A3 are selected from the group consisting of the following subformulae:
in which R21, X0, L21 and L22 have the meaning given in formula A3, and X0 is preferably F.
Particularly preferred compounds of formula A4 are selected from the group consisting of the following subformulae:
in which R21 is as defined in formula A4.
Preferably component B) of the LC medium comprises one or more compounds of formula B selected from the group consisting of the following formulae:
in which g, A31, A32, R31, X0, L31 and L32 have the meanings given in formula B, and X0 is preferably F. Particularly preferred are compounds of formulae B1 and B2.
Particularly preferred compounds of formula B1 are selected from the group consisting of the following subformulae:
in which R31, X0, L31 and L32 have the meaning given in formula B1, and X0 is preferably F.
Very particularly preferred compounds of formula B1a are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B1.
Very particularly preferred compounds of formula B1 b are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B1.
Particularly preferred compounds of formula B2 are selected from the group consisting of the following subformulae:
in which R31, X0, L31 and L32 have the meaning given in formula B2, L33, L34, L35 and L36 are each, independently of one another, H or F, and X0 is preferably F.
Very particularly preferred compounds of formula B2 are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2b are selected from the group consisting of the following subformulae
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2c are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2d and B2e are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2f are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2g are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2h are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2i are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2k are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Very particularly preferred compounds of formula B2l are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B2.
Alternatively to, or in addition to, the compounds of formula B1 and/or B2 component B) of the LC medium may also comprise one or more compounds of formula B3 as defined above.
Particularly preferred compounds of formula B3 are selected from the group consisting of the following subformulae:
in which R31 is as defined in formula B3.
Preferably component B) of the LC medium comprises, in addition to the compounds of formula A and/or B, one or more compounds of formula C
in which the individual radicals have the following meanings:
each, independently of one another, and on each occurrence, identically or differently
R41, R42 each, independently of one another, alkyl, alkoxy, oxaalkyl or alkoxyalkyl having 1 to 9 C atoms or alkenyl or alkenyloxy having 2 to 9 C atoms, all of which are optionally fluorinated,
Z41, Z42 each, independently of one another, —CH2CH2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, preferably a single bond,
h 0, 1, 2 or 3.
In the compounds of formula C, R41 and R42 are preferably selected from straight-chain alkyl or alkoxy with 1, 2, 3, 4, 5 or 6 C atoms, and straight-chain alkenyl with 2, 3, 4, 5, 6 or 7 C atoms.
In the compounds of formula C, h is preferably 0, 1 or 2.
In the compounds of formula C, Z41 and Z42 are preferably selected from COO, trans-CH═CH and a single bond, very preferably from COO and a single bond.
Preferred compounds of formula C are selected from the group consisting of the following subformulae:
wherein R41 and R42 have the meanings given in formula C, and preferably denote each, independently of one another, alkyl, alkoxy, fluorinated alkyl or fluorinated alkoxy with 1 to 7 C atoms, or alkenyl, alkenyloxy, alkoxyalkyl or fluorinated alkenyl with 2 to 7 C atoms.
Further preferably component B) of the LC medium comprises, in addition to the compounds of formula A and/or B, one or more compounds of formula D
in which A41, A42, Z41, Z42, R41, R42 and h have the meanings given in formula C or one of the preferred meanings given above.
Preferred compounds of formula D are selected from the group consisting of the following subformulae:
in which R41 and R42 have the meanings given in formula D and R41 preferably denotes alkyl bedeutet, and in formula D1 R42 preferably denotes alkenyl, particularly preferably —(CH2)2—CH═CH—CH3, and in formula D2 R42 preferably denotes alkyl, —(CH2)2—CH═CH2 or —(CH2)2—CH═CH—CH3.
Further preferably component B) of the LC medium comprises, in addition to the compounds of formula A and/or B, one or more compounds of formula E containing an alkenyl group
in which the individual radicals, on each occurrence identically or differently, each, independently of one another, have the following meaning:
RA1 alkenyl having 2 to 9 C atoms or, if at least one of the rings X, Y and Z denotes cyclohexenyl, also one of the meanings of RA2,
RA2 alkyl having 1 to 12 C atoms, in which, in addition, one or two non-adjacent CH2 groups may be replaced by —O—, —CH═CH—, —CO—, —OCO— or —COO— in such a way that O atoms are not linked directly to one another,
x 1 or 2.
RA2 is preferably straight-chain alkyl or alkoxy having 1 to 8 C atoms or straight-chain alkenyl having 2 to 7 C atoms.
Preferred compounds of formula E are selected from the following sub-formulae:
in which alkyl and alkyl* each, independently of one another, denote a straight-chain alkyl radical having 1-6 C atoms, and alkenyl and alkenyl* each, independently of one another, denote a straight-chain alkenyl radical having 2-7 C atoms. Alkenyl and alkenyl* preferably denote CH2═CH—, CH2═CHCH2CH2—, CH3—CH═CH—, CH3—CH2—CH═CH—, CH3—(CH2)2—CH═CH—, CH3—(CH2)3—CH═CH— or CH3—CH═CH—(CH2)2—.
Very preferred compounds of the formula E are selected from the following sub-formulae:
in which m denotes 1, 2, 3, 4, 5 or 6, i denotes 0, 1, 2 or 3, and Rb1 denotes H, CH3 or C2H5.
Very particularly preferred compounds of the formula E are selected from the following sub-formulae:
Most preferred are compounds of formula E1a2, E1a5, E3a1 and E6a1.
Further preferably component B) of the LC medium comprises, in addition to the compounds of formula A and/or B, one or more compounds of formula F
in which the individual radicals have, independently of each other and on each occurrence identically or differently, the following meanings:
R21, R31 each, independently of one another, alkyl, alkoxy, oxaalkyl or alkoxyalkyl having 1 to 9 C atoms or alkenyl or alkenyloxy having 2 to 9 C atoms, all of which are optionally fluorinated,
X0 F, Cl, halogenated alkyl or alkoxy having 1 to 6 C atoms or halogenated alkenyl or alkenyloxy having 2 to 6 C atoms,
Z21 —CH2CH2—, —CF2CF2—, —COO—, trans-CH═CH—, trans-CF═CF—, —CH2O—, —CF2O—, —C≡C— or a single bond, preferably —CF2O—,
L21, L22, L23, L24 each, independently of one another, H or F,
g 0, 1, 2 or 3.
Particularly preferred compounds of formula F are selected from the group consisting of the following formulae:
in which R21, X0, L21 and L22 have the meaning given in formula F, L25 and L26 are each, independently of one another, H or F, and X0 is preferably F.
Very particularly preferred compounds of formula F1-F3 are selected from the group consisting of the following subformulae:
In which R21 is as defined in formula F1.
The concentration of the compounds of formula A and B in the LC host mixture is preferably from 2 to 60%, very preferably from 3 to 45%, most preferably from 4 to 35%.
The concentration of the compounds of formula C and D in the LC host mixture is preferably from 2 to 70%, very preferably from 5 to 65%, most preferably from 10 to 60%.
The concentration of the compounds of formula E in the LC host mixture is preferably from 5 to 50%, very preferably from 5 to 35%.
The concentration of the compounds of formula F in the LC host mixture is preferably from 2 to 30%, very preferably from 5 to 20%.
Further preferred embodiments of this second preferred embodiment of the present invention are listed below, including any combination thereof.
2a) The LC host mixture comprises one or more compounds of formula A and/or B with high positive dielectric anisotropy, preferably with Δ∈>15.
2b) The LC host mixture comprises one or more compounds selected from the group consisting of formulae A1a2, A1 b1, A1 d1, A1 f1, A2a1, A2h1, A2l2, A2k1, B2h3, B2l1, F1a. The proportion of these compounds in the LC host mixture is preferably from 4 to 40%, very preferably from 5 to 35%.
2c) The LC host mixture comprises one or more compounds selected from the group consisting of formulae B2c1, B2c4, B2f4, C14. The proportion of these compounds in the LC host mixture is preferably from 4 to 40%, very preferably from 5 to 35%.
2d) The LC host mixture comprises one or more compounds selected from the group consisting of formulae C3, C4, C5, C9 and D2. The proportion of these compounds in the LC host mixture is preferably from 8 to 70%, very preferably from 10 to 60%.
2e) The LC host mixture comprises one or more compounds selected from the group consisting of formulae G1, G2 and G5, preferably G1a, G2a and GSa. The proportion of these compounds in the LC host mixture is preferably from 4 to 40%, very preferably from 5 to 35%.
2f) The LC host mixture comprises one or more compounds selected from the group consisting of formulae E1, E3 and E6, preferably E1a, E3a and E6a, very preferably E1a2, E1a5, E3a1 and E6a1. The proportion of these compounds in the LC host mixture is preferably from 5 to 60%, very preferably from 10 to 50%.
The combination of compounds of the preferred embodiments mentioned above with the polymerized compounds described above causes low threshold voltages, low rotational viscosities and very good low-temperature stabilities in the LC media according to the invention at the same time as constantly high clearing points and high HR values, and allows the rapid establishment of a particularly low pretilt angle in PSA displays. In particular, the LC media exhibit significantly shortened response times, in particular also the grey-shade response times, in PSA displays compared with the media from the prior art.
The LC media and LC host mixtures of the present invention preferably have a nematic phase range of at least 80 K, particularly preferably at least 100 K, and a rotational viscosity ≤250 mPa·s, preferably ≤200 mPa·s, at 20° C.
In the VA-type displays according to the invention, the molecules in the layer of the LC medium in the switched-off state are aligned perpendicular to the electrode surfaces (homeotropically) or have a a tilted homeotropic alignment. On application of an electrical voltage to the electrodes, a realignment of the LC molecules takes place with the longitudinal molecular axes parallel to the electrode surfaces.
LC media according to the invention based on compounds with negative dielectric anisotropy according to the first preferred embodiment, in particular for use in displays of the VA, UB-FFS, PS-VA and PS-UB-FFS type, have a negative dielectric anisotropy Δ∈, preferably from −0.5 to −10, in particular from −2.5 to −7.5, at 20° C. and 1 kHz.
The birefringence Δn in LC media according to the invention for use in displays of the VA, UB-FFS, PS-VA and PS-UB-FFS type is preferably below 0.16, particularly preferably from 0.06 to 0.14, very particularly preferably from 0.07 to 0.12.
In the OCB-type displays according to the invention, the molecules in the layer of the LC medium have a “bend” alignment. On application of an electrical voltage, a realignment of the LC molecules takes place with the longitudinal molecular axes perpendicular to the electrode surfaces.
LC media according to the invention for use in displays of the OCB, TN, IPS, posi-VA, FFS, PS-OCB, PS-TN, PS-IPS, PS-posi-VA and PS-FFS type are preferably those based on compounds with positive dielectric anisotropy according to the second preferred embodiment, and preferably have a positive dielectric anisotropy Δ∈ from +4 to +17 at 20° C. and 1 kHz.
The birefringence Δn in LC media according to the invention for use in displays of the OCB and PS-OCB type is preferably from 0.14 to 0.22, particularly preferably from 0.16 to 0.22.
The birefringence Δn in LC media according to the invention for use in displays of the TN, posi-VA, IPS, FFS, PS-TN, PS-posi-VA, PS-IPS and PS-FFS-type is preferably from 0.07 to 0.15, particularly preferably from 0.08 to 0.13.
LC media according to the invention, based on compounds with positive dielectric anisotropy according to the second preferred embodiment, for use in displays of the TN, posi-VA, IPS, FFS, PS-TN, PS-posi-VA, PS-IPS and PS-FFS-type, preferably have a positive dielectric anisotropy Δ∈ from +2 to +30, particularly preferably from +3 to +20, at 20° C. and 1 kHz.
The LC media according to the invention may also comprise further additives which are known to the person skilled in the art and are described in the literature, such as, for example, polymerization initiators, inhibitors, stabilizers, surface-active substances or chiral dopants. These may be polymerizable or non-polymerizable. Polymerizable additives are accordingly ascribed to the polymerizable component or component A). Non-polymerizable additives are accordingly ascribed to the non-polymerizable component or component B).
In a preferred embodiment the LC media contain one or more chiral dopants, preferably in a concentration from 0.01 to 1%, very preferably from 0.05 to 0.5%. The chiral dopants are preferably selected from the group consisting of compounds from Table B below, very preferably from the group consisting of R- or S-1011, R- or S-2011, R- or S-3011, R- or S-4011, and R- or S-5011.
In another preferred embodiment the LC media contain a racemate of one or more chiral dopants, which are preferably selected from the chiral dopants mentioned in the previous paragraph.
Furthermore, it is possible to add to the LC media, for example, 0 to 15% by weight of pleochroic dyes, furthermore nanoparticles, conductive salts, preferably ethyldimethyldodecylammonium 4-hexoxybenzoate, tetrabutyl-ammonium tetraphenylborate or complex salts of crown ethers (cf., for example, Haller et al., Mol. Cryst. Liq. Cryst. 24, 249-258 (1973)), for improving the conductivity, or substances for modifying the dielectric anisotropy, the viscosity and/or the alignment of the nematic phases. Substances of this type are described, for example, in DE-A 22 09 127, 22 40 864, 23 21 632, 23 38 281, 24 50 088, 26 37 430 and 28 53 728.
The individual components of the preferred embodiments a)-z) of the LC media according to the invention are either known or methods for the preparation thereof can readily be derived from the prior art by the person skilled in the relevant art, since they are based on standard methods described in the literature. Corresponding compounds of the formula CY are described, for example, in EP-A-0 364 538. Corresponding compounds of the formula ZK are described, for example, in DE-A-26 36 684 and DE-A-33 21 373.
The LC media which can be used in accordance with the invention are prepared in a manner conventional per se, for example by mixing one or more of the above-mentioned compounds with one or more polymerizable compounds as defined above, and optionally with further liquid-crystalline compounds and/or additives. In general, the desired amount of the components used in lesser amount is dissolved in the components making up the principal constituent, advantageously at elevated temperature. It is also possible to mix solutions of the components in an organic solvent, for example in acetone, chloroform or methanol, and to remove the solvent again, for example by distillation, after thorough mixing. The invention furthermore relates to the process for the preparation of the LC media according to the invention.
In a preferred embodiment the process of stabilization of the LC media according to the present invention comprises mixing one or more of the above-mentioned compounds with one or more stabilizers of formula I, and optionally with further liquid crystalline compounds and/or additives. In a particularly preferred embodiment, the desired amount of the components used in lesser amount is dissolved in the components making up the principal constituent.
When using a compound of formula I as stabilizers, it is further preferred to add it to the LC mixture under inert atmosphere, preferably under nitrogen or argon.
Advantageously, the mixing process is performed at elevated temperature, preferably above 20° C. and below 120° C., more preferably above 30° C. and below 100° C., most preferably above 40° C. and below 80° C.
It is also possible to mix solutions of the components in an organic solvent, for example in acetone, chloroform or methanol, and to remove the solvent again, for example by distillation, after thorough mixing. The invention furthermore relates to the process for the preparation of the LC media according to the invention.
The stabilization process according to the present invention is particularly useful for LC media exposed to an LCD backlight, typically during the operation of an LC display. Such backlights are preferably cold cathode fluorescent lamps (CCFL) or LED (light-emitting diode) light sources. Advantage of these types of light source is the fact that they do not emit UV light or if so, to a negligible extent. Hence, the light stress the LC mixture is exposed to is comparatively small, because of the absence of UV light which could trigger photochemical reactions.
The stabilizers of formula I are particularly effective when exposed to light with a very small or preferably no portion in the UV region of the spectrum and when used in concentrations of 1000 ppm in the LC mixtures.
The present invention further relates to LC displays comprising LC mixtures described above and below. The liquid crystal display panel includes first and second substrates, an active region on the first substrate, the active region including a plurality of thin film transistors and pixel electrodes, a sealing region along a periphery of the active region and along a corresponding region of the second substrate, sealant in the sealing region, the sealant attaching the first substrate and the second substrate to one another and maintaining a gap therebetween, and a liquid crystal layer within the gap and on the active region side of the sealant.
In another aspect of the present invention, a method of manufacturing an LCD panel includes forming a plurality of pixel electrodes in an active region on a first substrate, applying UV-type hardening sealant on a sealing region positioned along a periphery of the active region, attaching the first and second substrates to each other, and irradiating UV-rays to the sealant to harden the sealant.
In yet another aspect of the present invention, a method of manufacturing an LCD panel includes forming an UV-type hardening sealant in a first sealing region of a first substrate, and dropping liquid crystal on a surface of the first substrate. The first and second substrates are attached to each other at the first and second sealing regions and UV-rays are used to harden the sealant.
In a preferred embodiment according to the present invention, the active area of the display, i.e. the region of the display that contains switchable LC molecules, is during the LC display manufacturing process not exposed to UV light, at least not exposed to UV light except for the UV portion of ambient light, and preferably shielded from UV light. For example, when hardening a UV-type hardening sealant of the panel, the active region, i.e. the part of the display panel inside the frame used for displaying information, is preferably covered by a shadow mask.
In another preferred embodiment of the present invention, the LC display manufacturing process does not include a step of polymerizing the polymerizable compounds contained in the LC medium, for example by exposing the LC medium to heat or actinic radiation as applied in the process of manufacturing an PSA display.
It goes without saying to the person skilled in the art that the LC media according to the invention may also comprise compounds in which, for example, H, N, O, Cl, F have been replaced by the corresponding isotopes like deuterium etc.
The following examples explain the present invention without restricting it. However, they show the person skilled in the art preferred mixture concepts with compounds preferably to be employed and the respective concentrations thereof and combinations thereof with one another. In addition, the examples illustrate which properties and property combinations are accessible.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 15003124.3, filed Oct. 30, 2015, are incorporated by reference herein.
Throughout the patent application and in the working examples, the structures of the liquid-crystal compounds are indicated by means of acronyms. Unless indicated otherwise, the transformation into chemical formulae takes place in accordance with Tables I-III. All radicals CnH2n+1, CmH2m+1, CnH2n, CmH2m and CkH2k are straight-chain alkyl radicals or alkenyl radicals respectively, in each case having n, m or k C atoms; n and m each, independently of one another, denote 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, preferably 1, 2, 3, 4, 5 or 6, and k is 0, 1, 2, 3, 4, 5 or 6. In Table I the ring elements of the respective compound are coded, in Table II the bridging members are listed and in Table III the meanings of the symbols for the left-hand and right-hand side chains of the compounds are indicated.
TABLE I
Ring elements
TABLE II
Bridging members
E
—CH2CH2—
V
—CH═CH—
T
—C≡C—
W
—CF2CF2—
Z
—COO—
ZI
—OCO—
O
—CH2O—
OI
—OCH2—
Q
—CF2O—
QI
—OCF2—
TABLE III
Side chains
Left-hand side chain
Right-hand side chain
n-
CnH2n+1—
-n
—CnH2n+1
nO-
CnH2n+1—O—
-On
—O—CnH2n+1
V-
CH2═CH—
-V
—CH═CH2
nV-
CnH2n+1—CH═CH—
-nV
—CnH2n—CH═CH2
Vn-
CH2═CH—CnH2n—
-Vn
—CH═CH—CnH2n+1
nVm-
CnH2n+1—CH═CH—CmH2m—
-nVm
—CnH2n—CH═CH—CmH2m+1
N-
N≡C—
-N
—C≡N
F-
F—
-F
—F
Cl-
Cl—
-Cl
—Cl
M-
CFH2—
-M
—CFH2
D-
CF2H—
-D
—CF2H
T-
CF3—
-T
—CF3
MO-
CFH2O—
-OM
—OCFH2
DO-
CF2HO—
-OD
—OCF2H
TO-
CF3O—
-OT
—OCF3
T-
CF3—
-T
—CF3
A-
H—C≡C—
-A
—C≡C—H
FXO-
CF2═CHO—
-OXF
—OCH═CF2
Preferred mixture components are shown in Tables A1 and A2 below. The compounds shown in Table A1 are especially suitable for use in LC mixtures with positive dielectric anisotropy. The compounds shown in Table A2 are especially suitable for use in LC mixtures with negative dielectric anisotropy.
TABLE A1
CCP-nV-m
In Table A1, R1* denotes a group selected from the left-hand side chains and R2* denotes a group selected from the right-hand side chains listed in Table III, L1* and L2* are independently of each other H or F, m and n are independently of each other an integer from 1 to 12, preferably 1, 2, 3, 4, 5 or 6, k is 0, 1, 2, 3, 4, 5 or 6, and (O)CmH2m+1 means CmH2m+1 or OCmH2m+1.
TABLE A2
In the formulae below m and n are independently of each other an integer from 1 to 12, preferably 1, 2, 3, 4, 5 or 6, k is 0, 1, 2, 3, 4, 5 or 6 and (O)CmH2m+1 means CmH2m+1 or OCmH2m+1.
In a first preferred embodiment of the present invention, the LC media according to the invention, especially those with positive dielectric anisotropy, comprise one or more compounds selected from the group consisting of compounds from Table A1.
In a second preferred embodiment of the present invention, the LC media according to the invention, especially those with negaitve dielectric anisotropy, comprise one or more compounds selected from the group consisting of compounds from Table A2.
TABLE B
Table B shows possible chiral dopants which can be added to the LC media according to the invention.
The LC media preferably comprise 0 to 10% by weight, in particular 0.01 to 5% by weight, particularly preferably 0.1 to 3% by weight, of dopants. The LC media preferably comprise one or more dopants selected from the group consisting of compounds from Table B.
TABLE C
Table C shows possible stabilizers which can be added to the LC media according to the invention. Therein n denotes an integer from 1 to 12, preferably 1, 2, 3, 4, 5, 6, 7 or 8, and terminal methyl groups are not shown.
The LC media preferably comprise 0 to 10% by weight, in particular 1 ppm to 5% by weight, particularly preferably 1 ppm to 1% by weight, of stabilizers. The LC media preferably comprise one or more stabilizers selected from the group consisting of compounds from Table C.
TABLE D
RM-1
RM-2
RM-3
RM-4
RM-5
RM-6
RM-7
RM-8
RM-9
RM-10
RM-11
RM-12
RM-13
RM-14
RM-15
RM-16
RM-17
RM-18
RM-19
RM-20
RM-21
RM-22
RM-23
RM-24
RM-25
RM-26
RM-27
RM-28
RM-29
RM-30
RM-31
RM-32
RM-33
RM-34
RM-35
RM-36
RM-37
RM-38
RM-39
RM-40
RM-41
RM-42
RM-43
RM-44
RM-45
RM-46
RM-47
RM-48
RM-49
RM-50
RM-51
RM-52
RM-53
RM-54
RM-55
RM-56
RM-57
RM-58
RM-59
RM-60
RM-61
RM-62
RM-63
RM-64
RM-65
RM-66
RM-67
RM-68
RM-69
RM-70
RM-71
RM-72
RM-73
RM-74
RM-75
RM-76
RM-77
RM-78
RM-79
RM-80
RM-81
RM-82
RM-83
RM-84
RM-85
RM-86
RM-87
RM-88
RM-89
RM-90
RM-91
RM-92
RM-93
RM-94
RM-95
RM-96
RM-97
RM-98
RM-99
RM-100
RM-101
RM-102
RM-103
RM-104
RM-105
RM-106
RM-107
RM-108
RM-109
RM-110
RM-111
RM-112
RM-113
RM-114
RM-115
RM-116
RM-117
RM-118
RM-119
RM-120
RM-121
RM-122
RM-123
RM-124
RM-125
RM-126
RM-127
RM-128
RM-129
RM-130
RM-131
Table D shows illustrative reactive mesogenic compounds which can be used in the LC media in accordance with the present invention.
In a preferred embodiment, the mixtures according to the invention comprise one or more polymerizable compounds, preferably selected from the polymerizable compounds of the formulae RM-1 to RM-131. Of these, compounds RM-1, RM-4, RM-8, RM-17, RM-19, RM-35, RM-37, RM-43, RM-47, RM-49, RM-51, RM-59, RM-69, RM-71, RM-83, RM-97, RM-98, RM-104, RM-112, RM-115 and RM-116 are particularly preferred.
In addition, the following abbreviations and symbols are used:
V0 threshold voltage, capacitive [V] at 20° C.,
ne extraordinary refractive index at 20° C. and 589 nm,
no ordinary refractive index at 20° C. and 589 nm,
Δn optical anisotropy at 20° C. and 589 nm,
∈⊥ dielectric permittivity perpendicular to the director at 20° C. and 1 kHz,
∈∥ dielectric permittivity parallel to the director at 20° C. and 1 kHz,
Δ∈ dielectric anisotropy at 20° C. and 1 kHz,
cl.p., T(N,I) clearing point [° C.],
γ1 rotational viscosity at 20° C. [mPa·s],
K1 elastic constant, “splay” deformation at 20° C. [pN],
K2 elastic constant, “twist” deformation at 20° C. [pN],
K3 elastic constant, “bend” deformation at 20° C. [pN].
Unless explicitly noted otherwise, all concentrations in the present application relate to the corresponding mixture as a whole, comprising all solid or liquid-crystalline components, without solvents. Unless explicitly noted otherwise, the expression “x % of compound Y are added to the mixture” means that the concentration of compound Y in the final mixture, i.e. after its addition, is x %.
Unless explicitly noted otherwise, all temperature values indicated in the present application, such as, for example, for the melting point T(C,N), the transition from the smectic (S) to the nematic (N) phase T(S,N) and the clearing point T(N,I), are quoted in degrees Celsius (° C.). M.p. denotes melting point, cl.p.=clearing point. Furthermore, C=crystalline state, N=nematic phase, S=smectic phase and I=isotropic phase. The data between these symbols represent the transition temperatures.
All physical properties are and have been determined in accordance with “Merck Liquid Crystals, Physical Properties of Liquid Crystals”, Status Nov. 1997, Merck KGaA, Germany, and apply for a temperature of 20° C., and Δn is determined at 589 nm and Δ∈ at 1 kHz, unless explicitly indicated otherwise in each case.
The term “threshold voltage” for the present invention relates to the capacitive threshold (V0), also known as the Freedericks threshold, unless explicitly indicated otherwise. In the examples, the optical threshold may also, as generally usual, be quoted for 10% relative contrast (V10).
Unless stated otherwise, the process of polymerizing the polymerizable compounds in the PSA displays as described above and below is carried out at a temperature where the LC medium exhibits a liquid crystal phase, preferably a nematic phase, and most preferably is carried out at room temperature.
Unless stated otherwise, methods of preparing test cells and measuring their electrooptical and other properties are carried out by the methods as described hereinafter or in analogy thereto.
The display used for measurement of the capacitive threshold voltage consists of two plane-parallel glass outer plates at a separation of 25 μm, each of which has on the inside an electrode layer and an unrubbed polyimide alignment layer on top, which effect a homeotropic edge alignment of the liquid-crystal molecules.
The display or test cell used for measurement of the tilt angles consists of two plane-parallel glass outer plates at a separation of 4 μm, each of which has on the inside an electrode layer and a polyimide alignment layer on top, where the two polyimide layers are rubbed antiparallel to one another and effect a homeotropic edge alignment of the liquid-crystal molecules.
The polymerizable compounds are polymerized in the display or test cell by irradiation with UV light of defined intensity for a prespecified time, with a voltage simultaneously being applied to the display (usually 10 V to 30 V alternating current, 1 kHz). In the examples, unless indicated otherwise, a metal halide lamp and an intensity of 100 mW/cm2 is used for polymerization. The intensity is measured using a standard meter (Hoenle UV-meter high end with UV sensor).
The tilt angle is determined by crystal rotation experiment (Autronic-Melchers TBA-105). A low value (i.e. a large deviation from the 90° angle) corresponds to a large tilt here.
Unless stated otherwise, the term “tilt angle” means the angle between the LC director and the substrate, and “LC director” means in a layer of LC molecules with uniform orientation the preferred orientation direction of the optical main axis of the LC molecules, which corresponds, in case of calamitic, uniaxially positive birefringent LC molecules, to their molecular long axis.
The VHR value is measured as follows: 0.3% of a polymerizable monomeric compound is added to the LC host mixture, and the resultant mixture is introduced into VA-VHR test cells which comprise an unrubbed VA-polyimide alignment layer. The LC-layer thickness d is approx. 4 μm, unless stated othewise. The VHR value is determined after 5 min at 100° C. before and after UV exposure at 1 V, 60 Hz, 64 μs pulse (measuring instrument: Autronic-Melchers VHRM-105).
Example 1
Compound 1 is prepared as following.
1a: To a solution of isopropyl-triphenylphosphonium iodide (87.4 g, 0.2 mol) in 120 ml THF is added the solution of potassium tert-butylate (22.8 g; 0.2 mol) at max. 10° C. After stirred for 1 h, the solution of 4-bormo-benzaldehyde (34.0 g, 0.18 mol) in 30 ml THF is added at max. 10° C. The reaction mixture is allowed to warm up to room temperature and stirred overnight. After carefully neutralized with 2 M HCl, the reactive mixture is extracted three time with heptane. The organic phase is combined, dried over anhydrous sodium sulfate, and filtrated through silica gel. After removing solvent in vacuo, 1a is obtained at colorless oil (35.0 g).
1b: To a solution of 1a (35.0 g, 0.16 mol) and 4-benzoxylphenyl boronic acid (37.8 g, 0.16 mol) in 200 ml THF was added 110 ml dist. water and potassium carbonate (14.0 g, 0.25 mol). The resulted suspension is degassed carefully with argon, tris(dibenzylideneacetone)dipalladium(0) (0.84 g, 0.9 mmol) and CataCium A (0.91 g, 2.5 mmol) are then added. The reaction mixture is heated to reflux and stirred for 3 hs. After cooling to room temperature, the reaction mixture is neutralized carefully with 2 M HCl acid. The aqueous phase is extracted with methyl t-butyl ether. The organic phase is combined and washed with sat. aq. NaCl solution, dried over sodium sulfate. After removing solvent, the solid residue recrystallized from ethylacetate to provide 1b as off-white solid (45.0 g).
1c: To the suspension of 1b (45.0 g, 0.14 mol), 4-methylmorpholine-4-oxide (26.8 g; 0.2 mol) in 700 ml aceton and 50 ml distilled water was added 4% aqueous solution of osmium tetraoxide (17 ml, 2.7 mmol) at room temperature. After stirred at RT for 48 hrs, 250 m ml water is added, the mixture is carefully neutralized with 2 M HCl acid. The precipitated crude product is recrystallized with ethyl acetate to provide 1c as off-white solid (27.0 g).
1d: A solution of 1c (27.0 g, 77.5 mmol) in 270 ml tetrahydrofuran is treated with palladium (5%) on activated charcoal (7.5 g) and submitted to hydrogenation for 12 hs. The catalyst is then filtered off, and the remaining solution is concentrated in vacuo. The residue is recrystallized from acetonitrile to provide 1d as white solid (16.0 g).
1: Methacrylic acid (12.0 ml, 0.14 mol) and 4-(dimethylamino)pyridine (0.75 g, 6.1 mmol) is added to a suspension of 1d (16.0 g, 62.0 mmol) in 400 ml dichloromethane. The reaction mixture is treated dropwise at 0° C. with a solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (22.1 g, 0.14 mol) in dichloromethane (50 ml) and stirred for 20 h at room temperature. After removing solvent in vacuo, the oily residue is purified by silica gel chromatography with heptane/ethyl acetate 7:3 as eluent. The obtained product is recrystallized from heptane/ethanol solvent mixture to afford white crystals of 1 (14.0 g, mp. 111° C.).
Example 2
Compound 2 is prepared from the intermediate step 1c in the synthesis of Example 1 as following.
2a: To a solution of 1c (6.00 g, 17.2 mmol) in 80 ml dichloromethane are added 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidhydrochlorid (DAPECI) (4.1 g, 21.3 mmol). The reaction mixture is stirred at room temperature overnight. 100 ml water is added. The aqueous phase is extracted with dichloromethane. The organic phase is combined and dried over anhydrous sodium sulfate. After removing solvent in vacuo, the solid residue is purified by column chromatography with dichloromethane as eluent to provide 2a as white solid (6.4 g).
2b: A suspension of 2a (6.4 g, 12.6 mmol) in 70 ml THF is treated with palladium (5%) on activated charcoal (1.5 g) and submitted to hydrogenation for 10 hs. The catalyst is then filtered off. After removing solvent, the crude product is recrystallized from heptane/toluene solvent mixture to provide 2b as white solid (3.9 g).
2: Methacrylic acid (1.6 g, 18 mmol) and 4-(dimethylamino)pyridine (0.10 g, 0.8 mmol) is added to a suspension of 5b (2.50 g, 7.9 mmol) in dichloromethane (50 ml). The reaction mixture is treated dropwise at 0° C. with a solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (2.9 g, 18 mmol) in dichloromethane (10 ml) and stirred for 20 hs at room temperature. The reaction mixture is concentrated in vacuo, and the oily residue is purified by column chromatography on silica gel with heptane/ethyl acetate mixture as eluent. The obtained product is recrystallized from heptane/methyl tert-butyl ether 3:1 solvent mixture to afford 2 as colorless solid (1.9 g, mp. 26° C.).
Example 3
Compound 3 is prepared as following.
3a: To a solution of 5-bromo-2-hydroxyl-phenyl-acetic acid methyl ester (5.0 g, 20.4 mmol) in 50 ml DCM is added trimethylamine (3.4 ml, 24.4 mmol) and 4-dimethylamino-pyridine (0.13 g, 1.08 mmol) at 0° C. A solution of chloro-triisopropylsilane (4.8 ml, 22.4 mmol) in 20 ml DCM is then added at max. 5° C. After stirring at RT for 4 hrs, 100 ml distilled water is added. The aqueous phase is extracted with DCM. The organic phase is combined and dried over anhydrous sodium sulfate. After removing solvent in vacuo, the solid residue is purified by column chromatography with heptane/chlorobutane as eluent to provide 3a as yellowish oil (7.3 g).
3b: To a solution of 3a (7.3 g, 18.2 mmol) in 90 ml anhydrous THF is added dropwise methyl magnesium iodide (21.9 ml, 66 mmol) at max. −5° C. After slowly warmed up to RT and stirred for 4 hrs, the reaction was quenched by carefully added into 1 L ice-water mixture. After neutralization with 2 M HCl acid, the aqueous phase is extracted with methyl tert-butyl ether. The organic phase is combined and dried over anhydrous sodium sulfate. After removing solvent in vacuo, the oily residue is purified by column chromatography with heptane/DCM mixture as eluent to provide 3b as colorless oil (6.1 g).
3c: To a solution of 3b (6.1 g, 15.2 mmol) and 4-hydroxyl phenyl bis(pinacolato)diboronic ester (3.2 g, 23.0 mmol) in 60 ml THF is added the solution of sodium metaborate (3.2 g, 23 mmol) in 60 ml distilled water. After thoroughly degassing with argon, bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.25 g, 0.3 mmol) is added. The reaction mixture is heated to reflux and stirred for 4 hrs. After cooling to room temperature, the aqueous phase is separated and extracted with ethyl acetate. The organic phase is combined and dried over anhydrous sodium sulfate, and filtrated through silica gel. After removing solvent in vacuo, the oily residue is purified by column chromatography on silica gel with chlorobutane/ethyl acetate mixture as eluent to afford 3c as colorless oil (5.8 g).
3d: To a solution of 6c (5.8 g, 14.0 mmol) in 70 ml anhydrous THF was added dropwise 1 M tetrabutylamonium fluoride solution in THF (17.5 ml, 17.5 mmol) at max. −5° C., and stirred for 1 h. The reaction is then quenched by carefully adding 100 ml distilled water at 0° C. The reaction mixture is extracted with ethyl acetate. The aqueous phase is extracted with ethylacetate. The organic phase is combined and washed with sat. aq. NaCl solution, dried over sodium sulfate. After removing solvent in vacuo, the solid residue is purified by recrystallized from dichloromethane to provide 3d as white solid (2.1 g).
3: Methacrylic acid (2.12 ml, 24.0 mmol) and 4-(dimethylamino)pyridine (0.10 g, 0.81 mmol) is added to a suspension of 3d (2.1 g, 8.1 mmol) in dichloromethane (60 ml). The reaction mixture is treated dropwise at 0° C. with a solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (3.9 g, 25.0 mmol) in dichloromethane (20 ml) and stirred for 20 hs at room temperature. The reaction mixture is concentrated in vacuo, and the oily residue is purified by column chromatography on silica gel with heptane/ethyl acetate mixture as eluent. The obtained product is recrystallized from heptane/methyl tert-butyl ether mixture to afford white crystals of 3 (2.2 g, mp. 73° C.).
Examples 4-10
The following compounds are prepared in analogy to the methods described in Examples 1-3.
Mixture Example 1
The nematic LC host mixture N1 is formulated as follows.
CCH-501
9.00%
cl.p.
70.0°
C.
CCH-35
14.00%
Δn
0.0825
PCH-53
8.00%
Δε
−3.5
CY-3-O4
14.00%
ε||
3.5
CY-5-O4
13.00%
K3/K1
1.00
CCY-2-1
9.00%
γ1
141
mPa s
CCY-3-1
9.00%
V0
2.10
V
CCY-3-O2
8.00%
CCY-5-O2
8.00%
CPY-2-O2
8.00%
Mixture Example 2
The nematic LC host mixture N2 is formulated as follows.
CY-3-O2
18.00%
cl.p.
+74.5°
C.
CPY-2-O2
10.00%
Δn
0.1021
CPY-3-O2
10.00%
Δε
−3.1
CCY-3-O2
9.00%
ε||
3.5
CCY-4-O2
4.00%
K3/K1
1.16
PYP-23
9.00%
γ1
86
mPa s
CC-3-V
40.00%
V0
2.29
V
Polymerizable Mixture Examples
Polymerizable mixtures P11-P110 are prepared by adding one of polymerizable compounds 1 to 10, respectively, to nematic LC host mixture N1 at a concentration of 0.3% by weight.
Polymerizable mixtures P21-P210 are prepared by adding one of polymerizable compounds 1 to 10, respectively, to nematic LC host mixture N2 at a concentration of 0.3% by weight.
For comparison purposes polymerizable mixture C11 is prepared by adding polymerizable compound M1 of prior art to nematic LC host mixture N1 at a concentration of 0.3% by weight, and polymerizable mixture C21 is prepared by adding polymerizable compound M1 of prior art to nematic LC host mixture N2 at a concentration of 0.3% by weight.
Use Examples
Polymerizable mixtures C11 and C21, which contain M1 of prior art, are compared with polymerizable mixtures P11-P110 and P21-P210 which contain one of RMs 1-7 according to the invention with a hydroxy substituent.
Voltage Holding Ratio (VHR)
For measuring the VHR the polymerizable mixtures are inserted into electrooptic test cells. The test cells comprise two AF glass substrates with an ITO electrode layer of approx. 20 nm thickness and a VA-polyimide alignment layer (PI-4) of approx. 100 nm thickness. The LC layer thickness is approx. 4 μm. The VHR is measured at 100° C. with application of a voltage of 1 V/60 Hz. For the sun-test the test cells are irradiated at 20° C. for 2 h with light having an intensity of 750 W/m2 using a Xenon lamp (Atlas Suntest CPS+). For the UV test the test cells are irradiated for 10 min with UV light having an intensity of 100 mW/cm2 (Fe-doped Hg lamp with a 320 nm cut-off filter).
The results are shown in Table 1.
TABLE 1
VHR values
VHR (%)
Mixture
no illumination
2 h Suntest
C11
98.2
97.6
P11
98.8
98.8
P12
98.7
98.7
P13
99.1
98.8
P14
99.1
99.0
P15
98.7
98.7
P16
98.9
99.0
P17
98.3
98.6
P18
98.6
98.8
P19
98.6
98.8
P110
n.a.
n.a.
VHR (%)
Mixture
no illumination
2 h Suntest
10 min UV
C21
98.3
85.6
74.8
P21
98.3
95.4
95.0
P22
98.0
93.1
92.2
P23
98.8
92.3
85.2
P24
98.7
95.1
92.8
P25
98.1
90.8
86.3
P26
98.1
96.0
94.7
P27
98.0
77.7
85.0
P28
98.0
95.3
93.8
P29
97.8
95.5
93.6
P210
96.0
79.1
78.1
It can be seen that polymerizable mixtures P11-P110 and P21-P210 containing hydroxy-substituted compounds 1-7 according to the present invention show a VHR value after suntest and/or UV test that is significantly higher than that of polymerizable mixtures C11 and C21 containing compound M1 of prior art.
Residual RM
The polymerization speed is measured by determining the residual content of residual, unpolymerized monomer (in % by weight) in the mixture after UV exposure at a given intensity and lamp spectrum.
For this purpose the polymerizable mixtures are inserted into electrooptic test cells. The test cells comprise two soda-lime glass substrates with an ITO electrode layer of approx. 200 nm thickness and a VA-polyimide alignment layer (JALS-2096-R1) of approx. 30 nm thickness. The LC layer thickness is approx. 25 μm.
The test cells are irradiated with UV light having an intensity of 100 mW/cm2 (metal halide lamp with a 320 nm cut-off filter) for the time indicated, causing polymerization of the RM, while the temperature at the bottom side of the test cell is kept at 20° C.
The mixture is then rinsed out of the test cell using MEK (methyl ethyl ketone) and the residual amount of unreacted monomer is measured by HPLC. The results are shown in Table 2.
TABLE 2
Residual monomer content
Residual RM (%) after Exposure
Time (min)
Mixture
0
2
4
6
C11
0.300
0.264
0.203
0.173
P11
0.300
0.285
0.238
0.197
P12
0.300
0.252
0.123
0.054
P13
0.300
0.122
0.051
0.026
P14
0.300
0.230
0.122
0.078
P15
0.300
0.275
0.233
0.204
P16
0.300
0.256
0.200
0.147
P17
0.425
0.358
0.283
0.225
P18
0.384
0.344
0.274
0.231
P19
0.395
0.253
0.145
0.089
P110
0.393
0.360
0.310
0.258
Residual RM (%) after
Exposure Time (min)
Mixture
0
2
6
C21
0.300
0.185
0.067
P21
0.300
0.187
0.090
P22
0.300
0.139
0.034
P23
0.300
0.092
0.015
P24
0.300
0.158
0.065
P25
0.300
0.213
0.118
P26
0.300
0.165
0.075
P27
0.425
0.206
0.079
P28
0.384
0.189
0.089
P29
0.395
0.134
0.035
P210
0.393
0.215
0.112
Tilt Angle Generation
For measuring the tilt angle generation the polymerizable mixtures are inserted into electrooptic test cells. The test cells comprise two soda-lime glass substrates with an ITO electrode layer of approx. 200 nm thickness and a VA-polyimide alignment layer (JALS-2096-R1) of approx. 30 nm thickness which is rubbed antiparallel. The LC-layer thickness d is approx. 4 μm.
The test cells are irradiated with UV light having an intensity of 100 mW/cm2 (metal halide lamp with a 320 nm cut-off filter) for the time indicated, with application of a voltage of 24 VRMS (alternating current), causing polymerization of the RM.
The tilt angle is determined before and after UV irradiation by a crystal rotation experiment (Autronic-Melchers TBA-105). The results are shown in Table 3.
TABLE 3
Tilt angles
Tilt Angle (°) after Exposure Time (sec)
Mixture
0
30
60
120
240
360
C11
89.6
89.0
88.2
84.9
79.8
77.5
P11
88.9
87.6
86.5
83.8
78.5
76.1
P12
89.3
89.1
88.4
86.0
81.4
78.8
P13
89.9
83.5
78.8
74.1
71.9
70.5
P14
88.9
88.4
86.2
79.1
72.2
68.5
P15
89.6
89.4
88.6
86.9
83.8
82.1
P16
89.8
89.7
88.2
86.0
80.7
77.7
P17
89.1
88.9
87.8
85.4
80.4
78.0
P18
89.0
89.2
88.1
84.8
78.0
73.7
P19
89.2
89.2
86.0
79.3
71.4
68.6
P110
89.8
89.1
88.7
86.8
82.2
77.6
Tilt Angle (°) after
Exposure Time (sec)
Mixture
0
120
360
C21
88.8
77.2
70.3
P21
88.9
78.7
74.4
P22
89.8
77.2
74.7
P23
89.9
76.3
75.0
P24
89.7
78.3
75.2
P25
89.4
83.2
79.7
P26
89.6
81.7
76.9
P27
87.9
78.8
73.9
P28
88.9
78.1
72.3
P29
89.1
72.1
66.7
P210
89.0
79.8
72.1
The use examples demonstrate that the polymerizable compounds and polymerizable mixtures according to the present invention show in particular a quick polymerization with low amount of residual monomer, while maintaining sufficient pretilt angle generation and sufficient VHR values after suntest or UV exposure for display applications.
Stabilizer Examples
Examples S11-S27
To the nematic host mixture N1 or N2 one of the compounds of Examples 1-7 is added as stabilizer. The mixture compositions are shown in Table 4.
TABLE 4
Stabilized LC mixtures
Compound
LC Host
conc./
Example
Mixture
Compound
ppm
S11
N1
1
300
S12
N1
2
300
S13
N1
3
300
S14
N1
4
500
S21
N2
1
300
S23
N2
3
300
S24
N2
4
500
S25
N2
5
500
S26
N2
6
500
S27
N2
7
500
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
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15337456
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merck patent gmbh
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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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Apr 27th, 2022 09:11AM
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Apr 27th, 2022 09:11AM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 26th, 2022 12:00AM
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Nov 3rd, 2017 12:00AM
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https://www.uspto.gov?id=US11312730-20220426
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Metal complexes containing cyclopentadienyl ligands
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Metal complexes including cyclopentadienyl ligands and methods of using such metal complexes to prepare metal-containing films are provided.
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11312730
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1. A metal complex corresponding in structure to Formula I:
[(R1)nCp]2M1L1 (I)
wherein
M1 is scandium;
each R1 is independently C1-C5-alkyl or silyl;
n is 1, 2, 3, 4, or 5;
Cp is cyclopentadienyl ring; and
L1 is selected from the group consisting of: N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3; and R35, R36—C3HO2; wherein R4, R5, R6, R7, and R8 are each independently C1-C5-alkyl; R33, R34, R35, and R36 are each independently alkyl or silyl; and R32 is silyl.
2. The metal complex of claim 1, wherein each R1 is independently methyl, ethyl, propyl or silyl; R4, R5, R6, R7 and R8 are each independently methyl, ethyl or propyl; and R33, R34, R35, and R36 are each independently C1-C4-alkyl or silyl.
3. The metal complex of claim 1, wherein each R1 is independently methyl or ethyl; R4, R5, R6, R7, and R8 are each independently methyl, or ethyl; and R33, R34, R35, and R36 are each independently methyl, ethyl, propyl or silyl.
4. The metal complex of claim 1, wherein each R1 is methyl; R4, R5, R6, R7, and R8 are each independently methyl; and R32, R33, R34, R35, and R36 are each SiMe3.
5. The metal complex of claim 1, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl; and L1 is 1-(SiMe3)C3H4 or L1 is 1,3-bis-(SiMe3)2C3H3.
6. The metal complex of claim 1, wherein the complex is:
Sc(MeCp)2[1-(SiMe3)C3H4];
Sc(MeCp)2[1,3-bis-(SiMe3)2C3H3];
Sc(MeCp)2[N(SiMe3)2]; or
Sc(MeCp)2(3,5-Me2—C3HN2).
7. A metal complex corresponding in structure to Formula II:
[((R9)nCp)2M2L2]2 (II)
wherein
M2 is scandium;
each R9 is independently C1-C5-alkyl;
n is 1, 2, 3, 4 or 5;
Cp is cyclopentadienyl ring; and
L2 is selected from the group consisting of: Cl, F, Br, I, and 3,5-R10R11—C3HN2; wherein
R10 and R11 are each independently hydrogen or C1-C5-alkyl;
wherein when L2 is Cl, then R9 is C1-C5-alkyl.
8. The metal complex of claim 7, wherein each R9 is independently C1-C4-alkyl.
9. The metal complex of claim 7, wherein L2 is Cl and each R9 is independently methyl, ethyl or propyl.
10. The metal complex of claim 7, wherein the complex is: [Sc(MeCp)2]Cl]2.
11. A method of forming a metal-containing film by a vapor deposition process, the method comprising vaporizing at least one metal complex corresponding in structure to Formula I:
(R1Cp)2M1L1 (I)
wherein
M1 is scandium;
each R1 is independently C1-C5-alkyl or silyl;
Cp is cyclopentadienyl ring; and
L1 is selected from the group consisting of: N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3; and R35, R36—C3HO2; wherein R4, R5, R6, R7, and R8 are each independently C1-C5-alkyl; R33, R34, R35, and R36 are each independently alkyl or silyl; and R32 is silyl.
12. The method of claim 11, wherein each R1 is independently methyl, ethyl, propyl, or silyl; R4, R5, R6, R7, and R8 are each independently methyl, ethyl or propyl; and R33, R34, R35, and R36 are each independently C1-C4-alkyl or silyl.
13. The method of claim 11, wherein each R1 is independently methyl, or ethyl; and R4, R5, R6, R7, R8 are each independently methyl, or ethyl; and R33, R34, R35, and R36 are each independently methyl, ethyl, propyl or silyl.
14. The method of claim 11, wherein each R1 is methyl; R4, R5, R6, R7, and R8 are each independently methyl; and R32, R33, R34, R35, and R36 are each SiMe3.
15. The method of claim 11, wherein each R1 is independently C1-C4-alkyl or silyl; and L1 is 1-(SiMe3)C3H4 or L1 is 1,3-bis-(SiMe3)2C3H3.
16. The method of claim 11, wherein the complex is:
Sc(MeCp)2[1-(SiMe3)C3H4];
Sc(MeCp)2[1,3-bis-(SiMe3)2C3H3];
Sc(MeCp)2[N(SiMe3)2]; and/or
Sc(MeCp)2(3,5-Me2—C3HN2).
17. The method of claim 11, wherein the vapor deposition process is chemical vapor deposition or atomic layer deposition, wherein the chemical vapor deposition is pulsed chemical vapor deposition, continuous flow chemical vapor deposition, or liquid injection chemical vapor deposition, and wherein the atomic layer deposition is liquid injection atomic layer deposition or plasma-enhanced atomic layer deposition.
18. The method of claim 11, wherein the metal complex is delivered to a substrate in pulses alternating with pulses of an oxygen source, wherein the oxygen source is selected from the group consisting of H2O, H2O2, O2, ozone, air, i-PrOH, t-BuOH, and N2O.
19. The method of claim 11, further comprising vaporizing at least one co-reactant selected from the group consisting of hydrogen, hydrogen plasma, oxygen, air, water, ammonia, a hydrazine, a borane, a silane, ozone, and a combination of any two or more thereof, wherein the hydrazine is hydrazine (N2H4) or N,N-dimethylhydrazine.
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19
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CROSS-REFERENCE TO RELATED APPLICATIONS
This patent application is a U.S. national stage application under 35 U.S.C. § 371 of International Patent Application No. PCT/EP2017/001283 filed on 3 Nov. 2017, which claims the benefit of U.S. Provisional Patent Application No. 62/418,981 filed on 8 Nov. 2016. The entire disclosures of each of the above recited applications are incorporated herein by reference.
FIELD OF THE INVENTION
The present technology relates generally to metal complexes including cyclopentadienyl ligands, methods of preparing such complexes and methods of preparing metal-containing thin films using such complexes.
BACKGROUND
Various precursors are used to form thin films and a variety of deposition techniques have been employed. Such techniques include reactive sputtering, ion-assisted deposition, sol-gel deposition, chemical vapor deposition (CVD) (also known as metalorganic CVD or MOCVD), and atomic layer deposition (ALD) (also known as atomic layer epitaxy). CVD and ALD processes are increasingly used as they have the advantages of enhanced compositional control, high film uniformity, and effective control of doping. Moreover, CVD and ALD processes provide excellent conformal step coverage on highly non-planar geometries associated with modern microelectronic devices.
CVD is a chemical process whereby precursors are used to form a thin film on a substrate surface. In a typical CVD process, the precursors are passed over the surface of a substrate (e.g., a wafer) in a low pressure or ambient pressure reaction chamber. The precursors react and/or decompose on the substrate surface creating a thin film of deposited material. Volatile by-products are removed by gas flow through the reaction chamber. The deposited film thickness can be difficult to control because it depends on coordination of many parameters such as temperature, pressure, gas flow volumes and uniformity, chemical depletion effects, and time.
ALD is also a method for the deposition of thin films. It is a self-limiting, sequential, unique film growth technique based on surface reactions that can provide precise thickness control and deposit conformal thin films of materials provided by precursors onto surfaces substrates of varying compositions. In ALD, the precursors are separated during the reaction. The first precursor is passed over the substrate surface producing a monolayer on the substrate surface. Any excess unreacted precursor is pumped out of the reaction chamber. A second precursor is then passed over the substrate surface and reacts with the first precursor, forming a second monolayer of film over the first-formed monolayer of film on the substrate surface. This cycle is repeated to create a film of desired thickness.
Thin films, and in particular thin metal-containing films, have a variety of important applications, such as in nanotechnology and the fabrication of semiconductor devices. Examples of such applications include high-refractive index optical coatings, corrosion-protection coatings, photocatalytic self-cleaning glass coatings, biocompatible coatings, dielectric capacitor layers and gate dielectric insulating films in field-effect transistors (FETs), capacitor electrodes, gate electrodes, adhesive diffusion barriers, and integrated circuits. Dielectric thin films are also used in microelectronics applications, such as the high-κ dielectric oxide for dynamic random access memory (DRAM) applications and the ferroelectric perovskites used in infrared detectors and non-volatile ferroelectric random access memories (NV-FeRAMs). The continual decrease in the size of microelectronic components has increased the need for improved thin film technologies.
Technologies relating to the preparation of scandium-containing and yttrium-containing thin films (e.g., scandium oxide, yttrium oxide, etc.) are of particular interest. For example, scandium-containing films have found numerous practical applications in areas such as catalysts, batteries, memory devices, displays, sensors, and nano- and microelectronics and semiconductor devices. In the case of electronic applications, commercial viable deposition methods using scandium-containing and yttrium-containing precursors having suitable properties including volatility, low melting point, reactivity and stability are needed. However, there are a limited number of available scandium-containing and yttrium-containing compounds which possess such suitable properties. Accordingly, there exists significant interest in the development of scandium and yttrium complexes with performance characteristics which make them suitable for use as precursor materials in vapor deposition processes to prepare scandium-containing and yttrium-containing films. For example, scandium-containing and yttrium-containing precursors with improved performance characteristics (e.g., thermal stabilities, vapor pressures, and deposition rates) are needed, as are methods of depositing thin films from such precursors.
SUMMARY
According to one aspect, a metal complex of Formula I is provided: [(R1)nCp]2M1L1 (I), wherein M1 is a Group 3 metal or a lanthanide (e.g., scandium, yttrium and lanthanum); each R1 is independently hydrogen, C1-C5-alkyl or silyl; n is 1, 2, 3, 4, or 5; Cp is cyclopentadienyl ring; and L1 is selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3; and R35, R36—C3HO2; wherein R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen or C1-C5-alkyl; and R32, R33, R34, R35, and R36 are each independently alkyl or silyl; wherein when M1 is yttrium and L1 is 3,5-R7R8—C3HN2, R1 is C1-C5-alkyl or silyl; and wherein when M1 is yttrium and L1 is N(SiR4R5R6)2, n is 1, 2, 3, or 4.
In other aspects, a metal complex of Formula II is provided: [((R9)nCp)2M2L2]2 (II), wherein M2 is a Group 3 metal or a lanthanide (e.g., scandium, yttrium and lanthanum); each R9 is independently hydrogen or C1-C5-alkyl; n is 1, 2, 3, 4 or 5; Cp is cyclopentadienyl ring; and L2 is selected from the group consisting of: Cl, F, Br, I, and 3,5-R10R11—C3HN2; wherein R10 and R11 are each independently hydrogen or C1-C5-alkyl; wherein when M2 is scandium and L2 is Cl, R9 is C1-C5-alkyl.
In other aspects, methods of forming metal-containing films by vapor deposition, such as CVD and ALD, are provided herein. The method comprises vaporizing at least one metal complex corresponding in structure to Formula I: (R1Cp)2M1L1 (I), wherein M1 is a Group 3 metal or a lanthanide (e.g., scandium, yttrium and lanthanum); each R1 is independently hydrogen, C1-C5-alkyl or silyl; Cp is cyclopentadienyl ring; and L1 is selected from the group consisting of: NR2R3; N(SiR—4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3; and R35, R36—C3HO2; wherein R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen or C1-C5-alkyl; and R32, R33, R34, R35, and R36 are each independently alkyl or silyl.
Other embodiments, including particular aspects of the embodiments summarized above, will be evident from the detailed description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates XPS (X-ray Photoelectron Spectroscopy) analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 2 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 3 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 4 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate.
FIG. 5 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 6 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 7 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 8 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 9 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 10 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 11 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 12 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 13 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 14 illustrates XPS analysis of Sc2O3 films using Sc(MeCp)2(3,5-dimethyl-pyrazolate).
FIG. 15 illustrates dependence of ALD Y2O3 growth rate per cycle on the deposition temperature when depositing [Y(MeCp)2(3,5-MePn—C3HN2)]2.
FIG. 16 illustrates dependence of ALD Y2O3 growth rate per cycle on H2O purge time when depositing [Y(MeCp)2(3,5-MePn—C3HN2)]2 at 125° C., 150° C. and 200° C.
FIG. 17 illustrates ALD Y2O3 growth rate per cycle at 3 different positions in a cross-flow reactor along the precursor/carrier gas flow direction, the precursor inlet, the reactor center, and precursor outlet.
DETAILED DESCRIPTION
Before describing several exemplary embodiments of the present technology, it is to be understood that the technology is not limited to the details of construction or process steps set forth in the following description. The present technology is capable of other embodiments and of being practiced or being carried out in various ways. It is also to be understood that the metal complexes and other chemical compounds may be illustrated herein using structural formulas which have a particular stereochemistry. These illustrations are intended as examples only and are not to be construed as limiting the disclosed structure to any particular stereochemistry. Rather, the illustrated structures are intended to encompass all such metal complexes and chemical compounds having the indicated chemical formula.
In various aspects, metal complexes, methods of making such metal complexes, and methods of using such metal complexes to form thin metal-containing films via vapor deposition processes, are provided.
As used herein, the terms “metal complex” (or more simply, “complex”) and “precursor” are used interchangeably and refer to metal-containing molecule or compound which can be used to prepare a metal-containing film by a vapor deposition process such as, for example, ALD or CVD. The metal complex may be deposited on, adsorbed to, decomposed on, delivered to, and/or passed over a substrate or surface thereof, as to form a metal-containing film. In one or more embodiments, the metal complexes disclosed herein are nickel complexes.
As used herein, the term “metal-containing film” includes not only an elemental metal film as more fully defined below, but also a film which includes a metal along with one or more elements, for example a metal oxide film, metal nitride film, metal silicide film, and the like. As used herein, the terms “elemental metal film” and “pure metal film” are used interchangeably and refer to a film which consists of, or consists essentially of, pure metal. For example, the elemental metal film may include 100% pure metal or the elemental metal film may include at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.9%, or at least about 99.99% pure metal along with one or more impurities. Unless context dictates otherwise, the term “metal film” shall be interpreted to mean an elemental metal film. In some embodiments, the metal-containing film is an elemental scandium or yttrium film. In other embodiments, the metal-containing film is scandium oxide, yttrium oxide, scandium nitride, yttrium nitride, scandium silicide or yttrium silicide film. Such scandium-containing and yttrium-containing films may be prepared from various scandium and yttrium complexes described herein.
As used herein, the term “vapor deposition process” is used to refer to any type of vapor deposition technique, including but not limited to, CVD and ALD. In various embodiments, CVD may take the form of conventional (i.e., continuous flow) CVD, liquid injection CVD, or photo-assisted CVD. CVD may also take the form of a pulsed technique, i.e., pulsed CVD. In other embodiments, ALD may take the form of conventional (i.e., pulsed injection) ALD, liquid injection ALD, photo-assisted ALD, plasma-assisted ALD, or plasma-enhanced ALD. The term “vapor deposition process” further includes various vapor deposition techniques described in Chemical Vapour Deposition: Precursors, Processes, and Applications; Jones, A. C.; Hitchman, M. L., Eds. The Royal Society of Chemistry: Cambridge, 2009; Chapter 1, pp 1-36.
The term “alkyl” (alone or in combination with another term(s)) refers to a saturated hydrocarbon chain of 1 to about 12 carbon atoms in length, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, and so forth. The alkyl group may be straight-chain or branched-chain. “Alkyl” is intended to embrace all structural isomeric forms of an alkyl group. For example, as used herein, propyl encompasses both n-propyl and isopropyl; butyl encompasses n-butyl, sec-butyl, isobutyl and tert-butyl; pentyl encompasses n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl and 3-pentyl. Further, as used herein, “Me” refers to methyl, “Et” refers to ethyl, “Pr” refers to propyl, “i-Pr” refers to isopropyl, “Bu” refers to butyl, “t-Bu” refers to tert-butyl, “iBu” refers to isobutyl, “Pn” refers to and “NPn” refers to neopentyl. In some embodiments, alkyl groups are C1-C5- or C1-C4-alkyl groups.
The term “allyl” refers to an allyl (C3H5) ligand which is bound to a metal center. As used herein, the allyl ligand has a resonating double bond and all three carbon atoms of the allyl ligand are bound to the metal center in η3-coordination by π bonding. Therefore, the complexes of the invention are π complexes. Both of these features are represented by the dashed bonds. When the allyl portion is substituted by one X group, the X1 group replaces an allylic hydrogen to become [X1C3H4]; when substituted with two X groups X1 and X2, it becomes [X1X2C3H3] where X1 and X2 are the same or different, and so forth.
The term “silyl” refers to a —SiZ1Z2Z3 radical, where each of Z1, Z2, and Z3 is independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, amino, and combinations thereof.
The term “trialkylsilyl” refers to a —SiZ4Z5Z6 radical, wherein Z5, Z6, and Z7 are alkyl, and wherein Z5, Z6, and Z7 can be the same or different alkyls. Non-limiting examples of a trialkylsilyl include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS) and tert-butyldimethylsilyl (TBDMS).
Deposition of some metals, including scandium and yttrium, can be difficult to achieve due to thermal stability issues, being either unstable or too stable for deposition. The organometallic complexes disclosed in the embodiments of the invention allow for control of physical properties as well as provide for increased stability and simple high yield synthesis. In this regard, the metal complexes provided herein are excellent candidates for preparation of thin metal-containing films in various vapor deposition processes.
Therefore, according to one aspect, a metal complex of Formula I is provided: [(R1)nCp]2M1L1 (I), wherein M1 is a Group 3 metal or a lanthanide; each R1 is independently hydrogen, C1-C5-alkyl or silyl; n is 1, 2, 3, 4, or 5; Cp is cyclopentadienyl ring; and L1 is selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3; R35, R36—C3HO2; R12N═C—C—NR13; R14R15N—CH2—CH2—NR16—CH2—CH2—NR17R18; and R19O—CH2—CH2—NR20—CH2—CH2—OR21; wherein R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 are each independently hydrogen or C1-C5-alkyl and R32, R33, R34, R35, and R36 are each independently alkyl or silyl.
In some embodiments, M1 may be selected from the group consisting of scandium, yttrium and lanthanum. In other embodiments, M1 may be selected from the group consisting of scandium and yttrium. In particular, M1 may be scandium.
In other embodiments, when M1 is yttrium and L1 is 3,5-R7R8—C3HN2, R1 is C1-C5-alkyl or silyl and/or wherein when M1 is yttrium and L1 is N(SiR4R5R6)2, n is 1, 2, 3, or 4.
In some embodiments, L1 is selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3, and R35, R36—C3HO2.
In some embodiments, L1 is selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(SiMe3)C3H4(trimethyl silylallyl); 1,3-bis-(SiMe3)2C3H3(bis-trimethyl silylallyl), 6-methyl-2,4-heptanedionate.
R1, at each occurrence, can be the same or different. For example, if n is 2, 3, 4, or 5, each R1 may all be hydrogen or all be an alkyl (e.g., C1-C5-alkyl) or all be silyl. Alternatively, if n is 2, 3, 4, or 5, each R1 may be different. For example if n is 2, a first R1 may be hydrogen and a second R1 may be an alkyl (e.g., C1-C5-alkyl) or silyl.
R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 at each occurrence, can be the same or different. For example, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 may all be hydrogen or all be an alkyl (e.g., C1-C5-alkyl).
In one embodiment, up to and including sixteen of R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 may each be hydrogen. For example, at least one of, at least two of, at least three of, at least four of or at least five of, at least six of, at least seven of, at least eight of, at least nine of, at least ten of, at least eleven of, at least twelve of, at least thirteen of, at least fourteen of, at least fifteen of, or at least sixteen of R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R1, R18, R19, R20, and R21 may be hydrogen.
In another embodiment, up to and including sixteen of R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be an alkyl. For example, at least one of, at least two of, at least three of, at least four of or at least five of, at least six of, at least seven of, at least eight of, at least nine of, at least ten of, at least eleven of, at least twelve of, at least thirteen of, at least fourteen of, at least fifteen of, or at least sixteen of R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 may be an alkyl.
R32, R33, and R34 at each occurrence, can be the same or different. For example, R32, R33, and R34 may all be an alkyl (e.g., C1-C5-alkyl) or may all be silyl (e.g., SiMe3).
R35 and R36 at each occurrence, can be the same or different. For example, R35 and R36 may all be the same or different alkyl (e.g., C1-C5-alkyl), R35 and R36 may all be the same or different silyl (e.g., SiMe3) or R35 and R36 may be an alkyl (e.g., C1-C5-alkyl) and a silyl (e.g., SiMe3).
In one embodiment, up to and including two of R32, R33, R34, R35, and R36 each independently may be alkyl. For example, at least one of or at least two of R32, R33, R34, R35, and R36 may be an alkyl.
In another embodiment, up to and including two of R32, R33, R34, R35, and R36 each independently may be silyl. For example, at least one of or at least two of R32, R33, R34, R35, and R36 may be an silyl.
The alkyl groups discussed herein can be C1-C5-alkyl, C1-C7-alkyl, C1-C6-alkyl, C1-C5-alkyl, C1-C4-alkyl, C1-C3-alkyl, C1-C2-alkyl or C1-alkyl. In a further embodiment, the alkyl is C1-C5-alkyl, C1-C4-alkyl, C1-C3-alkyl, C1-C2-alkyl or C1-alkyl. The alkyl group may be straight-chained or branch. In particular, the alkyl is straight-chained. In a further embodiment the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and neopentyl.
The silyl group discussed herein can be, but is not limited to Si(alkyl)3, Si(alkyl)2H, and Si(alkyl)H2, wherein the alkyl is as described above. Examples of the silyl include, but are not limited to SiH3, SiMeH2, SiMe2H, SiMe3, SiEtH2, SiEt2H, SiEt3, SiPrH2, SiPr2H, SiPr3, SiBuH2, SiBu2H, SiBu3, where “Pr” includes i-Pr and “Bu” includes t-Bu.
In some embodiments, each R1 independently may be hydrogen, C1-C4-alkyl or silyl. In another embodiment, each R1 independently may be hydrogen, methyl, ethyl, propyl or silyl. In another embodiment, each R1 independently may be hydrogen, methyl, or ethyl. In particular, each R1 may be methyl.
In some embodiments, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be hydrogen or C1-C4-alkyl. In other embodiments, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be hydrogen, methyl, ethyl or propyl. In other embodiments, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may hydrogen, methyl, or ethyl. In particular, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be hydrogen or methyl.
In some embodiments, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 each independently may be hydrogen or C1-C4-alkyl.
In other embodiments, each R1 independently may be hydrogen, methyl, ethyl, propyl or silyl; and R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be hydrogen, methyl, ethyl or propyl.
In some embodiments, each R1 independently may be hydrogen, methyl, or ethyl; and R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be hydrogen, methyl, or ethyl. In another embodiment, each R1 may be methyl and R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 each independently may be hydrogen or methyl.
In some embodiments, R32, R33, R34, R35, and R36 each independently may be C1-C5-alkyl or silyl. In other embodiments, R32, R33, R34, R35, and R36 each independently may be C1-C4-alkyl or silyl. In other embodiments, R32, R33, R34, R35, and R36 each independently may be methyl, ethyl, propyl or silyl. In other embodiments, R32, R33, R34, R35, and R36 each independently may be methyl, ethyl or silyl. In other embodiments, R32, R33, R34, R35, and R36 each independently may silyl, such as but not limited to, SiH3, SiMeH2, SiMe2H, SiMe3, SiEtH2, SiEt2H, SiEt3, SiPrH2, SiPr2H, SiPr3, SiBuH2, SiBu2H, SiBu3. In particular, R32, R33, R34, R35, and R36 each independently may be SiMe3. In particular, R32, R33, and R34, each independently may be SiMe3. In other embodiments, R35 and R36 may each independently be C1-C4-alkyl, particularly methyl and/or butyl.
In some embodiments, L1 is selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 1-(R32)C3H4; and 1-R33-3-R34—C3H3.
In another embodiment, L1 may be selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 1-(SiMe3)C3H4; 1,3-bis-(SiMe3)2C3H3; and R35, R36—C3HO2.
In another embodiment, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and L1 is NR2R3, wherein R2 and R3 each independently may be hydrogen or C1-C4-alkyl. In another embodiment, each R1 independently may be hydrogen, methyl, ethyl, propyl or silyl; and R2 and R3 each independently may be hydrogen, methyl, ethyl or propyl. In another embodiment, each R1 independently may be hydrogen, methyl, or ethyl; and R2 and R3 each independently may be hydrogen, methyl, or ethyl. In particular, each R1 may be methyl; and R2 and R3 each independently may be hydrogen, methyl, or ethyl.
In another embodiment, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and L1 is N(SiR4R5R6)2, wherein R4, R5, and R6 each independently may be hydrogen or C1-C4-alkyl. In another embodiment, each R1 independently may be hydrogen, methyl, ethyl, propyl or silyl; and R4, R5, and R6 each independently may be hydrogen, methyl, ethyl or propyl. In another embodiment, each R1 independently may be hydrogen, methyl, or ethyl; and R4, R5, and R6 each independently may be hydrogen, methyl, or ethyl. In particular, each R1 may be methyl; and R4, R5, and R6 each independently may be hydrogen, methyl, or ethyl.
In some embodiments, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and L1 may be 3,5-R7R8—C3HN2, wherein R7 and R8 each independently may be hydrogen or C1-C5-alkyl. In other embodiments, each R1 independently may be hydrogen, methyl, ethyl, propyl or silyl. In other embodiments, each R1 independently may be hydrogen, methyl, or ethyl. In particular, each R1 may be methyl. In other embodiments, R7 and R8 each independently may be hydrogen or C1-C4-alkyl or hydrogen. In other embodiments, R7 and R8 each independently may be methyl, ethyl, propyl or hydrogen. In particular, R7 and R8 each independently may be methyl or ethyl.
In some embodiments, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and L1 may be 1-(R32)C3H4, wherein R32 may be C1-C5-alkyl or silyl. In another embodiment, R32 may be C1-C4-alkyl or silyl. In other embodiments, each R1 independently may be hydrogen, methyl, ethyl or silyl and R32 may be silyl. In another embodiment, each R1 independently may be hydrogen, methyl or ethyl and R32 may be a silyl, such as but not limited to, SiH3, SiMeH2, SiMe2H, SiMe3, SiEtH2, SiEt2H, SiEt3, SiPrH2, SiPr2H, SiPr3, SiBuH2, SiBu2H, SiBu3. In particular, each R1 independently may be methyl or ethyl and R32 may be SiMe3.
In other embodiments, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and L1 may be 1-R33-3-R34—C3H3, wherein R33 and R34 may be C1-C5-alkyl or silyl. In another embodiment, each R1 independently may be hydrogen, methyl, ethyl or silyl and R33 and R34 may each independently be C1-C4-alkyl or silyl and R32 may be silyl. In another embodiment, each R1 independently may be hydrogen, methyl or ethyl and R33 and R34 may each independently be a silyl, such as but not limited to, SiH3, SiMeH2, SiMe2H, SiMe3, SiEtH2, SiEt2H, SiEt3, SiPrH2, SiPr2H, SiPr3, SiBuH2, SiBu2H, SiBu3. In particular, each R1 independently may be methyl or ethyl and R33 and R34 may be SiMe3.
In other embodiments, each R1 independently may be hydrogen, C1-C4-alkyl or silyl; and L1 may be R35, R36—C3HO2, wherein R35 and R36 may be C1-C5-alkyl or silyl. In another embodiment, each R1 independently may be hydrogen, methyl, ethyl or silyl and R35 and R36 may each independently be C1-C4-alkyl or silyl. In another embodiment, each R1 independently may be hydrogen, methyl or ethyl and R35 and R36 may each independently be a silyl, such as but not limited to, SiH3, SiMeH2, SiMe2H, SiMe3, SiEtH2, SiEt2H, SiEt3, SiPrH2, SiPr2H, SiPr3, SiBuH2, SiBu2H, SiBu3. In another embodiment, each R1 independently may be hydrogen, methyl or ethyl and R35 and R36 may each independently be C1-C4-alkyl, particularly methyl and/or butyl. In particular, each R1 independently may be methyl or ethyl and R35 and R36 may independently each be methyl or butyl. In particular, each R1 independently may be methyl or ethyl and R35 and R36 may be SiMe3.
Examples of metal complexes corresponding in structure to Formula I are provided in Table 1.
TABLE 1
Complexes of Formula I
Sc(MeCp)2[1-(SiMe3)C3H4]
(1)
Sc(MeCp)2[1,3-bis-(SiMe3)2C3H3]
(2)
Sc(MeCp)2[N(SiMe3)2]
(3)
Sc(MeCp)2(3,5-Me2-C3HN2)
(4)
(5)
(6)
(7)
Y(MeCp)2(3,5-MePn-C3HN2)
(8)
(9)
(10)
In one embodiment, a mixture of two or more organometallic complexes of Formula I is provided.
In another embodiment, a metal complex of Formula II is provided: [((R9)nCp)2M2L2]2 (II), wherein M2 is a Group 3 metal or a lanthanide; each R9 is independently hydrogen or C1-C5-alkyl; n is 1, 2, 3, 4 or 5; Cp is cyclopentadienyl ring; and L2 is selected from the group consisting of: Cl; F; Br; I; 3,5-R10R11—C3HN2; R22N═C—C—NR23; R24R25N—CH2—NR26—CH2—NR27R28, and R29O—CH2—NR30—CH2—OR31; wherein R1, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 are each independently hydrogen or C1-C5-alkyl.
In some embodiments, M2 may be selected from the group consisting of scandium, yttrium and lanthanum. In other embodiments, M2 may be selected from the group consisting of scandium and yttrium. In particular, M2 may be scandium.
In other embodiments, wherein when M2 is scandium and L2 is Cl, R9 is C1-C5-alkyl.
In some embodiments, L2 is selected from the group consisting of: Cl; F; Br; I; and 3,5-R10R11—C3HN2
R9, at each occurrence, can be the same or different. For example, if n is 2, 3, 4, or 5, each R9 may all be hydrogen or all be an alkyl (e.g., C1-C5-alkyl). Alternatively, if n is 2, 3, 4, or 5, each R1 may be different. For example if n is 2, a first R9 may be hydrogen and a second R9 may be an alkyl (e.g., C1-C5-alkyl).
R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31, at each occurrence, can be the same or different. For example, R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 may all be hydrogen or all be an alkyl (e.g., C1-C5-alkyl).
In one embodiment, up to and including eleven of R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 may each be hydrogen. For example, at least one of, at least two of, at least three of, at least four of or at least five of, at least six of, at least seven of, at least eight of, at least nine of, at least ten of, at least eleven of R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 may be hydrogen.
In another embodiment, up to and including eleven of R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 each independently may be an alkyl. For example, at least one of, at least two of, at least three of, at least four of or at least five of, at least six of, at least seven of, at least eight of, at least nine of, at least ten of, at least eleven of R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 may be an alkyl.
The alkyl groups discussed herein can be C1-C5-alkyl, C1-C7-alkyl, C1-C6-alkyl, C1-C5-alkyl, C1-C4-alkyl, C1-C3-alkyl, C1-C2-alkyl or C1-alkyl. In a further embodiment, the alkyl is C1-C5-alkyl, C1-C4-alkyl, C1-C3-alkyl, C1-C2-alkyl or C1-alkyl. The alkyl group may be straight-chained or branch. In particular, the alkyl is straight-chained. In a further embodiment the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and neopentyl.
In some embodiments, each R9 independently may be C1-C5-alkyl. In other embodiments, each R9 independently may be hydrogen or C1-C4-alkyl. In another embodiment, each R9 independently may be hydrogen, methyl, ethyl, or propyl. In another embodiment, each R9 independently may be hydrogen, methyl, or ethyl. In particular, each R9 may be methyl.
In a particular embodiment, M2 may be scandium and each R9 independently may be a C1-C4-alkyl. In another embodiment, M2 may be scandium, L2 may be Cl and each R9 independently may be methyl, ethyl or propyl. In particular, each R9 may independently be methyl or ethyl.
In another particular embodiment, M2 may be yttrium and each R9 independently may be a C1-C4-alkyl. In another embodiment, M2 may be yttrium, L2 may be 3,5-R10R11—C3HN2, each R9 independently may be methyl, ethyl or propyl and R10 and R9 each independently may be a C1-C5-alkyl. In particular, each R9 independently may be methyl or ethyl.
Examples of metal complexes corresponding in structure to Formula II are provided in Table 2.
TABLE 2
Complexes of Formula II
[Sc(MeCp)2]Cl]2
[Y(MeCp)2(3,5-MePn-C3HN2)]2
(11)
(12)
Additional other metal complexes provided herein include Y(MeCp)2(3,5-tBu2—C3HN2)(THF), Y(MeCp)2(3,5-MePn—C3HN2)(THF), and Y(MeCp)2(3,5-tBu, iBu-C3HN2)(THF). As used herein, “THF” refers to tetrahydrofuran
The metal complexes provided herein may be prepared, for example, as shown below in Scheme A.
The metal complexes provided herein may be used to prepare metal-containing films such as, for example, elemental scandium, elemental yttrium, scandium oxide, yttrium oxide, scandium nitride, yttrium nitride and scandium silicide and yttrium silicide films. Thus, according to another aspect, a method of forming a metal-containing film by a vapor deposition process is provided. The method comprises vaporizing at least one organometallic complex corresponding in structure to Formula I, Formula II, or a combination thereof, as disclosed herein. For example, this may include (1) vaporizing the at least one complex and (2) delivering the at least one complex to a substrate surface or passing the at least one complex over a substrate (and/or decomposing the at least one complex on the substrate surface).
A variety of substrates can be used in the deposition methods disclosed herein. For example, metal complexes as disclosed herein may be delivered to, passed over, or deposited on a variety of substrates or surfaces thereof such as, but not limited to, silicon, crystalline silicon, Si(100), Si(111), silicon oxide, glass, strained silicon, silicon on insulator (SOI), doped silicon or silicon oxide(s) (e.g., carbon doped silicon oxides), silicon nitride, germanium, gallium arsenide, tantalum, tantalum nitride, aluminum, copper, ruthenium, titanium, titanium nitride, tungsten, tungsten nitride, and any number of other substrates commonly encountered in nanoscale device fabrication processes (e.g., semiconductor fabrication processes). As will be appreciated by those of skill in the art, substrates may be exposed to a pretreatment process to polish, etch, reduce, oxidize, hydroxylate, anneal and/or bake the substrate surface. In one or more embodiments, the substrate surface contains a hydrogen-terminated surface.
In certain embodiments, the metal complex may be dissolved in a suitable solvent such as a hydrocarbon or an amine solvent to facilitate the vapor deposition process. Appropriate hydrocarbon solvents include, but are not limited to, aliphatic hydrocarbons, such as hexane, heptane and nonane; aromatic hydrocarbons, such as toluene and xylene; and aliphatic and cyclic ethers, such as diglyme, triglyme, and tetraglyme. Examples of appropriate amine solvents include, without limitation, octylamine and N,N-dimethyldodecylamine. For example, the metal complex may be dissolved in toluene to yield a solution with a concentration from about 0.05 M to about 1 M.
In another embodiment, the at least one metal complex may be delivered “neat” (undiluted by a carrier gas) to a substrate surface.
In one embodiment, the vapor deposition process is chemical vapor deposition.
In another embodiment, the vapor deposition process is atomic layer deposition.
The ALD and CVD methods encompass various types of ALD and CVD processes such as, but not limited to, continuous or pulsed injection processes, liquid injection processes, photo-assisted processes, plasma-assisted, and plasma-enhanced processes. For purposes of clarity, the methods of the present technology specifically include direct liquid injection processes. For example, in direct liquid injection CVD (“DLI-CVD”), a solid or liquid metal complex may be dissolved in a suitable solvent and the solution formed therefrom injected into a vaporization chamber as a means to vaporize the metal complex. The vaporized metal complex is then transported/delivered to the substrate surface. In general, DLI-CVD may be particularly useful in those instances where a metal complex displays relatively low volatility or is otherwise difficult to vaporize.
In one embodiment, conventional or pulsed CVD is used to form a metal-containing film vaporizing and/or passing the at least one metal complex over a substrate surface. For conventional CVD processes see, for example Smith, Donald (1995). Thin-Film Deposition: Principles and Practice. McGraw-Hill.
In one embodiment, CVD growth conditions for the metal complexes disclosed herein include, but are not limited to:
a. Substrate temperature: 50-600° C.
b. Evaporator temperature (metal precursor temperature): 0-200° C.
c. Reactor pressure: 0-100 Torr
d. Argon or nitrogen carrier gas flow rate: 0-500 sccm
e. Oxygen flow rate: 0-500 sccm
f. Hydrogen flow rate: 0-500 sccm
g. Run time: will vary according to desired film thickness
In another embodiment, photo-assisted CVD is used to form a metal-containing film by vaporizing and/or passing at least one metal complex disclosed herein over a substrate surface.
In a further embodiment, conventional (i.e., pulsed injection) ALD is used to form a metal-containing film by vaporizing and/or passing at least one metal complex disclosed herein over a substrate surface. For conventional ALD processes see, for example, George S. M., et al. J. Phys. Chem., 1996, 100, 13121-13131.
In another embodiment, liquid injection ALD is used to form a metal-containing film by vaporizing and/or passing at least one metal complex disclosed herein over a substrate surface, wherein at least one metal complex is delivered to the reaction chamber by direct liquid injection as opposed to vapor draw by a bubbler. For liquid injection ALD processes see, for example, Potter R. J., et al., Chem. Vap. Deposition, 2005, 11(3), 159-169.
Examples of ALD growth conditions for metal complexes disclosed herein include, but are not limited to:
a. Substrate temperature: 0-400° C.
b. Evaporator temperature (metal precursor temperature): 0-200° C.
c. Reactor pressure: 0-100 Torr
d. Argon or nitrogen carrier gas flow rate: 0-500 sccm
e. Reactive gas flow rate: 0-500 sccm
f. Pulse sequence (metal complex/purge/reactive gas/purge): will vary according to chamber size
g. Number of cycles: will vary according to desired film thickness
In another embodiment, photo-assisted ALD is used to form a metal-containing film by vaporizing and/or passing at least one metal complex disclosed herein over a substrate surface. For photo-assisted ALD processes see, for example, U.S. Pat. No. 4,581,249.
In another embodiment, plasma-assisted or plasma-enhanced ALD is used to form a metal-containing film by vaporizing and/or passing at least one metal complex disclosed herein over a substrate surface.
In another embodiment, a method of forming a metal-containing film on a substrate surface comprises: during an ALD process, exposing a substrate to a vapor phase metal complex according to one or more of the embodiments described herein, such that a layer is formed on the surface comprising the metal complex bound to the surface by the metal center (e.g., nickel); during an ALD process, exposing the substrate having bound metal complex with a co-reactant such that an exchange reaction occurs between the bound metal complex and co-reactant, thereby dissociating the bound metal complex and producing a first layer of elemental metal on the surface of the substrate; and sequentially repeating the ALD process and the treatment.
The reaction time, temperature and pressure are selected to create a metal-surface interaction and achieve a layer on the surface of the substrate. The reaction conditions for the ALD reaction will be selected based on the properties of the metal complex. The deposition can be carried out at atmospheric pressure but is more commonly carried out at a reduced pressure. The vapor pressure of the metal complex should be low enough to be practical in such applications. The substrate temperature should be high enough to keep the bonds between the metal atoms at the surface intact and to prevent thermal decomposition of gaseous reactants. However, the substrate temperature should also be high enough to keep the source materials (i.e., the reactants) in the gaseous phase and to provide sufficient activation energy for the surface reaction. The appropriate temperature depends on various parameters, including the particular metal complex used and the pressure. The properties of a specific metal complex for use in the ALD deposition methods disclosed herein can be evaluated using methods known in the art, allowing selection of appropriate temperature and pressure for the reaction. In general, lower molecular weight and the presence of functional groups that increase the rotational entropy of the ligand sphere result in a melting point that yields liquids at typical delivery temperatures and increased vapor pressure.
A metal complex for use in the deposition methods will have all of the requirements for sufficient vapor pressure, sufficient thermal stability at the selected substrate temperature and sufficient reactivity to produce a reaction on the surface of the substrate without unwanted impurities in the thin film. Sufficient vapor pressure ensures that molecules of the source compound are present at the substrate surface in sufficient concentration to enable a complete self-saturating reaction. Sufficient thermal stability ensures that the source compound will not be subject to the thermal decomposition which produces impurities in the thin film.
Thus, the metal complexes disclosed herein utilized in these methods may be liquid, solid, or gaseous. Typically, the metal complexes are liquids or solids at ambient temperatures with a vapor pressure sufficient to allow for consistent transport of the vapor to the process chamber.
In one embodiment, an elemental metal, a metal nitride, a metal oxide, or a metal silicide film can be formed by delivering for deposition at least one metal complex as disclosed herein, independently or in combination with a co-reactant. In this regard, the co-reactant may be deposited or delivered to or passed over a substrate surface, independently or in combination with the at least one metal complex. As will be readily appreciated, the particular co-reactant used will determine the type of metal-containing film is obtained. Examples of such co-reactants include, but are not limited to hydrogen, hydrogen plasma, oxygen, air, water, an alcohol, H2O2, N2O, ammonia, a hydrazine, a borane, a silane, ozone, or a combination of any two or more thereof. Examples of suitable alcohols include, without limitation, methanol, ethanol, propanol, isopropanol, tert-butanol, and the like. Examples of suitable boranes include, without limitation, hydridic (i.e., reducing) boranes such as borane, diborane, triborane and the like. Examples of suitable silanes include, without limitation, hydridic silanes such as silane, disilane, trisilane, and the like. Examples of suitable hydrazines include, without limitation, hydrazine (N2H4), a hydrazine optionally substituted with one or more alkyl groups (i.e., an alkyl-substituted hydrazine) such as methylhydrazine, tert-butylhydrazine, N,N- or N,N′-dimethylhydrazine, a hydrazine optionally substituted with one or more aryl groups (i.e., an aryl-substituted hydrazine) such as phenylhydrazine, and the like.
In one embodiment, the metal complexes disclosed herein are delivered to the substrate surface in pulses alternating with pulses of an oxygen-containing co-reactant as to provide metal oxide films. Examples of such oxygen-containing co-reactants include, without limitation, H2O, H2O2, O2, ozone, air, i-PrOH, t-BuOH, or N2O.
In other embodiments, a co-reactant comprises a reducing reagent such as hydrogen. In such embodiments, an elemental metal film is obtained. In particular embodiments, the elemental metal film consists of, or consists essentially of, pure metal. Such a pure metal film may contain more than about 80, 85, 90, 95, or 98% metal. In even more particular embodiments, the elemental metal film is a scandium film or a yttrium film.
In other embodiments, a co-reactant is used to form a metal nitride film by delivering for deposition at least one metal complex as disclosed herein, independently or in combination, with a co-reactant such as, but not limited to, ammonia, a hydrazine, and/or other nitrogen-containing compounds (e.g., an amine) to a reaction chamber. A plurality of such co-reactants may be used. In further embodiments, the metal nitride film is a nickel nitride film.
In another embodiment, a mixed-metal film can be formed by a vapor deposition process which vaporizes at least one metal complex as disclosed herein in combination, but not necessarily at the same time, with a second metal complex comprising a metal other than that of the at least one metal complex disclosed herein.
In a particular embodiment, the methods of the present technology are utilized for applications such as dynamic random access memory (DRAM) and complementary metal oxide semi-conductor (CMOS) for memory and logic applications, on substrates such as silicon chips.
Any of the metal complexes disclosed herein may be used to prepare thin films of the elemental metal, metal oxide, metal nitride, and/or metal silicide. Such films may find application as oxidation catalysts, anode materials (e.g., SOFC or LIB anodes), conducting layers, sensors, diffusion barriers/coatings, super- and non-superconducting materials/coatings, tribological coatings, and/or, protective coatings. It is understood by one of ordinary skill in the art that the film properties (e.g., conductivity) will depend on a number of factors, such as the metal(s) used for deposition, the presence or absence of co-reactants and/or co-complexes, the thickness of the film created, the parameters and substrate employed during growth and subsequent processing.
Fundamental differences exist between the thermally-driven CVD process and the reactivity-driven ALD process. The requirements for precursor properties to achieve optimum performance vary greatly. In CVD a clean thermal decomposition of the complex to deposit the required species onto the substrate is critical. However, in ALD such a thermal decomposition is to be avoided at all costs. In ALD, the reaction between the input reagents must be rapid at the surface resulting in formation of the target material on the substrate. However, in CVD, any such reaction between species is detrimental due to their gas phase mixing before reaching the substrate, which could lead to particle formation. In general it is accepted that good CVD precursors do not necessarily make good ALD precursors due to the relaxed thermal stability requirement for CVD precursors. In this invention, Formula I metal complexes possess enough thermal stability and reactivity toward select co-reactants to function as ALD precursors, and they possess clean decomposition pathways at higher temperatures to form desired materials through CVD processes as well. Therefore, the metal complexes described by Formula I are advantageously useful as viable ALD and CVD precursors.
Reference throughout this specification to “one embodiment,” “certain embodiments,” “one or more embodiments” or “an embodiment” means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the present technology. Thus, the appearances of the phrases such as “in one or more embodiments,” “in certain embodiments,” “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily referring to the same embodiment of the present technology. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.
Although the present technology herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present technology. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present technology without departing from the spirit and scope of the present technology. Thus, it is intended that the present technology include modifications and variations that are within the scope of the appended claims and their equivalents. The present technology, thus generally described, will be understood more readily by reference to the following examples, which is provided by way of illustration and is not intended to be limiting.
The invention can additionally or alternatively include one or more of the following embodiments.
Embodiment 1
A metal complex corresponding in structure to Formula I: [(R1)nCp]2M1L1 (I), wherein M1 is a Group 3 metal or a lanthanide (e.g., scandium, yttrium and lanthanum); each R1 is independently hydrogen, C1-C5-alkyl or silyl; n is 1, 2, 3, 4, or 5; Cp is cyclopentadienyl ring; and L1 is selected from the group consisting of: NR2R3; N(SiR4R5R6)2; 3,5-R7R8—C3HN2; 1-(R32)C3H4; 1-R33-3-R34—C3H3; and R35, R36—C3HO2; R12N═C—C—NR13; R14R15N—CH2—CH2—NR16—CH2—CH2—NR17R18; and R19O—CH2—CH2—NR20—CH2—CH2—OR21; wherein R2, R3, R4, R5, R6, R7, R8, R12, R13, R4, R15, R16, R17, R18, R19, R20, and R21 are each independently hydrogen or C1-C5-alkyl; and R32, R33, R34, R35, and R36 are each independently alkyl or silyl; optionally, wherein when M1 is yttrium and L1 is 3,5-R7R8—C3HN2, R1 is C1-C5-alkyl or silyl; and optionally, wherein when M1 is yttrium and L1 is N(SiR4R5R6)2, n is 1, 2, 3, or 4.
Embodiment 2
The metal complex of embodiment 1, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl; and R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen or C1-C4-alkyl; and R32, R33, R34, R35, and R36 are each independently C1-C5-alkyl or silyl.
Embodiment 3
The metal complex of embodiment 1 or 2, wherein each R1 is independently hydrogen, methyl, ethyl, propyl or silyl, preferably hydrogen, methyl or ethyl, more preferably methyl; and R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen, methyl, ethyl or propyl, preferably hydrogen methyl or ethyl, more preferably hydrogen or methyl; and R32, R33, R34, R35, and R36 are each independently C1-C4-alkyl or silyl, preferably methyl, ethyl, propyl or silyl, more preferably SiMe3.
Embodiment 4
The metal complex of any one of the previous embodiments, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl; and L1 is NR2R3, wherein R2 and R3 are each independently hydrogen or C1-C4-alkyl.
Embodiment 5
The metal complex of embodiment 4, wherein each R1 is independently hydrogen, methyl, ethyl, propyl or silyl, preferably hydrogen, methyl, or ethyl, more preferably methyl; and R2 and R3 are each independently hydrogen, methyl, ethyl or propyl, preferably hydrogen, methyl or ethyl.
Embodiment 6
The metal complex of any one of the previous embodiments, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl; and L1 is N(SiR4R5R6)2, wherein R4, R5, and R6 are each independently hydrogen or C1-C4-alkyl.
Embodiment 7
The metal complex of embodiment 6, wherein each R1 is independently hydrogen, methyl, ethyl, propyl or silyl, preferably hydrogen, methyl, or ethyl, more preferably methyl; and R4, R5, and R6 are each independently hydrogen, methyl, ethyl or propyl, preferably hydrogen, methyl or ethyl.
Embodiment 8
The metal complex of any one of the previous embodiments, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl; and L1 is 3,5-R7R8—C3HN2, wherein R7 and R8 are each independently hydrogen or C1-C5-alkyl.
Embodiment 9
The metal complex of embodiment 8, wherein each R1 is independently hydrogen, methyl, ethyl, propyl or silyl, preferably hydrogen, methyl, or ethyl, more preferably methyl.
Embodiment 10
The metal complex of any one of the previous embodiments, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl, preferably hydrogen, methyl, ethyl or silyl; and L1 is 1-(R32)C3H4, wherein R32 is C1-C5-alkyl or silyl, preferably R32 is methyl, ethyl or silyl, more preferably L1 is 1-(SiMe3)C3H4.
Embodiment 11
The metal complex of any one of the previous embodiments, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl, preferably hydrogen, methyl, ethyl or silyl; and L1 is 1-R33-3-R34—C3H3, wherein R33 and R34 are each independently C1-C5-alkyl or silyl, preferably R33 and R34 are each independently methyl, ethyl or silyl, more preferably L1 is 1,3-bis-(SiMe3)2C3H3.
Embodiment 12
The metal complex of any one of the previous embodiments, wherein each R1 is independently hydrogen, C1-C4-alkyl or silyl, preferably hydrogen, methyl, ethyl or silyl; and L1 is R35, R36—C3HO2, wherein R35 and R36 are each independently C1-C5-alkyl or silyl, preferably R35 and R36 are each independently methyl, ethyl, propyl, butyl, or silyl, more preferably L1 is 6-methyl-2,4-heptanedionate, i.e., Me, iBu-C3HO2.
Embodiment 13
The metal complex of any one of the previous embodiments, wherein the complex is: Sc(MeCp)2[1-(SiMe3)C3H4]; Sc(MeCp)2[1,3-bis-(SiMe3)2C3H3]; Sc(MeCp)2[N(SiMe3)2]; Sc(MeCp)2(3,5-Me2—C3HN2); Sc(MeCp)2(Me, iBu-C3HO2), preferably Sc(MeCp)2[1-(SiMe3)C3H4]; Sc(MeCp)2[1,3-bis-(SiMe3)2C3H3]; Sc(MeCp)2[N(SiMe3)2]; and Sc(MeCp)2(3,5-Me2—C3HN2).
Embodiment 14
A metal complex corresponding in structure to Formula II: [((R9)nCp)2M2L2]2(II), wherein M2 is a Group 3 metal or a lanthanide (e.g., scandium, yttrium and lanthanum); each R9 is independently hydrogen or C1-C5-alkyl; n is 1, 2, 3, 4 or 5; Cp is cyclopentadienyl ring; and L2 is selected from the group consisting of: Cl; F; Br; I; 3,5-R10R11—C3HN2; R22N═C—C—NR23; R24R25N—CH2—NR26—CH2—NR27R28, and R29O—CH2—NR30—CH2—OR31; wherein R10, R11, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 are each independently hydrogen or C1-C5-alkyl, optionally wherein when M2 is scandium and L2 is Cl, R9 is C1-C5-alkyl.
Embodiment 15
The metal complex of embodiment 14, wherein each R9 is independently C1-C5-alkyl
Embodiment 16
The metal complex of embodiment 14 or 15, wherein each R9 is independently hydrogen or C1-C4-alkyl, preferably hydrogen, methyl, ethyl or propyl, preferably hydrogen, methyl, or ethyl, more preferably methyl.
Embodiment 17
The metal complex of embodiments 14, 15 or 16, wherein M2 is scandium; each R9 is independently a C1-C4-alkyl, preferably methyl, ethyl or propyl, more preferably methyl; and preferably L2 is Cl.
Embodiment 18
The metal complex of embodiments 14, 15 or 16, wherein M2 is yttrium; each R9 is independently a C1-C5-alkyl, preferably methyl, ethyl or propyl; more preferably methyl or ethyl; and preferably L2 is 3,5-R10R11—C3HN2 and each R9 is independently.
Embodiment 19
The metal complex of embodiments 14, 15, 16, 17 or 18, wherein the complex is [Sc(MeCp)2]Cl]2; and [Y(MeCp)2(3,5-MePn—C3HN2)]2.
Embodiment 20
A method of forming a metal-containing film by a vapor deposition process, the method comprising vaporizing at least one metal complex according to any one of the previous embodiments.
Embodiment 21
The method of embodiment 20, wherein the vapor deposition process is chemical vapor deposition, preferably pulsed chemical vapor deposition, continuous flow chemical vapor deposition, and/or liquid injection chemical vapor deposition.
Embodiment 22
The method of embodiment 20, wherein the vapor deposition process is atomic layer deposition, preferably liquid injection atomic layer deposition or plasma-enhanced atomic layer deposition.
Embodiment 23
The method of any one of embodiments 20, 21 or 22, wherein the metal complex is delivered to a substrate in pulses alternating with pulses of an oxygen source, preferably the oxygen source is selected from the group consisting of H2O, H2O2, O2, ozone, air, i-PrOH, t-BuOH, and N2O.
Embodiment 24
The method of any one of embodiments 20, 21, 22, or 23 further comprising vaporizing at least one co-reactant selected from the group consisting of hydrogen, hydrogen plasma, oxygen, air, water, ammonia, a hydrazine, a borane, a silane, ozone, and a combination of any two or more thereof, preferably the at least one co-reactant is a hydrazine (e.g., hydrazine (N2H4), N,N-dimethylhydrazine).
Embodiment 25
The method of any one of embodiments 20, 21, 22, 23 or 24, wherein the method is used for a DRAM or CMOS application.
EXAMPLES
Unless otherwise noted, all synthetic manipulations are performed under an inert atmosphere (e.g., purified nitrogen or argon) using techniques for handling air-sensitive materials commonly known in the art (e.g., Schlenk techniques).
Example 1: Preparation of Complex 11 ([Sc(MeCp)2Cl]2)
A 500 mL Schlenk flask equipped with a magnetic stirrer was charged with ScCl3 (15.5 g, 0.102 mol) and KMeCp (24.2 g, 0.205 mol) followed by anhydrous diethyl ether (200 mL). The mixture was stirred at room temperature (˜18° C. to ˜24° C.) for 12 hours under a nitrogen atmosphere, giving a maroon colored suspension. The solvent was removed under pressure and the resulting solid was extracted with 5×50 mL toluene, and filtered through a medium frit. The filtrate was removed from the solvent under reduced pressure to afford the final product as a yellow powder (16.4 g, 0.0344 mol, 67% yield). 1H NMR (C6D6) of product: δ 2.02 (12H, MeC5H4), 6.09 (8H, MeC5H4), 6.24 (8H, MeC5H4). 13C NMR (C6D6) of product: δ 15.4 (MeC5H4), 114.4 (MeC5H4), 116.0 (MeC5H4), 124.9 (MeC5H4).
Example 2: Preparation of Complex 3 (Sc(MeCp)2[N(SiMe3)2])
A 250 mL Schlenk flask equipped with magnetic stirrer was charged with [Sc(MeCp)2Cl]2 (4.6 g, 0.0098 mol) and KN(SiMe3)2(3.9 g, 0.020 mol) followed by anhydrous diethyl ether (100 mL). The mixture was stirred at room temperature (˜18° C. to ˜24° C.) for 12 hours under a nitrogen atmosphere, giving a peach-colored suspension. The solvent was removed under pressure and the resulting solid was extracted with 3×30 mL hexane, and filtered through a medium frit. The filtrate was removed from the solvent under reduced pressure to afford the final product as a yellow powder. (6.7 g, 0.018 mol, 90% yield. 1H NMR (C6D6) of product: δ 1.10 (18H, SiMe3), 2.04 (6H, MeC5H4), 5.85 (4H, MeC5H4), 6.00 (4H, MeC5H4). 13C NMR (C6D6) of product: δ 4.2 (SiMe3), 15.7 (MeC5H4), 114.3 (MeC5H4), 115.9 (MeC5H4), 125.0 (MeC5H4).
Example 3: Synthesis of Complex 2 (Sc(MeCp)2[1,3-bis(trimethylsilyl)allyl])
A 250 mL Schlenk flask equipped with a magnetic stirrer was charged with [Sc(MeCp)2Cl]2 (1.0 g, 2.1 mmol) and K(1,3-bis-trimethylsilyl-allyl) (1.05 g, 4.7 mmol) followed by addition of anhydrous diethyl ether (100 mL). The mixture was stirred at room temperature (˜18° C. to ˜24° C.) for 12 hours under a nitrogen atmosphere, giving an orange suspension. The solvent was removed under reduced pressure and the resulting solid was extracted with 3×30 mL hexane, and filtered through a medium frit. The filtrate was removed of solvent under reduced pressure to afford the final product as a red liquid. (1.0 g, 2.6 mmol, 62% yield). 1H NMR (C6D6) of product: δ 0.04 (18H, SiMe3), 1.84 (3H, MeC5H4), 1.94 (3H, MeC5H4), 4.90 (2H, allyl CH(TMS)), 5.97 (2H, MeC5H4), 6.04 (4H, MeC5H4), 6.29 (2H, MeC5H4), 7.67 (1H, allyl CH).
Example 4: Synthesis of Complex 1 (Sc(MeCp)2(1-trimethylsilylallyl))
A 250 mL Schlenk flask equipped with a magnetic stirrer was charged with [Sc(MeCp)2Cl]2 (5.2 g, 10.9 mmol) and K(trimethylsilyl-allyl) (3.3 g, 21.8 mmol) followed by addition of anhydrous diethyl ether (100 mL). The mixture was stirred at room temperature (˜18° C. to ˜24° C.) for 12 hours under a nitrogen atmosphere, giving an orange suspension. The solvent was removed under reduced pressure and the resulting solid was extracted with 3×30 mL pentane, and filtered through a medium frit. The filtrate was removed of solvent under reduced pressure to afford the final product as a red liquid. (3.7 g, 11.7 mmol, 54% yield). 1H NMR (C6D6) of product: δ −0.02 (9H, SiMe3), 1.82 (6H, MeC5H4), 2.29 (1H, allyl CH2), 4.15 (1H, allyl CH2), 4.73 (1H, allyl CH(TMS)), 5.94 (8H, MeC5H4), 7.47 (1H, allyl CH).
Example 5: Synthesis of Complex 4 (Sc(MeCp)2(3,5-dimethyl-pyrazolate))
A 500 mL Schlenk flask equipped with a magnetic stirrer was charged with [Sc(MeCp)2Cl]2 (12.0 g, 25.1 mmol) and KMe2Pz (6.75 g, 50.3 mmol) followed by addition of anhydrous THF (150 mL). The mixture was stirred at room temperature (˜18° C. to ˜24° C.) for 12 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the resulting yellow sticky solid was extracted with 5×20 mL toluene, and filtered through a medium frit. The filtrate was removed of solvent under reduced pressure to provide a red oil. Further distillation under vacuum afforded the final product as a light yellow liquid (10.7 g, 35.9 mmol, 72% yield). 1H NMR (C6D6) of product: δ 1.85 (6H, MeC5H4), 2.28 (6H, Me2Pz), 5.84 (4H, MeC5H4), 5.96 (1H, Me2Pz), 6.20 (4H, MeC5H4).
Example 6: Synthesis of Complex 8 (Y(MeCp)2(3-methyl-5-pentyl-pyrazolate))
A 500 mL Schlenk flask equipped with a magnetic stirrer was charged with [Y(MeCp)2Cl]2 (9.33 g, 16.5 mmol) and K(Me,Pn)Pz (6.28 g, 33.0 mmol) followed by addition of anhydrous THF (150 mL). The mixture was stirred at room temperature for 12 hours (˜18° C. to ˜24° C.) under a nitrogen atmosphere. The solvent was removed under reduced pressure and the resulting yellow sticky solid was extracted with 5×20 mL toluene, and filtered through a medium frit. The filtrated was removed of solvent under reduced pressure to provide a red oil. Further distillation under vacuum afforded the final product as a light yellow liquid (7.7 g, 19.3 mmol, 58% yield). 1H NMR (C6D6) of product: δ 0.94 (3H, Pentyl), 1.40 (4H, Pentyl), 1.75 (2H, Pentyl), 2.16 (6H, MeC5H4), 2.17 (3H, Me,PnPz), 2.65 (2H, Pentyl), 5.66 (4H, MeC5H4), 5.90 (1H, Me,PnPz), 5.96 (4H, MeC5H4).
Example 7: Synthesis of Complex 9 (Sc(MeCp)2(6-methyl-2,4-heptanedionate))
A 500 mL Schlenk flask equipped with a magnetic stirrer was charged with [Sc(MeCp)2Cl]2 (1.0 g, 1.8 mmol) and K(6-Methyl-2,4-heptanedionate) (0.67 g, 3.7 mmol) followed by addition of anhydrous THF (150 mL). The mixture was stirred at room temperature for 12 hours (˜18° C. to ˜24° C.) under a nitrogen atmosphere. The solvent was removed under reduced pressure and the resulting yellow sticky solid was extracted with 3×20 mL toluene, and filtered through a medium frit. The filtrated was removed of solvent under reduced pressure to provide an orange oil (0.8 g, 2.1 mmol, 58% yield). 1H NMR (C6D6) of product: δ 0.89 (6H, iBu), 1.71 (3H, Me), 1.89 (2H, iBu), 2.03 (6H, MeC5H4), 2.04 (1H, iBu), 5.24 (1H, diketonate), 5.85 (4H, MeC5H4), 6.05 (2H, MeC5H4), 6.14 (2H, MeC5H4).
Example 8: Synthesis of Complex 10 (Y(MeCp)2(6-Methyl-2,4-heptanedionate))
A 500 mL Schlenk flask equipped with a magnetic stirrer was charged with [Y(MeCp)2Cl]2 (1.5 g, 2.4 mmol) and K(6-Methyl-2,4-heptanedionate) (0.89 g, 4.9 mmol) followed by addition of anhydrous THF (150 mL). The mixture was stirred at room temperature for 12 hours (˜18° C. to ˜24° C.) under a nitrogen atmosphere. The solvent was removed under reduced pressure and the resulting yellow sticky solid was extracted with 3×20 mL toluene, and filtered through a medium frit. The filtrated was removed of solvent under reduced pressure to provide an orange oil (1.2 g, 2.9 mmol, 60% yield). 1H NMR (C6D6) of product: δ 0.89 (6H, iBu), 1.72 (3H, Me), 1.91 (2H, iBu), 2.04 (1H, iBu), 2.10 (6H, MeC5H4), 5.25 (1H, diketonate), 5.95 (4H, MeC5H4), 6.10 (2H, MeC5H4), 6.15 (2H, MeC5H4).
Example 9: ALD of Sc2O3 Film Using Complex 4 (Sc(MeCp)2(3,5-dimethyl-pyrazolate)) and Water
Sc(MeCp)2(3,5-dimethyl-pyrazolate) was heated to 100-115° C. in a stainless steel bubbler and delivered into an ALD reactor using about 20 sccm of nitrogen as the carrier gas, and pulsed for about 2 seconds followed by a ˜28-58 second purge. A pulse of water vapor (I second) was then delivered from a room temperature cylinder of water followed by a 60-second nitrogen purge. A needle valve was present between the deposition chamber and the water cylinder, and was adjusted so as to have an adequate water vapor dose. The scandium oxide was deposited at about 175-300° C. for up to 300 cycles onto silicon chips having a thin layer of native oxide, SiO2. The film was cooled down in the reactor to about 60° C. under vacuum with nitrogen purge before unloading. Film thicknesses in the range of 60-260 Å were obtained, and preliminary results show a growth rate of ˜1 Angstrom/cycle. XPS (X-ray Photoelectron Spectroscopy) analysis confirmed the existence of scandium oxide with N and C contaminants on the top surface, which were removed during the XPS analysis. The XPS data in FIGS. 1-14 shows the films have no more than 1% of any element except the desired scandium and oxygen once the surface contamination has been removed by sputtering. In the bulk, only Sc and O were detected, and the stoichiometry measured matched the theoretical composition of Sc2O3.
Example 10: ALD of Y2O3 Film Using Complex 12 ([Y(MeCp)2(3,5-MePn—C3HN2)]2)
General Methods
[Y(MeCp)2(3,5-MePn—C3HN2)]2 was heated to 130-180° C. in a stainless steel bubbler, delivered into a cross-flow ALD reactor using nitrogen as a carrier gas and deposited by ALD using water. H2O was delivered by vapor draw from a stainless steel ampule at room temperature. Silicon chips having a native SiO2 layer in the range of 14-17 Å thick were used as substrates. As-deposited films were used for thickness and optical property measurements using an optical ellipsometer. Selected samples were analyzed by XPS for film composition and impurity concentrations.
Example 10a
[Y(MeCp)2(3,5-MePn—C3HN2)]2 was heated to 170° C., delivered into an ALD reactor using 20 sccm of nitrogen as the carrier gas, and pulsed for 7 seconds from a bubbler followed by a 20 second of N2 purge, followed by a 0.015 second pulse of H2O and 90 second of N2 purge in each ALD cycle, and deposited at multiple temperatures from 125 to 250° C. for 200 or more cycles. As-deposited films were cooled down in the reactor to ˜80° C. under nitrogen purge before unloading. Film thickness in the range of 150 to 420 Å was deposited. Growth rate per cycle data at a fixed reactor inlet position were plotted in FIG. 15.
The curve in FIG. 15 indicates that the growth rate of Y2O3 from an un-optimized H2O ALD process appeared to be temperature dependent under the same deposition conditions. The higher the temperature, the higher the growth rate. Further tests revealed that the growth rate at higher temperatures appeared to be affected by the H2O purge time, which may be due to initial formation of Y(OH)3 and/or strong absorption of H2O by the Y2O3 film at higher temperatures. For example, no saturation was reached even after 120 seconds of H2O purge at 200° C., while its dependence on the H2O purge time is much smaller at ˜150° C. or lower as shown in FIG. 16.
Example 10b
[Y(MeCp)2(3,5-MePn—C3HN2)]2 was heated to 170-176° C., delivered into an ALD reactor using 20 sccm of nitrogen as the carrier gas, and pulsed from 3 to 13 seconds from a bubbler to generate various precursor doses, followed by a 60 second of N2 purge, then by a 0.015 second pulse of H2O and 30 second of N2 purge in each ALD cycle, and deposited at 135° C. for 350 cycles. The film thickness was monitored at 3 different positions in the cross-flow reactor along the precursor/carrier gas flow direction, the precursor inlet, the reactor center, and precursor outlet. Growth rate per cycle data are plotted in FIG. 17.
The saturation of the growth rate per cycle (GPC) at ˜0.79 Å/cycle with the precursor dose as well as the convergence of the growth rates at the three different positions suggest that the process at 135° C. is truly an ALD process with insignificant contribution of any CVD component to the growth rate. Under optimized saturated growth conditions, an excellent thickness uniformity of ≤±1.3% over a 6˜7″ diameter area of the cross-flow reactor has been achieved.
The full ALD window with deposition temperature has not yet been determined. This precursor was thermally stable at higher temperatures ≥250° C.
All publications, patent applications, issued patents and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.
The words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively.
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16347028
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merck patent gmbh
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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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Apr 27th, 2022 09:11AM
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Apr 27th, 2022 09:11AM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 19th, 2022 12:00AM
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Jun 8th, 2018 12:00AM
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https://www.uspto.gov?id=US11306080-20220419
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Crystalline form of a BACE inhibitor, compositions, and use
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The present invention provides a novel crystalline form of verubecestat (Crystalline Form II of Verubecestat) and pharmaceutically acceptable compositions thereof, each of which may be useful in treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof. Non-limiting examples of such Aβ pathologies, including Alzheimer's disease and mild cognitive impairment, are disclosed herein.
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11306080
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1. A crystalline form of verubecestat characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94 and 14.98 in a powder x-ray diffraction obtained using Cu K alpha radiation.
2. The crystalline form of verubecestat according to claim 1, characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94, 14.53, 14.98, 16.23, 16.63, and 26.18.
3. The crystalline form of verubecestat according to claim 2, characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94, 14.53, 14.98, 16.23, 16.63, 17.77, 21.77, 23.24, and 26.18.
4. The crystalline form of verubecestat according to claim 3, characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94, 14.53, 14.98, 16.23, 16.63, 17.77, 20.84, 21.77, 23.24, 26.18, 30.88, and 33.39.
5. The crystalline form of verubecestat according to claim 4 characterized by substantially the same powder x-ray diffraction pattern as shown in FIG. 1.
6. The crystalline form of verubecestat of claim 1 exhibiting a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
7. A crystalline form of verubecestat according to claim 6 exhibiting a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
8. The crystalline form of verubecestat according to claim 6 that exhibits a melting point substantially the same as shown in the differential scanning calorimetry scan of FIG. 2.
9. The crystalline form of verubecestat of claim 1 having a solid state 13C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
10. The crystalline form of verubecestat according to claim 9 having a solid state 13C NMR spectrum exhibiting any three of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
11. The crystalline form of verubecestat according to claim 9 having a solid state 13C NMR spectrum exhibiting any four of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
12. The crystalline form of verubecestat according to claim 9 having a solid state 13C NMR spectrum exhibiting any five of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
13. The crystalline form of verubecestat according to claim 9 having a solid state 13C NMR spectrum exhibiting the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
14. The crystalline form of verubecestat according to claim 9 having a solid state 13C NMR substantially as shown in FIG. 4.
15. The crystalline form of verubecestat of claim 1 having an ORTEP representation as shown in FIG. 5.
16. The crystalline form of verubecestat according to claim 1 further characterized as exhibiting a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
17. The crystalline form of verubecestat according to claim 16, further characterized as exhibiting a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
18. The crystalline form of verubecestat according to claim 1, further characterized by a solid state 13C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
19. The crystalline form of verubecestat according to claim 16, further characterized by a solid state 13C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
20. The crystalline form of verubecestat according to claim 17, further characterized by a solid state 13C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
21. The crystalline form of verubecestat according to claim 1, further having a ORTEP representation as shown in FIG. 5.
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FIELD OF THE INVENTION
This invention provides a novel crystalline form of verubecestat (described below), a potent inhibitor of BACE-1 and BACE-2, pharmaceutically acceptable compositions thereof, and methods for their preparation and use in treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof, such as Alzheimer's disease and mild cognitive impairment.
BACKGROUND
Amyloid beta peptide (“Aβ”) is a primary component of β amyloid fibrils and plaques, which are regarded as having a role in an increasing number of pathologies. Examples of such pathologies include, but are not limited to, Alzheimer's disease, Down's syndrome, Parkinson's disease, memory loss (including memory loss associated with Alzheimer's disease and Parkinson's disease), attention deficit symptoms (including attention deficit symptoms associated with Alzheimer's disease (“AD”), Parkinson's disease, and Down's syndrome), dementia (including pre-senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease, and Down's syndrome), progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment (including olfactory impairment associated with Alzheimer's disease, Parkinson's disease, and Down's syndrome), β-amyloid angiopathy (including cerebral amyloid angiopathy), hereditary cerebral hemorrhage, amnestic mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis (β2 microglobulins and complications arising therefrom), neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeld-Jakob disease, traumatic brain injury and the like.
Aβ peptides are short peptides which are made from the proteolytic break-down of the transmembrane protein called amyloid precursor protein (“APP”). Aβ peptides are made from the cleavage of APP by β-secretase activity at a position near the N-terminus of Aβ, and by gamma-secretase activity at a position near the C-terminus of Aβ. (APP is also cleaved by α-secretase activity, resulting in the secreted, non-amyloidogenic fragment known as soluble APPα.) Beta site APP Cleaving Enzyme-1 (“BACE-1”) is regarded as the primary aspartyl protease responsible for the production of Aβ by β-secretase activity. The inhibition of BACE-1 has been shown to inhibit the production of Aβ.
AD is estimated to afflict more than 20 million people worldwide and is believed to be the most common cause of dementia. AD is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary tangles. Presently, treatment of Alzheimer's disease is limited to the treatment of its symptoms rather than the underlying causes. Symptom-improving agents approved for this purpose include, for example, N-methyl-D-aspartate receptor antagonists such as memantine (Namenda®, Forest Pharmaceuticals, Inc.), cholinesterase inhibitors such as donepezil (Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine (Razadyne Reminyl®), and tacrine (Cognex®).
In AD, Aβ peptides, formed through β-secretase and gamma-secretase activity, can form tertiary structures that aggregate to form amyloid fibrils. Aβ peptides have also been shown to form Aβ oligomers (sometimes referred to as “Aβ aggregates” or “Abeta oligomers”). Aβ oligomers are small multimeric structures composed of 2 to 12 Aβ peptides that are structurally distinct from Aβ fibrils. Amyloid fibrils can deposit outside neurons in dense formations known as senile plaques, neuritic plaques, or diffuse plaques in regions of the brain important to memory and cognition. Aβ oligomers are cytotoxic when injected in the brains of rats or in cell culture. This Aβ plaque formation and deposition and/or Aβ oligomer formation, and the resultant neuronal death and cognitive impairment, are among the hallmarks of AD pathophysiology. Other hallmarks of AD pathophysiology include intracellular neurofibrillary tangles comprised of abnormally phosphorylated tau protein, and neuroinflammation.
Evidence suggests that Aβ, Aβ fibrils, aggregates, oligomers, and/or plaque play a causal role in AD pathophysiology. (Ohno et al., Neurobiology of Disease, No. 26 (2007), 134-145). Mutations in the genes for APP and presenilins 1/2 (PS1/2) are known to cause familial AD and an increase in the production of the 42-amino acid form of Aβ is regarded as causative. Aβ has been shown to be neurotoxic in culture and in vivo. For example, when injected into the brains of aged primates, fibrillar Aβ causes neuronal cell death around the injection site. Other direct and circumstantial evidence of the role of Aβ in Alzheimer etiology has also been published.
BACE-1 has become an accepted therapeutic target for the treatment of Alzheimer's disease, including prodromal treatment. For example, McConlogue et al., J. Bio. Chem., Vol. 282, No. 36 (September 2007), have shown that partial reductions of BACE-1 enzyme activity and concomitant reductions of Aβ levels lead to a dramatic inhibition of AO-driven AD-like pathology, making β-secretase a target for therapeutic intervention in AD. Ohno et al. Neurobiology of Disease, No. 26 (2007), 134-145, report that genetic deletion of BACE-1 in 5XFAD mice abrogates Aβ generation, blocks amyloid deposition, prevents neuron loss found in the cerebral cortex and subiculum (brain regions manifesting the most severe amyloidosis in 5XFAD mice), and rescues memory deficits in 5XFAD mice. The group also reports that Aβ is ultimately responsible for neuron death in AD and concludes that BACE-1 inhibition has been validated as an approach for the treatment of AD. Roberds et al., Human Mol. Genetics, 2001, Vol. 10, No. 12, 1317-1324, established that inhibition or loss of β-secretase activity produces no profound phenotypic defects while inducing a concomitant reduction in Aβ. Luo et al., Nature Neuroscience, Vol. 4, No. 3, March 2001, report that mice deficient in BACE-1 have normal phenotype and abolished β-amyloid generation.
More recently, Jonsson, et al. have reported in Nature, Vol. 488, pp. 96-99 (August 2012), that a coding mutation (A673T) in aPP gene protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. More specifically, a allele of rs63750847, a single nucleotide polymorphism (SNP), results in an alanine to threonine substitution at position 673 in APP (A673T). This SNP was found to be significantly more common in a healthy elderly control group than in an Alzheimer's disease group. A673T substitution is adjacent to aspartyl protease beta-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in a heterologous cell expression system in vitro. Jonsson, et al. report that an APP-derived peptide substrate containing a673T mutation is processed 50% less efficiently by purified human BACE-1 enzyme when compared to a wild-type peptide. Jonsson et al. indicate that the strong protective effect of aPP-A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease.
BACE-1 has also been identified or implicated as a therapeutic target for a number of other diverse pathologies in which Aβ or Aβ fragments have been identified to play a causative role. One such example is in the treatment of AD-type symptoms of patients with Down's syndrome. The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Down's syndrome. Down's syndrome patients tend to acquire AD at an early age, with almost all those over 40 years of age showing Alzheimer's-type pathology. This is thought to be due to the extra copy of aPP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of Aβ causing the prevalence of AD seen in this population. Furthermore, Down's patients who have a duplication of a small region of chromosome 21 that does not include aPP gene do not develop AD pathology. Thus, it is thought that inhibitors of BACE-1 could be useful in reducing Alzheimer's type pathology in Down's syndrome patients.
Another example is in the treatment of glaucoma (Guo et al., PNAS, Vol. 104, No. 33, Aug. 14, 2007). Glaucoma is a retinal disease of the eye and a major cause of irreversible blindness worldwide. Guo et al. report that Aβ colocalizes with apoptotic retinal ganglion cells (RGCs) in experimental glaucoma and induces significant RGC cell loss in vivo in a dose- and time-dependent manner. The group report having demonstrated that targeting different components of aβ formation and aggregation pathway, including inhibition of β-secretase alone and together with other approaches, can effectively reduce glaucomatous RGC apoptosis in vivo. Thus, the reduction of Aβ production by the inhibition of BACE-1 could be useful, alone or in combination with other approaches, for the treatment of glaucoma.
Another example is in the treatment of olfactory impairment. Getchell et al., Neurobiology of Aging, 24 (2003), 663-673, have observed that the olfactory epithelium, a neuroepithelium that lines the posterior-dorsal region of the nasal cavity, exhibits many of the same pathological changes found in the brains of AD patients, including deposits of Aβ, the presence of hyperphosphorylated tau protein, and dystrophic neurites among others. Other evidence in this connection has been reported by Bacon A W, et al., Ann NY Acad Sci 2002; 855:723-31; Crino P B, Martin J A, Hill W D, et al., Ann Otol Rhinol Laryngol, 1995; 104:655-61; Davies D C, et al., Neurobiol Aging, 1993; 14:353-7; Devanand D P, et al., Am J Psychiatr, 2000; 157:1399-405; and Doty R L, et al., Brain Res Bull, 1987; 18:597-600. It is reasonable to suggest that addressing such changes by reduction of Aβ by inhibition of BACE-1 could help to restore olfactory sensitivity in patients with AD.
For compounds which are inhibitors of BACE-2, another example is in the treatment of type-II diabetes, including diabetes associated with amyloidogenesis. BACE-2 is expressed in the pancreas. BACE-2 immunoreactivity has been reported in secretory granules of beta cells, co-stored with insulin and IAPP, but lacking in the other endocrine and exocrine cell types. Stoffel et al., WO2010/063718, disclose the use of BACE-2 inhibitors in the treatment of metabolic diseases such as Type-II diabetes. The presence of BACE-2 in secretory granules of beta cells suggests that it may play a role in diabetes-associated amyloidogenesis. (Finzi, G. Franzi, et al., Ultrastruct Pathol. 2008 November-December; 32(6):246-51.)
Other diverse pathologies characterized by the formation and deposition of Aβ or fragments thereof, and/or by the presence of amyloid fibrils, oligomers, and/or plaques, include neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, traumatic brain injury (“TBI”), Creutzfeld-Jakob disease and the like, type II diabetes (which is characterized by the localized accumulation of cytotoxic amyloid fibrils in the insulin producing cells of the pancreas), and amyloid angiopathy. In this regard reference can be made to the patent literature. For example, Kong et al., US2008/0015180, disclose methods and compositions for treating amyloidosis with agents that inhibit Aβ peptide formation. As another example, Loane, et al. report the targeting of amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. (Loane et al., “Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury”, Nature Medicine, Advance Online Publication, published online Mar. 15, 2009.) Still other diverse pathologies characterized by the inappropriate formation and deposition of Aβ or fragments thereof, and/or by the presence of amyloid fibrils, and/or for which inhibitor(s) of BACE are expected to be of therapeutic value are discussed further hereinbelow.
The compound:
and its tautomer:
which are collectively and individually referred to herein as “verubecestat”, and pharmaceutically acceptable salts thereof, are disclosed in PCT Patent Publication No. WO2011/044181 (incorporated herein by reference), as a potent inhibitor of BACE-1 and BACE-2, together with pharmaceutical compositions thereof. Also disclosed is the use of verubecestat in treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof, including Alzheimer's disease. A preparation of verubecestat is also disclosed therein.
The “endo” (or “amino”) tautomer of verubecestat may be depicted as
and named as N-[3-[(5R)-3-amino-5,6-dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide.
The “exo” (or “imine”) tautomer of verubecestat, which is also shown above, may be depicted as
and named as 5-fluoro-N-[4-fluoro-3-[(5R)-tetrahydro-3-imino-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiazin-5-yl]phenyl]-2-pyridinecarboxamide.
For ease of description, and unless otherwise specified, the structural formula:
is intended to encompass the endo form, or the exo form, or a mixture of both of the endo and exo forms.
The physical and biological attributes of a drug's active ingredient, such as solubility, stability, melting point, bioavailability, and the like can be affected by the solid-state form. PCT publication numbers WO2016/025364 and WO2016053767 disclose certain forms of verubecestat. The present invention provides a novel crystalline form of verubecestat described herein, which, surprisingly and advantageously exhibits improved thermodynamic stability while maintaining good chemical stability and other advantageous properties, as described herein.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a novel crystalline form of verubecestat, here referred to as “Crystalline Form II of Verubecestat” (or alternatively as “Crystalline Form II of verubecestat,” or alternatively as “Cyrstalline Form II of Verubecestat”, or alternatively as “Cyrstalline Form II”, or as “Form II”). In other embodiments, the present invention provides pharmaceutically acceptable compositions of Crystalline Form II of Verubecestat. In further embodiments, the present invention provides methods for the use of the Crystalline Form II of Verubecestat in the preparation of a medicament which may be useful (alone or together with additional active ingredients) in treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof. Non-limiting examples of such Aβ pathologies, including Alzheimer's disease and amnestic mild cognitive impairment, are disclosed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of a Powder X-Ray Diffraction (“PXRD”) pattern of Crystalline Form II of Verubecestat, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2Θ) in degrees.
FIG. 2 is a graph of a differential scanning calorimetry (“DSC”) thermogram of Crystalline Form II of Verubecestat. The graph plots the normalized heat flow in units of Watts/gram (W/g) versus the measured sample temperature (° C.) with exotherms up.
FIG. 3 is a graph of a thermal gravimetric analysis (“TGA”) of Crystalline Form II of verubecestat. The graph plots the weight (percentage) against temperature (° C.).
FIG. 4 depicts a solid state NMR (nuclear magnetic resonance) spectrum of Crystalline Form II of verubecestat.
FIG. 5 is an ORTEP representation of the single crystal structure of Crystalline Form II of Verubecestat generated from the crystallographic coordinates shown in Table 4.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims.
“FIG” (or “FIG.” or “Fig.” or “Fig” or “fig.” or “fig”) means “Figure” (or “figure”) and refers to the corresponding drawing.
“Patient” includes both human and other animals.
“Mammal” includes humans and other mammalian animals.
“m/z” refers to a mass spectrum peak.
“PXRD” refers to powder x-ray diffraction.
“DSC” refers to differential scanning calorimetry.
“TGA” refers to thermal gravimetric analysis.
“Excipient” means an essentially inert substance used as a diluent or to give form or consistency to a formulation.
The term “composition” (or “pharmaceutical composition” or “pharmaceutically acceptable composition”) as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. The term is intended to encompass a product comprising active ingredient(s), and the inert ingredient(s), if any, that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the invention encompass any composition made by admixing the Crystalline Form II of Verubecestat and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term “composition” (or “pharmaceutical composition” or “pharmaceutically acceptable composition”) as used herein is also intended to encompass either the bulk composition and/or individual dosage units. (Such compositions and units can additionally comprise additional active ingredients as described herein.) The bulk composition and each individual dosage unit can contain fixed amounts of active agent(s). The bulk composition is material that has not yet been formed into individual dosage units. Non-limiting examples of dosage units include oral dosage units such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass administration of afore-said bulk composition and individual dosage units.
As noted above, verubecestat is capable of tautomerism and may therefore be depicted as the “endo” (or “amine”) form or the “exo” (or “imine”) form, each of which are shown above. Those skilled in the art will appreciate that the relative amount(s) of each tautomeric form of verubecestat that is (or is not) present in a given sample may vary as influenced by the physical conditions in which the compound is present. As noted below, the endo (or amino) form of verubecestat has been observed to be the dominant tautomeric form in Crystalline Form II of Verubecestat. Thus, while the term “verubecestat” generally refers to each, and both, tautomeric forms, individually and together, all references to the various characterizations of Crystalline Form II of Verubecestat in each of the aspects and embodiments described herein include reference to the endo (amino) tautomeric form.
Synthesis of Verubecestat
A synthesis for the preparation of verubecestat is disclosed in WO2011/044181. Another synthesis is described in Applicant's PCT publication No. WO2016/025359, published Feb. 18, 2016, entitled “Process for the Preparation for a BACE inhibitor”. Other syntheses are described in Applicant's PCT publication nos. WO2016025364 and WO2016053767. Additionally, a synthesis of verubecestat may be described according to General Scheme A and by the description that follows. Reactants for which a synthesis is not described are available commercially for purchase or within the level of the ordinarily skilled synthetic chemist.
Sulfonamide 2 was treated with n-hexyllithium in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) then condensed with ketamine 1 to form the non-isolated intermediate 3. This intermediate was treated with hydrochloric acid to form the amine 4 and then subsequently isolated as the (S)-mandelate salt 5. Mandelate salt 5 was free-based before undergoing coupling to 5-fluoropicolinamide 6 to afford C—N coupled intermediate 7. The para-methoxybenzyl (PMB) group was removed under acidic conditions to yield intermediate 8. Intermediate 8 was alkylated with cyanogen bromide (CNBr) before undergoing intramolecular cyclization to yield verubecestat which was initially isolated as the tosylate salt (9).
Crystalline Form II of Verubecestat
As noted above, the present invention provides a novel crystalline form of verubecestat as an anhydrous free base, herein referred to as “Crystalline Form II of verubecestat” (or alternatively as “Crystalline Form II” or “crystalline form II” or “Form II” or “form II”).
Crystalline Form II of Verubecestat was prepared according to the procedure described below. As those skilled in the art will appreciate, the use of seed crystal in the preparation described below is not initially required but is used for optimal production after initial quantities of Crystalline Form II are produced. For the preparation of Crystalline Form II, suitable starting quantities of verubecestat, e.g., in the form of the tosylate salt of verubecestat, may be obtained from any suitable synthesis including those referenced and described above.
Preparation of the Crystalline Form II of Verubecestat
To a reactor (R1) equipped with a temperature probe, nitrogen inlet, and agitator was charged EtOAc (19.6 L) followed by the tosylate salt of verubecestat (1.96 kg) obtained as described in Scheme A above. Agitation of R1 was begun and the reaction mixture kept at 15-25° C. To R1 was charged 1 M aqueous K2CO3 (4.05 L) and the mixture agitated before the layers were allowed to settle and the bottom aqueous layer was removed; this process was repeated. Water (5.88 L) was then charged to R1 and the mixture agitated before the layers were allowed to settle and the bottom aqueous layer was removed, resulting in verubecestat in the organic layer. The temperature of RI was adjusted to less than 35° C. and the batch was concentrated to 10.3 liters (L). Ethyl acetate (17.6 L) was added to R1 and the batch was again concentrated to 10.3 L.
The reactor (R1) was heated to 68° C. to 72° C. and the mixture was agitated for 30 minutes. The temperature was adjusted to 45° C. to 55° C. and n-heptane (0.43 L) was charged. Form 2 seeds (0.06 kg) were added to R1. The batch was allowed to age for 2 hours. n-Heptane (13.7 L) was then charged to R1 over 10 hours. The temperature was adjusted to 15° C. to 25° C. The solids were collected and washed with Ethyl Acetate/n-heptane (40/60 v/v, 5.88 L) and then heptane (5.88 L). The crystals were dried to provide Crystalline Form II of Verubecestat (1.27 kg).
In the procedure described above, the presence of certain impurities (even if present in otherwise acceptably small amounts) in the tosylate salt of verubecestat obtained in accordance with Scheme A above can kinetically impede the formation of Crystalline Form II of Verubecestat. For example, referring to Scheme A above, the conversion of intermediate 8 to verubecestat can result in the production of small amounts of (R)—N-(3-(3-cyanamido-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-4-fluorophenyl)-5-fluoropicolinamide that remain after the isolation of tosylate salt 9. Thus, strict regulation of the amount of CNBr can minimize the formation of such impurities and improve the rate of production of Crystalline Form II of Verubecestat.
Alternatively, Form II of Verubecestat can be prepared by conversion of a slurry of Crystalline Anhydrous Form 1 of Verubecestat (obtained as described in WO2016/025364) to Crystalline Form II of Verubecestat at a pH at or above 7.8, preferably between 7.8 and 10, more preferably at pH 10. Thus, in one example, Crystalline Form 2 of Verubecestat was prepared by adding 100 mg of Crystalline Anhydrous Form 1 of Verubecestat obtained as described in WO2016/025364 to 10 ml of 0.05M phosphate buffer solution at pH of 7.8 to a vial. In another example, Crystalline Form 2 of Verubecestat was prepared by adding 100 mg of Crystalline Anhydrous Form 1 of Verubecestat obtained as described in WO2016/025364 to 10 ml of Fisher blue buffer solution at pH of 10.00 to a vial. The slurry of Form 1 and buffer in each example was mixed at ambient temperature for 24 hours and filtered. The resulting solid in each example was confirmed by PXRD to be Crystalline Form 2 of Verubecestat.
Physical Characterization of the Crystalline Form II of Verubecestat
Powder X-ray diffraction (PXRD) pattern studies, differential scanning calorimeter (DSC) studies, thermogravimetric analysis (TGA), solid state NMR, and/or single crystal diffractometry are widely used to characterize molecular structures, crystallinity, and polymorphism and were used where indicated to characterize Crystalline Form II of Verubecestat. Those skilled in the art will appreciate that a crystalline form of a substance can be further characterized by combinations of measured PXRD values, DSC values, NMR, TGA, and/or crystal structure measurements. Thus, in another aspect, Crystalline Form II of Verubecestat is characterized by any combination of each of the aspects described herein.
Powder X-Ray Diffraction (PXRD)
Crystalline Form II of Verubecestat obtained as described above was subjected to PXRD analysis. Powder X-ray diffraction (PXRD) patterns were generated on a Philips Analytical X'Pert PRO X-ray Diffraction System™ with PW3040/60 console. A PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation was used as the source. Data were acquired between 2° and 40° 2 theta with a step size of 0.02 degrees over step durations of 46 seconds. Samples were prepared on a zero background silicon holder. Those skilled in the art will recognize that the measurements of the PXRD peak locations for a given crystalline form of the same compound will vary within a margin of error. The margin of error for the 2-theta values measured as described herein is typically +/−0.2° 2-theta. Variability can depend on such factors as the system, methodology, sample, and conditions used for measurement. As will also be appreciated by the skilled crystallographer, the intensities of the various peaks reported in the figures herein may vary due to a number of factors such as orientation effects of crystals in the x-ray beam, the purity of the material being analyzed, and/or the degree of crystallinity of the sample. The skilled crystallographer also will appreciate that measurements using a different wavelength will result in different shifts according to the Bragg-Brentano equation. Such further PXRD patterns generated by use of alternative wavelengths are considered to be alternative representations of the PXRD patterns of the crystalline material of the present invention and as such are within the scope of the present invention.
A PXRD pattern of Crystalline Form II of Verubecestat generated using the equipment and procedures described above is displayed in FIG. 1. The intensity of the peaks (y-axis is in counts per second) is plotted versus the 2 theta angle (x-axis is in degrees 2 theta). In addition, the data were plotted with detector counts normalized for the collection time per step versus the 2 theta angle. Peak locations (on the 2 theta x-axis) consistent with these profiles are displayed in Table 1, (+/−0.2° 2 theta). The locations of these PXRD peaks are characteristic of the Crystalline Form II of Verubecestat.
TABLE 1
Peak Location
(degrees 2 theta
(+/−0.2° 2 theta))
d-spacing [Å]
2.15
41.07
8.20
10.79
10.32
8.57
10.94
8.09
12.63
7.01
13.11
6.75
14.53
6.10
14.98
5.92
16.23
5.46
16.63
5.33
17.77
4.99
18.14
4.89
19.53
4.55
20.51
4.33
20.84
4.26
21.77
4.08
22.94
3.88
23.24
3.83
24.35
3.66
25.41
3.51
26.18
3.40
26.47
3.37
27.19
3.28
27.41
3.25
28.39
3.14
29.31
3.05
29.98
2.98
30.22
2.96
30.88
2.90
31.13
2.87
31.71
2.82
31.94
2.80
32.78
2.73
33.39
2.68
34.43
2.61
35.20
2.55
35.94
2.50
36.69
2.45
37.24
2.41
38.00
2.37
38.90
2.32
39.43
2.28
39.61
2.28
Thus, in one aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern having each of the peak locations listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern comprising two or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern comprising three or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern comprising four or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern comprising six or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern comprising nine or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by a powder x-ray diffraction pattern comprising twelve or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
In another aspect, Crystalline Form II of Verubecestat is characterized by the powder x-ray diffraction pattern substantially as shown in FIG. 1.
In a further aspect, the PXRD peak locations displayed in Table 1 and/or in FIG. 1 most characteristic of Crystalline Form II of Verubecestat can be selected and grouped to conveniently distinguish Crystalline Form II of Verubecestat from other crystalline forms. Selections of such characteristic peaks are set out in Table 2, (wherein each peak location is +/−0.2° 2 theta).
TABLE 2
Peak Location
Peak Location
(degrees 2 theta
d-spacing
Group No.
(+/−0.2° 2 theta))
(angstroms)
Group 1
10.94
8.09
14.98
5.92
Group 2
10.94
8.09
14.98
5.92
14.53
6.10
16.23
5.46
16.63
5.33
26.18
3.40
Group 3
10.94
8.09
14.53
6.10
14.98
5.92
16.23
5.46
16.63
5.33
17.77
4.99
21.77
4.08
23.24
3.83
26.18
3.40
Group 4
10.94
8.09
14.53
6.10
14.98
5.92
16.23
5.46
16.63
5.33
17.77
4.99
20.84
4.26
21.77
4.08
23.24
3.83
26.18
3.40
30.88
2.90
33.39
2.68
Thus, in another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location Group 1 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the two listed characteristic PXRD peak locations of Group 1, (each +/−0.2° 2-theta). In another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location
Group 2 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the two characteristic PXRD peak locations of Group No. 1 and from one to four (in another aspect from two to four, and in yet another aspect from three to four) of the additional peak locations listed in Group 2, (each +/−0.2° 2-theta). In another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location Group 2 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the two characteristic PXRD peak locations of Group No. 1 and each of the four additional peak locations listed in Group 2, (each +/−0.2° 2-theta).
In another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location Group 3 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the exhibits at least the PXRD peak locations of Group No. 2 and from one to three (in yet another aspect from two to three) of the additional peak locations listed in Group 3, (each +/−0.2° 2-theta). In another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location Group 3 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the six characteristic PXRD peak locations of Group No. 2 and each of the three additional peak locations listed, (each +/−0.2° 2-theta).
In another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location Group 4 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the nine characteristic PXRD peak locations of Group No. 3 and from one to three (in yet another aspect from two to three) of the additional peak locations listed, (each +/−0.2° 2-theta). In another aspect, Crystalline Form II of Verubecestat is characterized by Peak Location Group 4 of Table 2, wherein the PXRD pattern obtained as described above exhibits at least the nine characteristic PXRD peak locations of Group No. 3 and each of the three additional peak locations listed, (each +/−0.2° 2-theta).
Differential Scanning Calorimetry
A differential scanning calorimeter (DSC) was used to monitor thermal events as a function of temperature increase. The DSC data reported herein were acquired using a using TA Instruments DSC 2910 or equivalent. A suitable amount of sample was weighed into a pan, covered and placed at the sample position in the calorimeter cell. An empty pan was placed at the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10° C./min to a temperature that is above all thermal events. When the run was completed, the data were analyzed using the DSC analysis program contained in the system software. The thermal events were integrated between baseline temperature points that were above and below the temperature range over which the thermal event was observed. The data reported were the onset temperature, peak temperature and enthalpy. Those skilled in the art will appreciate that the accuracy of measurements will vary within a margin of error. The accuracy of the measured sample temperature with this method is within +/−1° C. The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram (“W/g”). The plot was made with the endothermic peaks pointing down.
Using the differential scanning calorimetry (DSC) equipment and procedures described above, the Crystalline Form II of Verubecestat was subjected to DSC analysis. FIG. 2 depicts a typical DSC curve of Crystalline Form II of Verubecestat. FIG. 2 shows a single sharp melting endotherm with an extrapolated onset temperature of 181.7° C. and a peak temperature of 183.5° C., which is indicative of a single crystalline species. (The sample appears to decompose above approximately 200° C., as indicated by the DSC thermogram.)
These melt temperatures can be used, alone or in combination with any of the other characterizations described herein, to identify Crystalline Form II of Verubecestat and to distinguish it from other crystal forms of verubecestat. Thus, in another aspect, Crystalline Form II of Verubecestat is characterized by a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.) as measured by DSC. In another aspect, Crystalline Form II of Verubecestat is characterized by a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.) as measured by DSC. In another aspect, Crystalline Form II of Verubecestat is characterized by the DSC curve substantially as shown in FIG. 2.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by any of the these DSC measurements and/or the DSC curve substantially as shown in FIG. 2, alone or in combination with any of the other characterizations described herein. Thus, in yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized as exhibiting a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized as exhibiting a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the DSC curve substantially as shown in FIG. 2.
Solid State NMR
Solid State 13C nuclear magnetic resonance (NMR) data reported herein were acquired on a Bruker AV400 NMR spectrometer operating at a 1H resonance frequency of 500.14 MHz, using a Bruker 4 mm H/F/X BB triple resonance CPMAS probe and an MAS rate of 13 kHz. The experiment temperature was controlled with a Bruker VT control unit and set to 270 degrees Kelvin (degrees K). Based on temperature calibration experiments, a set temperature of 270 K corresponds to an actual sample temperature of 295 K. All 13C spectra were externally referenced using a sample of glycine with the carboxylic carbon in glycine assumed at 176.70 ppm. A Lorentzian line broadening of 30 Hz and zero filling to 32 k data points were applied to all 13C spectra before Fourier Transformation.
The 13C Cross Polarization Magic Angle Spinning (CPMAS) spectra were collected utilizing 100 kHz 1H π/2 excitation pulses. The 1H pulse power was ramped up linearly from 47 kHz to 83 kHz over a 3 ms contact time, to enhance CP efficiency. The pulse power of the 13C square CP pulse was matched to the 1H ramp to produce maximum signal. High-power TPPM 1H decoupling at 100 kHz was applied during 13C data acquisition. The pulse delay time used and number of scans acquired for signal averaging were 9.0 s and 4096, respectively.
Using the 13C solid state NMR equipment and procedures described above, the solid state 13C (carbon-13) CPMAS NMR spectrum for the Crystalline Form II of verubecestat was obtained. These data are shown in FIG. 4. Characteristic peaks for Crystalline Form II of Verubecestat are observed at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm. This NMR measurement can be used, alone or in combination with any of the other characterizations described herein, to identify Crystalline Form II of Verubecestat and to distinguish it from other crystal forms of verubecestat. Thus, in another aspect, Crystalline Form II of Verubecestat is characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum as shown in FIG. 4. In another aspect, Crystalline Form II of Verubecestat is characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by the above described NMR characteristic peaks and/or the data shown in FIG. 4, alone or in combination with any of the other characterizations described herein.
Thus, in yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4.
In another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm, or by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4, and each further characterized by a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.) as measured by DSC.
In another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm, or by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4, and each further characterized by a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.) as measured by DSC.
In another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm, or by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4, and each further characterized by a melting endotherm with substantially as shown in FIG. 2.
Single-Crystal X-Ray Structure
The single crystal structure of Crystalline Form II of Verubecestat was determined. The acquisition and cell parameters that were determined for Crystalline Form II of Verubecestat are shown in Table 3. FIG. 5 is an ORTEP representation of the molecule generated from the crystallographic coordinates. ORTEP is an abbreviation of Oak Ridge Thermal Ellipsoid Plot, a representation of molecular structure as determined by x-ray diffraction. The ORTEP drawing provides the exact position in space of every atom within the crystal and can be used to generate a complete three dimensional image of the crystal. As can be seen, the ORTEP drawing indicates that Crystalline Form II of Verubecestat appears to exist substantially in the amino tautomeric form. This crystal structure can be used, alone or in combination with any of the other characterizations described herein, to identify Crystalline Form II of Verubecestat and to distinguish it from other crystal forms of verubecestat. Thus, in another aspect, Crystalline Form II of Verubecestat is characterized by the ORTEP depicted in FIG. 5. In another aspect, Crystalline Form II of Verubecestat is characterized by the single crystal structure values shown in Table 3.
In yet another aspect, Crystalline Form II of Verubecestat is alternatively characterized by the ORTEP depicted in FIG. 5 or the single crystal structure information shown in Table 3, alone and/or in combination with each of the aspects of PXRD characterizations described above, and/or each of the DSC aspects described above, and/or with the NMR characteristic peaks described above and/or with the NMR data shown in FIG. 4, and/or with any of the TGA measurements and/or with the TGA curve substantially as shown in FIG. 3.
TABLE 3
Crystal system
Tetragonal
Space group
P41212
Unit cell dimensions
a = 12.2581(4) Å
α = 90°.
b = 12.2581(4) Å
β = 90°.
c = 24.6362(9) Å
γ = 90°.
Volume
3701.9(3) Å3
Z
8
Density (calculated)
1.469 Mg/m3
In yet another aspect, Crystalline Form II of Verubecestat is characterized by the above described single crystal structure (described in Table 3 and/or as depicted by the ORTEP of FIG. 5) alone or in combination with any of the other characterizations described herein.
Thus, in yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the single crystal structure described in Table 3 or in FIG. 5.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the single crystal structure described in Table 3 or in FIG. 5., and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the single crystal structure described in Table 3 or in FIG. 5., and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 3.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the single crystal structure described in Table 3 or in FIG. 5., and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm, or by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4, and each further characterized by a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.) as measured by DSC.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the single crystal structure described in Table 3 or in FIG. 5., and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm, or by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4, and each further characterized by a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.) as measured by DSC.
In yet another aspect, Crystalline Form II of Verubecestat is characterized by PXRD Peak Location Group 1, or by PXRD Peak Location Group 2, or by PXRD Peak Location Group 3, or by PXRD Peak Location Group 4, each as described above, and each further characterized by the single crystal structure described in Table 3 or in FIG. 5., and each further characterized by a solid state 13C (carbon-13) CPMAS NMR spectrum having peaks at 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm, or by a solid state 13C (carbon-13) CPMAS NMR spectrum substantially as shown in FIG. 4, and each further characterized by a melting endotherm with substantially as shown in FIG. 2.
Thermogravimetric Analysis
Thermal gravimetric analysis (TGA) data were acquired using a Perkin Elmer model TGA 7 or equivalent. Experiments were performed under a flow of nitrogen and using a heating rate of 10° C./min to a maximum temperature of approximately 250° C. After automatically taring the balance, an appropriate amount of sample was added to the platinum pan, the furnace raised, and the heating program started. Analysis of the results were carried out by selecting the Delta Y function within the instrument software and choosing the temperatures between which the weight loss is to be calculated. Weight losses were reported up to the onset of decomposition/evaporation.
Using the thermogravimetric analysis (TGA) equipment and procedures described above, Crystalline Form II of Verubecestat was subjected to TGA analysis. FIG. 3 shows a typical TGA analysis curve for Crystalline Form II of verubecestat. The data show 0.5 wt. % loss up to 150° C., followed by thermal decomposition above 200° C. This TGA analysis can be used, alone or in combination with any of the other characterizations described herein, to identify Crystalline Form II of Verubecestat and to distinguish it from other crystal forms of verubecestat. Thus, in another aspect, Crystalline Form II of Verubecestat is characterized by a TGA curve substantially as shown in FIG. 3. In yet another aspect, Crystalline Form II of Verubecestat is characterized by any of these TGA measurements and/or the TGA curve substantially as shown in FIG. 3, alone or in combination with any of the other characterizations described herein, including each of the aspects of PXRD characterizations described above, and/or each of the DSC aspects described above.
Properties
The Crystalline Form II of Verubecestat described and characterized herein exhibits excellent physical properties while minimizing the difficulties associated with drug product manufacturing, processing and storage. For example, Crystalline Form II of Verubecestat exhibits unexpectedly improved thermodynamic stability and comparable chemical stability in drug product (tablet formulation) compared to crystalline Form I of verubecestat while remaining a BCS Class I category substance. Despite its desirable properties, Crystalline Form II of Verubecestat did not appear during routine polymorph screening; it was surprisingly and advantageously invented after many batches of other crystalline forms (such as Crystalline Anhydrous Form I described in WO2016/025364) were produced using multiple synthetic routes in a variety of conditions at multiple manufacturing sites.
The thermodynamic stability of Crystalline Form II of Verubecestat was assessed using competitive slurry experiments in various solvent systems. Crystalline Form I of Verubecestat, obtained using the procedures set out in WO2016025364, and Crystalline Form II of verubecestat material obtained as described above were slurried in various solvents for an extended period of time and at a controlled temperature. At the end of the experiments, the solvent was removed and the remaining crystalline material were evaluated using Powder X-ray Diffraction (PXRD) to confirm the resultant form. Typically the more stable form will remain and the less stable form will convert to the more stable form. In all cases, Crystalline Form II of Verubecestat was the only form remaining and thus the more stable form.
To assess the chemical stability of Crystalline Form II of verubecestat in the tablet formulation, a 4 week open dish accelerated stability experiment was performed at a controlled temperature and humidity. Identical measurements were made to Crystalline Form I of verubecestat, which Form I is described in WO2016025364 for comparison. (12 mg tablets were used because the available stability data for tablets comprising Form I of verubecestat indicated that 12 mg tablet is more susceptible to degradation than the 40 mg tablet.) Thus, 12 mg tablets of Crystalline Form I of verubecestat and 12 mg tablets of Crystalline Form II of Verubecestat were placed in an open dish and the temperature maintained at 40° C. and 75% relative humidity (RH) for four weeks. At the end of two weeks and of four weeks, tablets were analyzed using HPLC. The data obtained are reported in the following table, where “Hyd1” and “Hyd2” indicate observed degradation product:
TABLE 1
Chemical Stability of 12 mg Tablets
Stored in Open Dish at 40° C./75% RH
Crystalline Form I
Crystalline Form II
Degradation
Degradation
Time
Assay
Product (%)
Assay
Product (%)
Point
(% LC)
Hyd1
Hyd2
Total
(% LC)
Hyd1
Hyd2
Total
0
98.5
—
—
—
104.3
—
—
—
2 weeks
98.5
0.30
0.16
0.46
104.6
0.21
0.10
0.31
4 weeks
97.4
0.52
0.26
0.78
102.4
0.39
0.18
0.56
“—”means not more than 0.05%
As can be seen from the data reported in the table above, Crystalline Form II of Verubecestat unexpectedly exhibited comparable amounts of degradation product at each timepoint compared with Crystalline Form I of verubecestat while exhibiting improved thermodynamic stability. Additionally, the melting point of Crystalline Form II was measured at above 180 C. By comparison, the melting point of Crystalline Form I was measured at 160 C. The higher melting point of Crystalline Form II is further indication of superior thermal stability.
Crystalline Form II of Verubecestat exhibits good chemical stability and is more thermodynamically stable compared to Form I of verubecestat while maintaining a preferred BCS (Biopharmaceutics Classification System) designation as a Class 1 substance. Accordingly, compositions comprising the Crystalline Form II of Verubecestat may be synthesized using a crystallization process that is more efficient and results in improved particle size and morphology relative to other known forms of verubecestat. Employing a novel crystalline form of verubecestat according to the invention may allow the use of conventional processing methods and formulation strategies. This is significant in that Crystalline Form II of Verubecestat exhibits a reduced physical stability risk compared to higher energy state forms. Ultimately this may allow for less protective and potentially less expensive packaging configurations. A conventional formulation also allows for the use of standard, well-known processing trains (fluidized bed granulation, blending, and compression). These standard processing trains have been optimized to provide high yield, are easily scalable, and are abundant throughout the pharmaceutical manufacturing facilities worldwide. In addition, the manufacture of non-standard formulations of verubecestat may require higher energy inputs (extrusion) or the use of solvents (e.g., spray drying). Thus, the novel Crystalline Form II of Verubecestat may provide a potential for improved overall cost of goods.
Pharmaceutical Compositions
As noted above, another embodiment provides a pharmaceutical composition comprising Crystalline Form II of Verubecestat (as characterized by any of the characterizations, alone or in combination, described herein). In such compositions, Crystalline Form II comprises either the sole active agent, or is optionally present in combination with one or more additional therapeutic agents. In either case, said pharmaceutical compositions can further comprise one or more pharmaceutically acceptable carriers, excepients and/or diluents. Non-limiting examples of additional therapeutic agents which may be useful in combination with a Crystalline Form II of Verubecestat are described in WO2011/044181 and include those selected from the group consisting of: (a) drugs that may be useful for the treatment of Alzheimer's disease and/or drugs that may be useful for treating one or more symptoms of Alzheimer's disease, (b) drugs that may be useful for inhibiting the synthesis Aβ, (c) drugs that may be useful for treating neurodegenerative diseases, and (d) drugs that may be useful for the treatment of type II diabetes and/or one or more symptoms or associated pathologies thereof.
Additional non-limiting examples of therapeutic agents which may be useful in combination with a Crystalline Form II of Verubecestat include drugs that may be useful for the treatment, prevention, delay of onset, amelioration of any pathology associated with Aβ and/or a symptom thereof. Non-limiting examples of pathologies associated with Aβ include: Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss, memory loss associated with Alzheimer's disease, memory loss associated with Parkinson's disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease (“AD”), Parkinson's disease, and/or Down's syndrome, dementia, stroke, microgliosis and brain inflammation, pre-senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment, olfactory impairment associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (from β2 microglobulins and complications arising therefrom in hemodialysis patients), scrapie, bovine spongiform encephalitis, and Creutzfeld-Jakob disease, comprising administering to said patient Crystalline Form II of Verubecestat in an amount effective to inhibit or treat said pathology or pathologies.
Additional non-limiting examples of therapeutic agents that may be useful in combination with Crystalline Form II of Verubecestat include: muscarinic antagonists (e.g., m1 agonists (such as acetylcholine, oxotremorine, carbachol, or McNa343), or m2 antagonists (such as atropine, dicycloverine, tolterodine, oxybutynin, ipratropium, methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors such as donepezil (Aricept®, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride), galantamine (Razadyne®), and rivastigimine (Exelon®); N-methyl-D-aspartate receptor antagonists (e.g., Namenda® (memantine HCl, available from Forrest Pharmaceuticals, Inc.); combinations of cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists; gamma secretase modulators; gamma secretase inhibitors; non-steroidal anti-inflammatory agents; anti-inflammatory agents that can reduce neuroinflammation; anti-amyloid antibodies (such as bapineuzemab, Wyeth/Elan); vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; antibiotics; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); Tau aggregation inhibitors (e.g., Rember®); RAGE inhibitors (e.g., TTP 488 (PF-4494700)); anti-Abeta vaccine; APP ligands; agents that upregulate insulin, cholesterol lowering agents such as HMG-CoA reductase inhibitors (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin) and/or cholesterol absorption inhibitors (such as Ezetimibe), or combinations of HMG-CoA reductase inhibitors and cholesterol absorption inhibitors (such as, for example, Vytorin®); fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); combinations of fibrates and cholesterol lowering agents and/or cholesterol absorption inhibitors; nicotinic receptor agonists; niacin; combinations of niacin and cholesterol absorption inhibitors and/or cholesterol lowering agents (e.g., Simcor® (niacin/simvastatin, available from Abbott Laboratories, Inc.); LXR agonists; LRP mimics; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (Epix Pharmaceuticals)); 5-HT6 receptor antagonists; mGluR1 receptor modulators or antagonists; mGluR5 receptor modulators or antagonists; mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; agents that can induce Abeta efflux such as gelsolin; Metal-protein attenuating compound (e.g., PBT2); and GPR3 modulators; and antihistamines such as Dimebolin (e.g., Dimebon®, Pfizer).
When used in combination with additional therapeutic agents, Crystalline Form II of Verubecestat and the one or more additional agents may be administered together or sequentially, as noted above. When used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the Crystalline Form II is contemplated. However, the combination therapy may also include therapies in which the Crystalline Form II of Verubecestat and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, Crystalline Form II of Verubecestat and the other active ingredient(s) may be used in lower doses than when each is used singly. Further, such other drugs may be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with Crystalline Form II of verubecestat. When Crystalline Form II is used contemporaneously with one or more other drugs, a pharmaceutical composition comprising such other drugs in addition to the Crystalline Form II are prepared without undue experimentation in accordance with the methods described herein and/or known in the art.
The weight ratio of Crystalline Form II to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when Crystalline Form II of Verubecestat is combined with another agent, the weight ratio of the Crystalline Form II and the second agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200, wherein, in each case an effective dose for the intended purpose is used. Such combinations may be administered separately or concurrently, and the administration of one may be prior to, concurrent with, or subsequent to the administration of the other agent(s).
For preparing the pharmaceutical compositions described herein, pharmaceutically acceptable carriers can be solid or liquid, or in any other known dosage form such as aerosols or lotions. Non-limiting examples of solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of any of the weight % values of active ingredient described herein, and in any desired dose (e.g., doses as described herein).
Crystalline Form II of Verubecestat may conveniently be presented in a dosage unit form which may be prepared by any of the methods well known in art of pharmacy. All methods include the step of bringing Crystalline Form II into association with the carrier which constitutes accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing active ingredient into association with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition active ingredient(s) is included in an effective amount. “Effective amount” or “therapeutically effective amount” is meant to describe an amount of Crystalline Form II of Verubecestat effective to elicit the biological or medical response of a tissue, system, animal or human, that is being sought by the researcher, medical doctor, veterinarian, or other clinician. It is recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient at risk for the disease or disorder with an effective amount of Crystalline Form II of verubecestat. As used herein, the terms “treatment” or “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the diseases or disorders described herein, but does not necessarily indicate a total elimination of all disorder pathologies or symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. In the case of Alzheimer's disease, treatments can be directed to persons who have been diagnosed with Alzheimer's disease, or those with MCI (Mild Cognitive Impairment) or prodromal Alzheimer's disease, or prior to such diagnosis in those who are (or are suspected of being) at risk of developing Alzheimer's disease who, as directed by the attending healthcare professional. The terms “administration of” and/or “administering a Crystalline Form II of verubecestat should be understood to mean providing a Crystalline Form II, or a composition comprising Crystalline Form II, to an individual in need thereof.
Pharmaceutical compositions intended for oral use may be prepared in accordance with methods described herein and other methods well known to art for the manufacture of pharmaceutical compositions. Such compositions may further contain active agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents where pharmaceutically elegant and/or palatable preparations are desired. Tablets and capsules are contemplated. Tablets or capsules may contain active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, mannitol, micrystalline cellulose, starch, lactose (e.g., lactose monohydrate or lactose anhydrate), calcium phosphate or sodium phosphate; granulating or disintegrating agents, for example, crospovidone, corn starch, croscarmellose sodium or alginic acid; binding agents, for example starch, hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), silicone dioxide, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. Suitable solid carriers also may include magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
Liquid and topical form preparations are also contemplated. Such forms include solutions, suspensions and emulsions. Non-limiting examples which may be useful include water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation are also contemplated. Such forms include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration are also contemplated. Such liquid forms include solutions, suspensions and emulsions. Transdermal delivery preparations are also contemplated. Transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in art for this purpose. Subcutaneous delivery forms are also contemplated. Additional examples of dosage forms, formulations, and pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Another embodiment provides suitable dosages and dosage forms of Crystalline Form II of Verubecestat and its use in the various methods described herein. Suitable doses for administering Crystalline Form II of Verubecestat to patients may readily be determined by those skilled in art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency and duration of administration, use with other active ingredients, and/or indication for which the Crystalline Form II is administered. Thus, the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The doses may be administered to patients in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Doses may range from about 0.001 to 500 mg/kg (subject to tolerability limits) of body weight per day of Crystalline Form II. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight per day of Crystalline Form II of verubecestat. In one embodiment, the dosage is from about 0.1 to about 1 mg/kg of body weight per day of Crystalline Form II. In one embodiment, the dosage is from about 0.24 to about 0.8 mg/kg of body weight per day of Crystalline Form II. In another embodiment, the quantity of active Crystalline Form II in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. In another embodiment, the compositions may be provided in the form of tables containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 12, 15, 20, 25, 40, 50, 60, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the adjustment of dosage according to the degree of Aβ lowering or other biological process desired.
In one embodiment, the dose is about 5 mg of Crystalline Form II of Verubecestat per dose. In another embodiment, the dose is about 10 mg of Crystalline Form II of Verubecestat per dose. In another embodiment, the dose is about 12 mg of Crystalline Form II of Verubecestat per dose. In another embodiment, the dose is about 40 mg of Crystalline Form II of Verubecestat per dose. In another embodiment, the dose is about 60 mg of Crystalline Form II of Verubecestat per dose. In another embodiment, the dose is about 100 mg of Crystalline Form II of Verubecestat per dose.
The Crystalline Form II of Verubecestat may be formulated for administration on, e.g., a regimen of from 1 to 4 times per day, including once or twice per day; in one embodiment once per day. In an alternative of each of the foregoing embodiments, the formulation is for once daily dosing.
In one embodiment, a dosage formulation comprises 12 mg of Crystalline Form II of verubecestat, lactose monohydrate, Povidone K29/32, croscarmellose sodium, and magnesium stearate.
In one embodiment, a dosage formulation comprises an intra granular layer comprising 12 mg of Crystalline Form II of verubecestat, lactose monohydrate, povidone, microcrystalline cellulose, and croscarmellose sodium, an extra granular layer comprising croscarmellose sodium and magnesium stearate, and optionally a film coating comprising Opadry II Blue coating material.
In one embodiment, a dosage formulation comprises 40 mg of Crystalline Form II of verubecestat, lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
In one embodiment, a dosage formulation comprises an intra granular layer comprising 40 mg of Crystalline Form II of verubecestat, lactose monohydrate, microcrystalline cellulose, povidone, and croscarmellose sodium, an extra granular layer comprising croscarmellose sodium and magnesium stearate, and optionally a film coating comprising Opadry II Blue.
Example 1 provides a non-limiting example of a preparation of a coated tablet comprising 12 mg Crystalline Form II of verubecestat. Example 2 provides a non-limiting example of a preparation of a coated tablet comprising 40 mg Crystalline Form II of verubecestat.
Example 1
Purified water (700 g) was charged to a stainless steel container equipped with an agitator. Povidone (100 g) was added into the water while being stirred to form a granulation binder solution. Lactose Monohydrate (1185 g), Crystalline Form II of Verubecestat (150 g) and croscarmellose sodium (30 g) were charged directly into a fluidized bed granulator. This material was fluidized and the binder solution (600 g) was sprayed into the granulator to form granules. At the completion of the spraying process, the granules were dried and milled with a rotating impeller screening mill. The milled granules were charged into a diffusion-type mixer, croscarmellose sodium (45 g) was added into the mixer and blended for 75 revolutions. Magnesium stearate (15 g) was added into the mixer after passing through a stainless steel screen and blended for 45 revolutions. The blended material was compressed into tablet (cores) with target tablet weight of 120 mg using a rotary tablet press equipped with the product-specific tooling. The tablet cores were coated with Opadry® II film coating suspension.
Example 2
Purified water (700 g) was charged to a stainless steel container equipped with an agitator. Povidone (100 g) was added into the water while being stirred to form a granulation binder solution. Lactose Monohydrate (835 g), Crystalline Form II of Verubecestat (500 g) and croscarmellose sodium (30 g) were charged directly into a fluidized bed granulator. This material was fluidized and the binder solution (600 g) was sprayed into the granulator to form granules. At the completion of the spraying process, the granules were dried and milled with a rotating impeller screening mill. The milled granules were charged into a diffusion-type mixer, croscarmellose sodium (45 g) was added into the mixer and blended for 75 revolutions. Magnesium stearate (15 g) was added into the mixer after passing through a stainless steel screen and blended for 45 revolutions. The blended material was compressed into tablet (cores) with target tablet weight of 120 mg using a rotary tablet press equipped with the product-specific tooling. The tablet cores were coated with Opadry® II film coating suspension.
Methods of Use
As noted above, the scientific literature and recent clinical trials support the use of inhibitors of BACE-1 and BACE-2, including verubecestat, in a wide variety of indications, including Alzheimer's disease, including prodromal Alzheimer's disease. In each of these embodiments, reference to administration of the Crystalline Form II of Verubecestat refers to either administration of the neat chemical or in the form of a composition as described herein.
Thus, another embodiment provides a method of inhibiting β-secretase (BACE) comprising exposing a population of cells expressing β-secretase to Crystalline Form II of Verubecestat in an amount effective to inhibit β-secretase. In one such embodiment, said population of cells is in vivo. In another such embodiment, said population of cells is ex vivo. In another such embodiment, said population of cells is in vitro.
Additional embodiments in which the Crystalline Form II of Verubecestat may be useful include: a method of inhibiting β-secretase in a patient in need thereof, a method of inhibiting the formation of Aβ from APP in a patient in need thereof, and a method of inhibiting the formation of Aβ plaque and/or Aβ fibrils and/or Aβ oligomers and/or senile plaques and/or neurofibrillary tangles and/or inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), in a patient in need thereof. Each such embodiment comprises administering the Crystalline Form II of Verubecestat in a therapeutically effective amount to inhibit said pathology or condition in said patient.
Additional embodiments in which the Crystalline Form II of Verubecestat may be useful include: a method of treating, preventing, and/or delaying the onset of one or more pathologies associated with Aβ and/or one or more symptoms of one or more pathologies associated with Aβ. Non-limiting examples of pathologies which may be associated with Aβ include: Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss, memory loss associated with Alzheimer's disease, memory loss associated with Parkinson's disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease (“AD”), Parkinson's disease, and/or Down's syndrome, dementia, stroke, microgliosis and brain inflammation, pre-senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment, olfactory impairment associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (from β2 microglobulins and complications arising therefrom in hemodialysis patients), scrapie, bovine spongiform encephalitis, and Creutzfeld-Jakob disease, said method(s) comprising administering to said patient in need thereof at least one Crystalline Form II in an amount effective to inhibit said pathology or pathologies.
Another embodiment in which the Crystalline Form II of Verubecestat may be useful includes a method of treating Alzheimer's disease, wherein said method comprises administering an effective amount of the Crystalline Form II of verubecestat, optionally in further combination with one or more additional therapeutic agents which may be effective to treat Alzheimer's disease or a disease or condition or one or more symptoms associated therewith, to a patient in need of treatment. In embodiments wherein additional therapeutic agents are administered, such agents may be administered sequentially or together, and formulated accordingly. Non-limiting examples of associated diseases or conditions, and non-limiting examples of suitable additional therapeutically active agents, are as described above.
Another embodiment in which the Crystalline Form II of Verubecestat may be useful includes a method of treating mild cognitive impairment (“MCI”), wherein said method comprises administering an effective amount of a Crystalline Form II of Verubecestat to a patient in need of treatment. In one such embodiment, treatment is commenced prior to the onset of symptoms.
Another embodiment in which the Crystalline Form II of Verubecestat may be useful includes a method of preventing, or alternatively of delaying the onset, of mild cognitive impairment or, in a related embodiment, of preventing or alternatively of delaying the onset of Alzheimer's disease. In such embodiments, treatment can be initiated at the earliest signs or symptoms (or sets of signs or symptoms) of Alzheimer's disease, e.g., as in prodromal patients, prior to the onset of symptoms, in some embodiments significantly before (e.g., from several months to several years before) the onset of symptoms to a patient at risk for developing MCI or Alzheimer's disease. Thus, such methods comprise administering, prior to the onset of symptoms or clinical or biological evidence of MCI or Alzheimer's disease (e.g., from several months to several years before, an effective and over a period of time and at a frequency of dose sufficient for the therapeutically effective degree of inhibition of the BACE enzyme over the period of treatment, an amount of a Crystalline Form II of Verubecestat to a patient in need of treatment.
Another embodiment in which the Crystalline Form II of Verubecestat may be useful includes a method of treating Down's syndrome, comprising administering an effective amount of a Crystalline Form II of Verubecestat to a patient in need of treatment.
In another embodiment, the invention provides methods of treating a disease or pathology, wherein said disease or pathology is Alzheimer's disease, olfactory impairment associated with Alzheimer's disease, Down's syndrome, olfactory impairment associated with Down's syndrome, Parkinson's disease, olfactory impairment associated with Parkinson's disease, stroke, microgliosis brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type II diabetes, diabetes-associated amyloidogenesis, scrapie, bovine spongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakob disease. Such methods comprise administering the Crystalline Form II of Verubecestat to a patient in need thereof in an amount effective to treat said disease or pathology.
In another embodiment, the invention provides for the use of the Crystalline Form II of Verubecestat for use as a medicament, or in medicine, or in therapy.
In another embodiment, the invention provides for use of the Crystalline Form II of Verubecestat for the manufacture of a medicament for the treatment of a disease or pathology, wherein said disease or pathology is Alzheimer's disease, olfactory impairment associated with Alzheimer's disease, Down's syndrome, olfactory impairment associated with Down's syndrome, Parkinson's disease, olfactory impairment associated with Parkinson's disease, stroke, microgliosis brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type II diabetes, diabetes-associated amyloidogenesis, scrapie, bovine spongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakob disease.
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16622323
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merck sharp & dohme corp.
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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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Apr 20th, 2022 03:02PM
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Apr 20th, 2022 03:02PM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 19th, 2022 12:00AM
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Jun 20th, 2019 12:00AM
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https://www.uspto.gov?id=US11306125-20220419
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PCSK9 antagonists bicyclo-compounds
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Disclosed are compounds of Formula I, or a salt thereof cyclic polypeptide of Formula I: Formula I where A, B, E, R4, and R8 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions
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11306125
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1. A compound of the Formula I:
wherein:
R4 is: (a) linear, branched or cyclic alkyl of up to 6 carbon atoms; (b) —(CH2)x—R13B, wherein: x is 1-4, and R13B is —NH2 or —N+H3; (c) —(CH2)x—R13C, wherein: x is 1-4, and R13C is —N(R13D)2 or —N(R13D)3 wherein R13D is a linear or branched alkyl of up to 4 carbon atoms; (d) —CH2NH—C(O)—O—C(CH3)3; or
(e) —CH2—NH—C(O)—[(CH2)2—O—]y—(CH2)2—R13E, wherein, y is 1 to 4 and R13E is —NH2, —N+H3, or —N+(CH3)3;
R8 is a moiety of the formula:
wherein R8a is —H, or a linear, branched or cyclic alkyl of up to four carbon atoms;
A is (a) —CH2—; or
(b) a moiety of the formula:
wherein R3 is:
(i) linear, branched or cyclic alkyl of up to 6 carbon atoms;
(ii) —(CH2)z—R14A, wherein: z is 1-4, and R14A is —NH2 or —N+H3;
(iii) —(CH2)z—R14B, wherein: z is 1-4, and R14B is —N(CH3)2 or —N+(CH3)3; or
(iv) —CH2—NH—C(O)—[(CH2)y—O—]2—(CH2)2—R14C wherein, y′ is 1 to 6, and R14C is —NH2, —N+H3, or —N+(CH3)3;
B is:
(a) a moiety of the formula:
wherein:
R1 is —H or —NH—C(O)—CH3;
R2 is —H or —C(O)—R15A, wherein R15A is —NH2, —N+H3, or —N+(CH3)3; and
C1 is —CH2— or —(CH2)2—O—; or
(b) a moiety of the formula:
D is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein R12 is —H or —CH3; and
E is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 having the formula of Formula II:
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is:
(a) —CH3;
(b) —CH(CH3)2;
(c) —(CH2)x—R13b, wherein: x is 1-4, and R13b is —NH2 or —N+H3; (d) —CH2NH—C(O)—O—C(CH3)3; or (iv) —CH2—NH—C(O)—[(CH2)2—O—]2—(CH2)2—R13, wherein R13c is —NH2, —N+H3, or —N+(CH3)3.
4. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R8 is a moiety of the formula:
wherein R8b is —H, —CH3, or —C(CH3)3.
5. A compound of claim 2, or a pharmaceutically acceptable salt thereof,
Wherein:
A is a moiety of the formula:
and
R3 is
(i) —CH3;
(ii) —CH(CH3)2;
(iii) —(CH2)z—R13a, wherein: z is 1-4, and R13a is —NH2 or —N+H3; or
(iv) —CH2—NH—C(O)—[(CH2)2—O—]2—(CH2)2—R13c, wherein R13c is —NH2, —N+H3, or —N+(CH3)3.
6. A compound of claim 2 having the formula of Formula III:
or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 having the Formula IV:
wherein:
B2 is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein:
R1 is —H or —NH—C(O)—CH3;
R2 is —H or —C(O)—R16A NH2 R16A is —NH2, —N+H3, —N(CH3)2, or —N+(CH3)3,
or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1, which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1, which is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
10. A composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
11. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 10.
12. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
13. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.
14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for treating hypercholesterolemia.
15. A compound of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
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15
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CROSS REFERENCE TO RELATED APPLICATION
This application is a 35 U.S.C. § 371 filing of International Patent Application No. PCT/US2019/038158, filed Jun. 20, 2019, which claims priority to U.S. Application No. 62/688,020, filed Jun. 21, 2018, which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
The identification of compounds and/or agents that are effective in the treatment of cardiovascular affliction is highly desirable. In clinical trials, reductions in LDL cholesterol levels have been directly related to the rate of coronary events; Law et al., 2003 BMJ 326:1423-1427. The moderate lifelong reduction in plasma LDL cholesterol levels was found to correlate with a substantial reduction in the incidence of coronary events; Cohen et al., 2006 N. Engl. J. Med. 354:1264-1272. This was the case even in populations with a high prevalence of non-lipid-related cardiovascular risk factors; supra. Accordingly, there is great benefit to be reaped from the managed control of LDL cholesterol levels.
Proprotein convertase subtilisin-kexin type 9 (hereinafter called “PCSK9”), also known as neural apoptosis-regulated convertase 1 (“NARC-1”), is a proteinase K-like subtilase identified as the 9th member of the secretory subtilase family; see Seidah et al., 2003 PNAS 100:928-933. PCSK9 belongs to the mammalian proprotein convertase family of serine proteases and contains an N-terminal signal sequence, a prodomain, a catalytic domain, and a C-terminal domain; see Seidah et al., 2012 Nat. Rev. Drug Discov. 11:367-383. A study of PCSK9 transcriptional regulation demonstrated that it is regulated by sterol regulatory element-binding proteins (“SREBP”), as seen with other genes involved in cholesterol metabolism; Maxwell et al., 2003 J. Lipid Res. 44:2109-2119, as is typical of other genes implicated in lipoprotein metabolism; Dubuc et al., 2004 Arterioscler. Thromb. Vase. Biol. 24:1454-1459. Statins have been shown to upregulate PCSK9 expression in a manner attributed to the cholesterol-lowering effects of the drugs; supra. Moreover, it has been shown that PCSK9 promoters possess two conserved sites involved in cholesterol regulation, a sterol regulatory element and an Sp1 site; supra.
While in the endoplasmic reticulum, PCSK9 performs as its only catalytic activity an autocleavage between residues Gln-152 and Ser-153; see Naureckiene et al., 2003 Arch. Biochem. Biophys. 420:55-67; Seidah et al., 2003 Proc. Natl Acad. Sci. U.S.A 100:928-933. The prodomain remains tightly associated with the catalytic domain during subsequent trafficking through the trans-Gogli network. The maturation via autocleavage has been demonstrated to be critical for PCSK9 secretion and subsequent extracellular function (see Benjannet et al., 2012 J. Biol. Chem. 287:33745-33755). Accordingly, several lines of evidence demonstrate that PCSK9, in particular, lowers the amount of hepatic LDLR protein and thus compromises the liver's ability to remove LDL cholesterol from the circulation.
Adenovirus-mediated overexpression of PCSK9 in the liver of mice results in the accumulation of circulating LDL-C due to a dramatic loss of hepatic LDLR protein, with no effect on LDLR mRNA levels; Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875; Maxwell & Breslow, 2004 PNAS 101:7100-7105; Park etai, 2004 J. Biol. Chem. 279:50630-50638; and Lalanne etai, 2005 J. Lipid Res. 46:1312-1319. The effect of PCSK9 overexpression on raising circulating LDL-C levels in mice is completely dependent on the expression of LDLR, again, indicating that the regulation of LDL-C by PCSK9 is mediated through downregulation of LDLR protein. In agreement with these findings, mice lacking PCSK9 or in which PCSK9 mRNA has been lowered by antisense oligonucleotide inhibitors have higher levels of hepatic LDLR protein and a greater ability to clear circulating LDL-C; Rashid etai, 2005 PNAS 102:5374-5379; and Graham etai, 2007 J. Lipid Res. 48(4):763-767. In addition, lowering PCSK9 levels in cultured human hepatocytes by siRNA also results in higher LDLR protein levels and an increased ability to take up LDL-C; Benjannet et al., 2004 J. Biol Chem. 279:48865-48875; and Lalanne et al., 2005 J. Lipid Res. 46:1312-1319. Together, these data indicate that PCSK9 action leads to increased LDL-C by lowering LDLR protein levels.
A number of mutations in the gene PCSK9 have also been conclusively associated with autosomal dominant hypercholesterolemia (“ADH”), an inherited metabolism disorder characterized by marked elevations of low density lipoprotein (“LDL”) particles in the plasma which can lead to premature cardiovascular failure; see Abifadel et al., 2003 Nature Genetics 34:154-156; Timms et al, 2004 Hum. Genet. 114:349-353; Leren, 2004 Clin. Genet. 65:419-422. A later-published study on the S127R mutation of Abifadel et al., supra, reported that patients carrying such a mutation exhibited higher total cholesterol and apoB100 in the plasma attributed to (1) an overproduction of apoB100-containing lipoproteins, such as low density lipoprotein (“LDL”), very low density lipoprotein (“VLDL”) and intermediate density lipoprotein (“IDL”), and (2) an associated reduction in clearance or conversion of said lipoproteins; Ouguerram et al., 2004 Arterioscler. Thromb. Vase. Biol. 24:1448-1453.
Accordingly, there can be no doubt that PCSK9 plays a role in the regulation of LDL. The expression or upregulation of PCSK9 is associated with increased plasma levels of LDL cholesterol, and the corresponding inhibition or lack of expression of PCSK9 is associated with reduced LDL cholesterol plasma levels. Decreased levels of LDL cholesterol associated with sequence variations in PCSK9 have been found to confer protection against coronary heart disease; Cohen, 2006 N. Eng. J. Med. 354:1264-1272.
Thus, identification of compounds and/or agents effective in the treatment of cardiovascular affliction is highly desirable, including antagonism of PCSK9's role in LDL regulation, however, in general, because PCSK9 circulates in blood and has modest binding affinity to cell surface LDL receptors here-to-fore attempts to utilize this mechanism in treatment of diseases related to high serum LDL levels have been focused on the use of large biomolecules, for example, antibodies. Accordingly, there is scant publication reflecting activity toward this target using small peptides or small molecules to inhibit PCSK9, see for example, Zhang et al., 2014 J. Biol. Chemistry, 289(2): 942-955. Moreover, there is a paucity of compounds which are amenable to formulation into a dosage form for utilizing an oral administration route of dosing such compounds, a route which would be highly desirable for the provision of therapy for conditions in which regulation of the activities of PCSK9 could play a role.
The present invention advances these interests by providing antagonists of PCSK9 which are believed to be of use for inhibiting the activities of PCSK9 and the corresponding role PCSK9 plays in various conditions for which the administration of a PCSK9 antagonist provides therapy.
SUMMARY OF THE INVENTION
In one aspect the invention provides a compound of Formula I:
wherein:
R4 is:
(a) linear, branched or cyclic alkyl of up to 6 carbon atoms, and in some embodiments is preferably —CH3 or —CH(CH3)2
(b) —(CH2)x—R13B, wherein: x is 1-4, and R13B is —NH2 or —N+H3; (c) —(CH2)x—R13C, wherein: x is 1-4, and R13C is —N(R13D)2 or —N+(R13D)3 wherein R13D is a linear or branched alkyl of up to 4 carbon atoms, and in some embodiments is preferably —CH3;
(d) —CH2NH—C(O)—O—C(CH3)3; or
(e) —CH2—NH—C(O)—[(CH2)2—O—]y—(CH2)2—R13E, wherein: y is 1 to 6, and in some
embodiments is preferably 2, and R13E is —NH2, —N+H3, or —N+(CH3)3;
R8 is a moiety of the formula:
wherein R8a is —H, or a linear, branched or cyclic alkyl of up to four carbon atoms, and in some embodiments is preferably —CH3, or —C(CH3)3;
A is (a) —CH2—; or
(b) a moiety of the formula:
wherein R3 is:
(i) linear, branched or cyclic alkyl of up to 6 carbon atoms, and in some embodiments is preferably —CH3 or —CH(CH3)2;
(ii) —(CH2)z—R14A, wherein: z is 1-4, and R14A is —NH2 or —N+H3;
(iii) —(CH2)z—R14B, wherein: z is 1-4, and R14B is —N(CH3)2 or —N+(CH3)3; or
(iv) —CH2—NH—C(O)—[(CH2)2—O—]y—(CH2)2—R14C, wherein, y′ is 1 to 6, and in some embodiments is preferably 2, and R14C is —NH2, —N+H3, or —N+(CH3)3;
B is:
(a) a moiety of the formula:
wherein:
R1 is —H or —NH—C(O)—CH3;
R2 is —H or —C(O)—R15A, wherein R15A is —NH2, —N+H3, or —N+(CH3)3; and
C1 is —CH2— or —(CH2)2—O—; or
(b) a moiety of the formula:
D is:
(a) a moiety of the formula:
(b) a moiety of the formula:
wherein R12 is —H or —CH3; and
E is:
(a) a moiety of the formula:
(b) a moiety of the formula:
or a pharmaceutically acceptable salt thereof.
In one aspect the present invention is a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In one aspect the present invention is a compound of the formula:
or a pharmaceutically acceptable salt thereof.
In one embodiment the present invention provides pharmaceutical compositions comprising a compound of the invention, for example, a compound of Formula I, and at least one pharmaceutical excipient, preferably a composition directed to oral administration.
In one aspect the present invention provides a method of antagonizing PCSK9 in the provision of therapy for disease states related to PCSK9 activity, for example, atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions, by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a salt thereof, preferably in the form of a pharmaceutical composition.
DETAILED-DESCRIPTION OF THE INVENTION
In the description that follows conventional structural representation is employed and includes conventional stereochemical notation for certain asymmetric carbon centers.
Thus, structural representation of compounds of the invention includes conventional stereochemical notation for some asymmetric carbon centers shown in the example compounds. Accordingly, in such instances, solid black “wedge” bonds represent bonds projecting from the plane of the reproduction medium, “hashed wedge” bonds representing descending bonds into the plane of the reproduction medium, and a “wavy” line appended to a carbon bearing a double bond indicates both possible cis and trans orientations are included. As is conventional, plain solid lines represent all spatial configurations for the depicted bonding. Accordingly, where no specific stereochemical notation is supplied the representation contemplates all stereochemical and spatial orientations of the structural features.
As is shown in the examples of the invention, and mentioned above, particular asymmetric carbon centers are structurally represented using conventional “Solid Wedge” and “Hash Wedge” bonding representation. For the most part, absolute configuration has not been determined for the example compounds, but has been assigned by analogy to specific example compounds which were prepared using the same or analogous reaction conditions and starting reagents of known stereochemical configurations, were isolated under the same chromatographic conditions, and for which absolute stereochemistry was determined by X-ray crystallography. Accordingly, specific assignment of the configurations structurally represented herein is meant to identify the specific compounds prepared and is not put forth as being the product of absolute structural determination unless otherwise noted in the data presented.
It will be appreciated that were isomeric mixtures are obtained, the preparation of individual stereoisomers in significant percentages of enantiomeric excess can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product.
Where indicated herein, absolute stereochemistry is determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Unless a particular isomer, salt, solvate (including hydrates) or solvated salt of such racemate, enantiomer, or diastereomer is indicated, the present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and mixtures thereof.
The present invention also embraces isotopically-labeled compounds of the present invention which are structurally identical to those recited herein, but for the fact that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope usually found in nature, thus altering the naturally occurring abundance of that isotope present in a compound of the invention. The present invention is meant to include all suitable isotopic variations of the compounds of Formula I.
Examples of isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, 123I and 125I. It will be appreciated that other isotopes may be incorporated by known means also.
In particular, certain isotopically-labeled compounds of the invention (e.g., those labeled with 3H, 11C and 14C) are recognized as being particularly useful in compound and/or substrate tissue distribution assays using a variety of known techniques. Additionally, compounds of the invention contemplate isotopic substitution include different isotopic forms of hydrogen (H), including protium (1H) and deuterium (2H or D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
In describing the compounds of the invention the term “linear-alkyl” or “branched-alkyl” means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of linear alkyl or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. The term “Cycloalkyl” means a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Where an alkyl moiety is specified by the number of carbon atoms, for example, “ . . . a linear, branched, or cyclic alkyl of up to four carbon atoms” means all 4 carbon alkyl moieties, and includes methyl, ethyl, propyl, isopropyl, n-butyl, secondary-butyl, iso-butyl, tertiarybutyl, cyclo propyl, methyl-cyclopropyl-, -methylene-cyclopropyl and cyclobutyl.
Where a wavy line terminates a conventional bond (as opposed to connecting two atoms within a structure) it indicates a point of bonding to a structure, e.g.:
indicates a the secondary-butyl moiety is bonded via the methylene group via the bond terminated with the wavey line. Where an alphabetical notation is used to depict a substituent moiety, a dash is employed to indicate the point of bonding to the indicated substrate, e.g.: —CH2—C(O)—CH2Cl indicates the acetyl chloride moiety is bonded via the methylene portion of the moiety.
When any variable (e.g., n, Ra, Rb, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise specified at the point of definition. One of ordinary skill in the art will recognize that choice of combinations of the various substituents defined in a structural representation, i.e. R1, RA, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability, and combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds embraced by Formula I.
Where any variable or moiety is expressed in the form of a range, eg (—CH2—)1-4, both of the extrema of the specified range are included (i.e. 1 and 4 in the example) as well as all of the whole number values in between (i.e. 2 and 3 in the example).
The term “Halogen” includes fluorine, chlorine, bromine and iodine unless specified otherwise at the point of use.
As the term is used herein, “subjects” (alternatively “patients”) refers to an animal, preferably a mammal, and in particular a human or a non-human animal including livestock animals and domestic animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals in need of treatment. In some embodiments the subject is preferably a human. As used herein, the term “administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of Formula I means providing the compound, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment.
As mentioned above, in one aspect the present invention includes the provision of compounds of Formula I, or a pharmaceutically acceptable salt thereof, which have properties that antagonize PCSK9 function.
In some embodiments, it is preferred for the compounds of Formula I to have the structure of Formula II, or a pharmaceutically acceptable salt thereof:
wherein: A, B, D, R4, and R8 are as defined above.
In some embodiments R4 is preferably: (a) —CH3; (b) —CH(CH3)2; (c) —(CH2)x—R13b, wherein: x is 1-4, and R13b is —NH2 or —N+H3; (d) —CH2NH—C(O)—O—C(CH3)3; or (iv) —CH2—NH—C(O)—[(CH2)2—O—]2—(CH2)2—R13c, wherein R13c is —NH2, —N+H3, or —N+(CH3)3.
In some embodiments R8 is a moiety of the formula:
wherein R8b is —H, —CH3, or —C(CH3)3.
In some embodiments wherein A is a moiety of the formula:
R3 is preferably (i) —CH3; (ii) —CH(CH3)2; (iii) —(CH2)z—R13a, wherein: z is 1-4, in some embodiments, preferably 4, and R13a is-NH2, —N+H3 or —N+(CH3)3−; or (iv) —CH2—NH—C(O)—[(CH2)2—O—]2—(CH2)2—R13c, wherein R13c is —NH2, —N+H3, or —N+(CH3)3.
In some embodiments wherein B is a moiety pf the formula
wherein C1 is as defined above, R1 is preferably —H or —NH—C(O)—CH3; and R2 is preferably —H or —C(O)—NH2.
In some embodiments, it is preferred for the compounds of Formula I to have the structure of Formula III, or a pharmaceutically acceptable salt thereof:
wherein R4, R8, A and B are as defined above, or a pharmaceutically acceptable salt thereof.
In some embodiments, it is preferred for the compounds of Formula I to have the structure of Formula IV, or a pharmaceutically acceptable salt thereof:
wherein:
R3, R4, and R8, are as defined above; and
B2 is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein:
R1 is —H or —NH—C(O)—CH3;
R2 is —H or —C(O)—R16A NH2 R16A is —NH2, —N+H3, —N(CH3)2, or —N+(CH3)3,
or a pharmaceutically acceptable salt thereof.
Also provided herein as compounds of Formula I are compounds Ex-B01, Ex-B02, Ex-B03, Ex-B04, Ex-C01, Ex-C02, Ex-C03, Ex-C04, Ex-C05, Ex-C06, Ex-C07, Ex-OT-03, Ex-OT-04, Ex-OT-05, and Ex-OT-06, or any pharmaceutically acceptable salt thereof. These compounds are also referred to herein as “compounds of the invention.”
The term “salt(s)”, and its use in the phrase “pharmaceutically acceptable salts” employed herein, includes any of the following: acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, zwitterionic and quaternary ammonium complexes. Salts of compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.
Compounds of the invention contain tri-coordinate nitrogen atoms, for example, primary, secondary or tertiary amino moieties, wherein the lone pair of electrons residing on the nitrogen atom may be protonated with an appropriate acid or alkylated with an appropriate reagent, for example, alkyl bromide, under the appropriate reaction conditions to provide tetracoordinate charged nitrogen stabilized by an anion generated in the process, for example, a halogen ion or conjugate base. Accordingly, compounds of the invention may be prepared in the form of a free-base or isolated in the form of a quaternary complex or a salt complex. In some instances where there is an appropriate acidic proton proximal to a basic nitrogen formation of a zwitterionic complex is possible. As the term is employed herein, salts of the inventive compounds, whether acidic salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, and quaternary ammonium complexes are included in the scope of the inventive compounds described herein.
Accordingly, structural representation of compounds of the invention, whether in a free-base form, a salt form, a zwiterionic form or a quaternary ammonium form, also include all other forms of such compounds discussed above. Thus, one aspect of the invention is the provision of compounds of the invention in the form of a pharmaceutically acceptable salt, zwitterionic complex or quaternary ammonium complex. Those skilled in the art will recognize those instances in which the compounds of the invention may form such complexes, including where a tetracoordinate nitrogen can be quaternized or protonated and the charged nitrogen form stabilized by an associated anion. The term “pharmaceutically acceptable salt” refers to a salt (including a quaternary ammonium complex and an inner salt such as a zwitterion complex) which possesses effectiveness similar to or greater than a free-base form of the compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference.
The present invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe” for use in the preparation of pharmaceutical formulations, termed herein as “pharmaceutically acceptable salts”. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like.
Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be converted to an ammonium ion or quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
In general, salts of compounds are intended to be pharmaceutically acceptable salts within the scope of the invention.
The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan. Compounds of the invention include any form of the compound including in situ in a reaction mixture as well as in isolated and purified form obtained by routine techniques. Also included are polymorphic forms of the compounds of the invention and solvates and prodrugs thereof.
Certain compounds of the invention may exist in different tautomeric forms, for example, but are not limited to, ketone/enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:
In the same manner, unless indicated otherwise, presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such tautomeric forms of the compound. Accordingly, where compounds of the invention, their salts, and solvates and prodrugs thereof, may exist in different tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced by, and included within the scope of the invention.
In another aspect, the present invention provides pharmaceutical compositions comprising one or more compounds of the invention. As used herein, the term “pharmaceutical composition” comprises at least one pharmaceutically active compound and at least one excipient, and is intended to encompass both the combination of the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
As will be appreciated by the ordinarily skilled artisan, excipients are any constituent which adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect. In general compositions comprise more than one excipient depending upon the route of administration and the characteristics of the active being administered. Examples of excipients which impart to the composition properties which make it easier to handle or process include, but are not limited to, lubricants or pressing aids in powdered medicaments intended to be tableted, and emulsion stabilizers in compositions in which the active is present in the form of an emulsion. Examples of excipients which adapt a composition to a desired route of administration are, for example, but not limited to, for oral administration, absorption enhancers promoting absorption from the gastrointestinal tract, for transdermal ortransmucosal administration, penetration enhancers, for example, those employed in adhesive skin “patch” or compositions for buccal administration.
Notwithstanding the function excipients perform in a composition, excipients are collectively termed herein “a carrier”. Typically, formulations may comprise up to about 95 percent active ingredient and the balance carrier, although formulations with different ratios may be prepared. In general, acceptable pharmaceutical compositions contain a suitable concentration of the active that an effective amount of the PCSK9 antagonist can be provided in an individual dosage form of acceptable volume based upon the route of administration such that it can provide a therapeutic serum level of the active for an acceptable period of time in a subject to whom the composition is administered and the composition will retain biological activity during storage within an acceptable temperature range for an acceptable period of time.
Pharmaceutical composition, as used herein, refers both to a bulk composition, that is, formulated material that has not yet been formed into individual dosage units for administration, and the composition contained within individual dosage units.
While compositions of the invention may be employed in bulk form, it will be appreciated that for most applications compositions will be incorporated into a dosage form providing individual units suitable for administration to a patient, each dosage form comprising an amount of the selected composition which contains an effective amount of said one or more compounds of Formula I. Examples of suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for administration through tissues of the oral cavity, for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachet or a needle array suitable for providing intramucosal administration; (iii) a dosage form adapted for administration via the mucosa of the nasal or upper respiratory cavity, for example a solution, suspension or emulsion formulation for dispersion in the nose or airway; (iv) a dosage form adapted for transdermal administration, for example, a patch, cream or gel; (v) a dosage form adapted for intradermal administration, for example, a microneedle array; (vi) a dosage form adapted for intravenous (IV) infusion, for example, over a prolonged period using an I.V. infusion pump; (vii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties; (viii) a dosage form adapted for drip intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag; (ix) a dosage form adapted for subcutaneous administration, including administration over an extended time period by implanting a rod or other device which diffuses the compound into the surround tissue and thereby provides a continuous serum therapeutic level; or (x) a dosage form adapted for delivery via rectal or vaginal mucosa, for example, a suppository.
Pharmaceutical compositions can be solid, semi-solid or liquid. Solid, semi-solid and liquid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration. In addition, liquid form preparations include, but are not limited to, solutions, suspensions and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for ingestion, inhalation or intravenous administration (IV), for example, but not limited to, administration via drip IV or infusion pump, intramuscular injection (IM), for example, of a bolus which is released over an extended duration, direct IV injection, or adapted to subcutaneous routes of administration.
Other routes of administration which may be contemplated include intranasal administration, or for administration to some other mucosal membrane. Formulations prepared for administration to various mucosal membranes may also include additional components adapting them for such administration, for example, viscosity modifiers.
Although in some embodiments, compositions suitable for use in a solid oral dosage form, for example, a tablet or quick-melt mouth-dissolving formulation are preferable routes of administration for a compound of the invention or a salt thereof, a composition of the invention may be formulated for administration via other routes mentioned above. Examples include aerosol preparations, for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to a suspension or a solution, for example, for oral or parenteral administration. Examples of such solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.
For example, the compounds of the invention may also be deliverable transdermally ortransmucosally, for example, from a liquid, suppository, cream, foam, gel, or rapidly dissolving solid form. It will be appreciated that transdermal compositions can take also the form of creams, lotions, aerosols and/or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any know in the art, for example, a patch which incorporates either a matrix comprising the pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound.
Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions mentioned above may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md. Additional examples of publications addressing formulation issues may be found in: Pharmaceutical compositions may be formulated by any number of strategies known in the art, see, e.g., McGoff and Scher, 2000 Solution Formulation of Proteins/Peptides: In—McNally, E. J., ed. Protein Formulation and Delivery. New York, N.Y.: Marcel Dekker; pp. 139-158; Akers & Defilippis, 2000, Peptides and Proteins as Parenteral Solutions. In—Pharmaceutical Formulation Development of Peptides and Proteins. Philadelphia, Pa.: Taylor and Francis; pp. 145-177; Akers et al., 2002, Pharm. Biotechnol. 14:47-127.
In another aspect the present invention provides methods of employing PCSK9-specific antagonist compounds described herein for antagonizing PCSK9 function; said methods of which are further described below. Use of the term “antagonizing” throughout the present application refers to providing to the affected tissue(s) a substance which opposes the action of, inhibits, counteracts, neutralizes or curtails one or more functions of PCSK9 in the affected tissues. Inhibition or antagonism of one or more of PCSK9-associated functional properties can be readily determined according to methodologies known to the art (see, e.g., Barak & Webb, 1981 J. Cell Biol. 90:595-604; Stephan & Yurachek, 1993 J. Lipid Res. 34:325330; and McNamara et al., 2006 Clinica Chimica Acta 369:158-167) as well as those described herein. Inhibition or antagonism will effectuate a decrease in PCSK9 activity relative to that seen in the absence of the antagonist or, for example, that seen when a control antagonist of irrelevant specificity is present. Preferably, a PCSK9-specific antagonist in accordance with the present invention antagonizes PCSK9 functioning to the point that there is a decrease of at least 10%, of the measured parameter including but not limited to the activities disclosed herein, and more preferably, a decrease of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 95% of the measured parameter. Such inhibition/antagonism of PCSK9 functioning is particularly effective in those instances where PCSK9 functioning is contributing at least in part to a particular phenotype, disease, disorder or condition which is negatively impacting the subject.
In one aspect, the present invention provides a method for antagonizing the activity of PCSK9, which comprises contacting a cell, population of cells or tissue sample capable of being affected by PCSK9 (i.e., which expresses and/or comprises LDL receptors) with a PCSK9-specific antagonist disclosed herein under conditions that allow said antagonist to bind to PCSK9 when present and inhibit PCSK9's inhibition of cellular LDL uptake. In some embodiments of the present invention include such methods wherein the cell is a human cell. Additional embodiments of the present invention include such methods wherein the cell is a murine cell.
In one aspect, the present invention provides a method for antagonizing the activity of PCSK9 in a subject, which comprises administering to the subject a therapeutically effective amount of a PCSK9-specific antagonist of the present invention. In some embodiments, the methods for antagonizing PCSK9 function are for the treatment, as defined herein, of a PCSK9-associated disease, disorder or condition or, alternatively, for providing therapy in a disease, disorder or condition that could benefit from the effects of a PCSK9 antagonist.
The present invention, thus, contemplates the use of PCSK9-specific antagonists described herein in various methods of treatment where antagonizing PCSK9 function is desirable. As used herein, the term “method of treatment” relates to a course of action resulting in a change in at least one symptom of a disease state which can be prophylactic or therapeutic in nature. In some embodiments, the present invention relates to a method of treatment for a condition associated with/attributed to PCSK9 activity, or a condition where the functioning of PCSK9 is contraindicated for a particular subject, the method comprising administering to the subject a therapeutically effective amount of a PCSK9-antagonist compound of the present invention. In some embodiments, the condition may be atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular disease and cardiometabolic conditions, or may be a disease state or condition in which PCSK9 activity is contraindicated.
Methods of treatment in accordance with the present invention comprise administering to an individual a therapeutically (or prophylactically) effective amount of a PCSK9-specific antagonist of the present invention. Use of the terms “therapeutically effective” or “prophylactically effective” in reference to an amount refers to the amount necessary at the intended dosage to achieve the desired therapeutic/prophylactic effect for the period of time desired. The desired effect may be, for example, the alleviation, amelioration, reduction or cessation of at least one symptom associated with the treated condition. These amounts will vary, as the skilled artisan will appreciate, according to various factors, including but not limited to the disease state, age, sex and weight of the individual, and the ability of the PCSK9-specific antagonist to elicit the desired effect in the individual. The response may be documented by in vitro assay, in vivo non-human animal studies, and/or further supported from clinical trials.
In some embodiments it is preferred to administer a PCSK9 antagonist compound of the invention in the form of a pharmaceutical composition as described herein.
Dosing of antagonist therapeutics is well within the realm of the skilled artisan, see, e.g., Lederman et al., 1991 Int. J. Cancer 47:659-664; Bagshawe et al., 1991 Antibody, Immunoconjugates and Radiopharmaceuticals 4:915-922, and will vary based on a number of factors, for example, but not limited to, those mentioned above, including the condition of the patient, the area being treated, the route of administration, and the treatment desired, for example, prophylaxis or acute treatment and the like. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective therapeutic amount of the antagonist.
The subject may be in need of, or desire, treatment for an existing disease or medical condition. As used herein, the subject “in need” of treatment of an existing condition encompasses both a determination of need by a medical professional as well as the desire of the subject for such treatment. When a compound or a salt thereof is provided in combination with one or more other active agents, “administration” and its variants are each understood to include provision of the compound or its salt and the other agents contemporaneously or simultaneously or over a course of separate administrations over a period of time. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately. It is understood that a “combination” of active agents can be a single composition containing all of the active agents or multiple compositions each containing one or more of the active agents. In the case of two active agents a combination can be either a single composition comprising both agents or two separate compositions each comprising one of the agents; in the case of three active agents a combination can be either a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two compositions one of which comprises two of the agents and the other comprises the third agent; and so forth.
The compositions and combinations of the present invention are suitably administered in effective amounts. The term “effective amount” means the amount of active compound sufficient to antagonize PCSK9 and thereby elicit the response being sought (i.e., induce a therapeutic response in the treatment or management of conditions associated with or impacted by PCSK9 function, including, but not limited to atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular disease and cardiometabolic conditions in an animal or human).
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art, for example, as described in the standard literature, for example, as described in the “Physicians' Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA), the Physician's Desk Reference, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, N.J. 07645-1742), or the Physician's Desk Reference, 57th Edition, 2003 (published by Thompson PDR, Montvale, N.J. 07645-1742); the disclosures of which is incorporated herein by reference thereto. For convenience, the total daily dosage may be divided and administered in portions during the day as required or delivered continuously.
The PCSK9-specific antagonist may be administered to an individual by any route of administration appreciated in the art, including but not limited to oral administration, administration by injection (specific embodiments of which include intravenous, subcutaneous, intraperitoneal or intramuscular injection), or administration by inhalation, intranasal, or topical administration, either alone or in combination with other agents designed to assist in the treatment of the individual. The PCSK9-specific antagonist may also be administered by injection devices, injector pens, needleless devices; and subcutaneous patch delivery systems. The route of administration should be determined based on a number of considerations appreciated by the skilled artisan including, but not limited to, the desired physiochemical characteristics of the treatment.
One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I. An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula I, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or agents, including but not limited to anti-hypertensive agents, anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and/or antiobesity agents may be used in any combination with the compound of Formula I in a single dosage formulation (a fixed dose drug combination), or may be administered to the subject in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents).
Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril), angiotensin II receptor antagonists (e.g., losartan i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR®); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g. urea derivatives of di- and tri-peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives (U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chains linked by non-peptidic bonds (U.S. Pat. No. 5,114,937), di- and tri-peptide derivatives, peptidyl amino diols and peptidyl beta-aminoacyl aminodiol carbamates, and small molecule renin inhibitors (including diol sulfonamides and sulfinyls), N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and fluoro- and chloro-derivatives of statone-containing peptides, enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g. sildenafil, tadalfil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, ormetoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alpha methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g. hydralazine); lipid lowering agents e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), fluvastatin (particularly the sodium salt sold in LESCOL®), crivastatin, and pitavastatin; a cholesterol absorption inhibitor such as ezetimibe (ZETIA®) and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms and/or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents including insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and other PPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARγ modulators (SPPARyM's), (e.g., such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™; and (iii) protein tyrosine phosphatase-1 B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro and inhalable formulations of each); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide); α-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021 and KT6-971); incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof); bile acid sequestering agents (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), acyl CoA:cholesterol acyltransferase inhibitors, (e.g., avasimibe); antiobesity compounds; agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenase type 1, (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, and LY-2523199); CETP inhibitors (e.g., anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose 1,6-bisphosphatase, (e.g., such as those disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated Protein Kinase (AMPK) activators; other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., such as those disclosed in WO 2009/001836); neuromedin U receptor agonists (e.g., such as those disclosed in WO 2009/042053, including, but not limited to, neuromedin S (NMS)); SCD modulators; GPR-105 antagonists (e.g., such as those disclosed in WO 2009/000087); SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin, canagliflozin, BI-10773, ertugliflozin, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); inhibitors of acyl coenzyme A: diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthase; inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; PPAR agonists; protein tyrosine phosphatase-1B (PTP-1B) inhibitors; IL-1b antibodies, (e.g., XOMA052 and canakinumab); and bromocriptine mesylate and rapid-release formulations thereof; or with other drugs beneficial for the treatment of the above-mentioned conditions or disorders including the free-acid, free-base, and pharmaceutically acceptable salt forms of the above active agents where chemically possible.
The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of known variants. Other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Abbreviations listed below may used in the exemplary schemes and/or examples herein.
ACN is acetonitrile
AcOH is acetic acid
AcO—NH4 is ammonium acetate
Boc2O is di-tert-butyl dicarbonate
Bn is benzyl
BnBr is benzyl bromide
BzCl is benzoyl chloride
CBr4 is perbromomethane
Cbz-Cl is benzyl chloroformate
DBU is 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCC is dicyclohexylcarbodiimide
DCE is 1,2-dichloroethane
DCM is dichloromethane
DEA is N,N-diethylamine
DIAD is (E)-diisopropyl diazene-1,2-dicarboxylate
DIEA or DIPEA is N,N-diisopropylethylamine
DMAP is 4-dimethylaminopyridine
DMF is N,N-dimethylformamide
DMSO is dimethyl sulfoxide
EA or EtOAc is ethyl acetate
EtOH is ethanol
Et2O is diethyl ether
Fmoc is fluorenylmethyloxycarbonyl protecting group
Fmoc-Cl is (9H-fluoren-9-yl)methyl carbonochloridate
Fmoc-D-Dap(Boc)-OH is N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-beta-t-butyloxycarbonyl-D-2,3-diaminopropionic acid
Fmoc-Osu is Fmoc N-hydroxysuccinimide ester
HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
HPLC is High Performance Liquid Chromatography
IPA is isopropyl alcohol
LiOH is lithium hydroxide
LC/MS is Liquid chromatography-mass spectrometry
Me3N is trimethyl amine
MeOH is methanol
MPLC is Medium pressure liquid chromatography
MsCl is methanesulfonyl chloride
NaBH(OAc)3 is sodium triacetoxyborohydride
NMR is Nuclear Magnetic Resonance
NsCl is 4-nitrobenzene-1-sulfonyl chloride
PE is petroleum ether
Pd2(dba)3(HCCl3) is tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct PPh3 is triphenylphosphine
PdCl2(dppf) or Pd(ii)(dppf)Cl2 is dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)
Pd(dppf)Cl2CH2Cl2 is dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(I) dichloromethane adduct
Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium
PPTs is pyridinium p-toluenesulfonate
[Rh(OAc)2]2 is rhodium(II) acetate dimer
RT or r.t. or rt is room temperature
tBuOAc is tert-butyl acetate
TEA is triethylamine
TFA is trifluoroacetic acid
TFE is tetrafluoroethylene
THE is tetrahydrofuran
Tf2O is trifluoromethanesulfonic anhydride
Teoc-OSu is 2,5-dioxopyrrolidin-1-yl (2-(trimethylsilyl)ethyl) carbonate
TBAF is tetrabutylammonium fluoride
TMS is tetramethylsilane
Zhan's catalyst 1B is dichloro(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)((5-((dimethylamino)sulfonyl)-2-(1-methylethoxy-O)phenyl)methylene-C)ruthenium(II) [also described as 1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl[methyleneruthenium (II) dichloride]
Example 1 Preparation of Ex-B03
As illustrated above in Scheme 1, in general, compounds of the invention are prepared by forming intermediate compounds which contain key portions of the desired final compound and coupling them together using chemistry detailed below, followed by cyclization and derivatization of the ring with the desired substituents, as is illustrated below for the preparation of compound Ex-B04 (Example 2). Presented below also is the synthesis of the relevant intermediate compounds.
Preparation of Compound Ex-B03
Step I: Preparation of Compound Intermediate 30
To a solution of intermediate 29, prepared in accordance with the procedure detailed below, (41 mg, 0.027 mmol) in DMF (4 ml) at ambient temperature was added HATU (12.28 mg, 0.032 mmol), the resulting solution was stirred at rt for 30 min, then added CH2Cl2 (90 mL) followed by addition of DIEA (0.014 ml, 0.081 mmol), the resulting solution was stirred at room temperature for 1 hour. The volatile was removed on rotary evaporator, and the resulting DMF solution was purified on reverse phase MPLC (C18) using acetonitrile (0.05% TFA)/water (0.05% TFA) as eluting solvents to give Intermediate 30. LC/MS: (M+1)+: 1469.0
Step II: Preparation of Compound Ex-B03
To the solution of intermediate 30 (2.7 mg, 1.838 μmol) in CH2Cl2 (1 ml) was added triisopropylsilane (0.873 mg, 5.52 μmol) and HCl (0.1 mL, 0.400 mmol) (4N in dioxane), the resulting solution was stirred at ambient temperature for 1 hour, then concentrated on rotary evaporator, the residue (Ex-B03 crude) was purified on reverse phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) eluting solvents to give Example Compound EX-B03. LC/MS: (M+1)+: 1312.0.
Preparation of the following intermediates from which intermediate Int 29 was ultimately synthesized are described next:
Preparation of Intermediate 10
Step A: 1-benzyl 2-methyl (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (2)
Benzyl chloroformate (0.865 mL, 6.06 mmol) was added to a cold (ice bath) mixture of (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate hydrochloride 1 (1 g, 5.51 mmol), CH2Cl2 (55 mL) and TEA (1.919 mL, 13.77 mmol). The reaction was stirred at 0° C. for 1 h followed by NH4Cl (aq, sat) quench. The crude reaction mixture was worked up with water/dichloromethane and the combined DCM extracts were dried over Na2SO4, filtered and evaporated in vacuo. The pot residue was purified by reverse-phase chromatography (C18, 86 g cartridge). The column was eluted by a acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled and evaporated in vacuo to afford a colorless solid as (2S,3S)-1-benzyl 2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate (1.3363 g, 4.78 mmol, 87% yield). LCMS calc.=279.11; found=280.29.
Step B: 1-benzyl 2-methyl (2S,3S)-3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-1,2-dicarboxylate (3)
A mixture of Intermediate 2 (1.2296 g, 4.40 mmol) and DCM (40 mL) was degassed with nitrogen for 5 min followed by addition of rhodium(II) acetate dimer (0.195 g, 0.440 mmol), and the mixture cooled in an ice bath. Tert-butyl diazoacetate (0.915 mL, 6.60 mmol) was added into this mixture slowly over 80 min (syringe pump). An aliquot was taken and partitioned w/ water and the organic layer was checked by LCMS. The reaction was stirred at 0° C. for additional 1.5 h after addition of diazo reagent and then quenched by adding water. The reaction crude was worked up with water/dichloromethane. The combined organic extracts were evaporated in vacuo. The pot residue was purified by reverse-phase chromatography (C18, 130 g cartridge). The column was eluted by a acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled and evaporated in vacuo to afford (2S,3S)-1-benzyl 2-methyl 3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-1,2-dicarboxylate (1.0499 g) and recovered starting material (2S,3S)-1-benzyl 2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate. LCMS calc.=393.18; found=416.39 (M+Na+).
Step C: (2S,3S)-methyl 3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylate Hydrochloride (4)
A mixture of Intermediate 3 (1.0499 g, 2.67 mmol), MeOH (25 mL) and Pd—C (0.284 g, 0.267 mmol) were degassed with cycles of vacuum/H2 flush then stirred under a balloon of H2 at room temperature overnight. The reaction crude was filtered and HCl (2.67 mL, 2.67 mmol) was added into the filtrate. The filtrate was concentrated under reduced pressure to afford (2S,3S)-methyl 3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylate hydrochloride. LCMS calc.=259.14; found=260.34.
Step D: (2S,3S)-methyl 3-(2-(tert-butoxy)-2-oxoethoxy)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoyl)pyrrolidine-2-carboxylate (5)
Intermediate 4 (346 mg, 1.170 mmol), DMF (3 ml) and (S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid (377 mg, 1.170 mmol) were stirred in a ice bath followed by addition of Hunig's Base (0.511 ml, 2.92 mmol) and HATU (489 mg, 1.287 mmol) for 1 hour. The reaction crude was purified by reverse phase chromatography (C18, 130 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid mixture (0% to 62%). Related fractions were pooled and evaporated to afford (2S,3S)-methyl 3-(2-(tert-butoxy)-2-oxoethoxy)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoyl)pyrrolidine-2-carboxylate. LCMS calc.=563.26; found=586.48 (M+Na+).
Step E: (2S,3S)-methyl 1-((S)-2-amino-3-(5-fluoro-1H-indol-3-yl)propanoyl)-3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylate Methanesulfonate (6)
Methanesulfonic acid (0.046 ml, 0.710 mmol) was added into a room temperature mixture of Intermediate 5 (200 mg, 0.355 mmol) in t-butyl acetate (3 ml) and CH2Cl2 (0.750 ml). The reaction was stirred at room temperature for additional 2 h. LCMS indicated completion of reaction, which was used in the next step without further purification. LCMS calc.=463.21; found=464.30.
Step F: methyl (2S,3S)-1-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)propanamido)-3-(5-fluoro-1H-indol-3-yl)-propanoyl)-3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylate (7)
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)-methyl)phenyl)propanoic acid (211 mg, 0.409 mmol), DMF (5 ml), HATU (169 mg, 0.445 mmol) and Hunig's Base (0.373 ml, 2.134 mmol) were stirred at room temperature and transferred into the crude mixture from Step E. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was purified by reverse-phase chromatography (C18, 130 g cartridge). The column was eluted by a acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled and evaporated in vacuo to afford a colorless solid as (2S,3S)-methyl 1-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)propanamido)-3-(5-fluoro-1H-indol-3-yl)propanoyl)-3-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylate. LCMS calc.=961.43; found=962.24.
Step G: 2-(((2S,3S)-1-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(aminomethyl)phenyl)propanamido)-3-(5-fluoro-1H-indol-3-yl)propanoyl)-2-(methoxy-carbonyl)pyrrolidin-3-yl)oxy)acetic Acid (8)
TFA (0.4 mL, 5.19 mmol) was added into a room temperature solution of Intermediate 7 (20.6 mg, 0.021 mmol) in CH2Cl2 (0.8 ml). The reaction was stirred at room temperature for 2 h. LCMS indicated completion of reaction. Volatiles were removed under reduced pressure to afford a yellow glass as the 2-(((2S,3S)-1-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(aminomethyl)phenyl)propanamido)-3-(5-fluoro-1H-indol-3-yl)propanoyl)-2-(methoxycarbonyl)pyrroidin-3-yl)oxy)acetic acid used in the next step without further purification. LCMS calc.=805.31; found=806.56.
Step H: methyl (12S,13S,9S,12S)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-12-((5-fluoro-1H-indol-3-yl)methyl)-4,10,13-trioxo-2-oxa-5,11-diaza-1(3,1)-pyrroidina-7(1,3)-benzenacyclotridecaphane-12-carboxylate (9)
Intermediate 8, HATU (318 mg, 0.836 mmol) and DMF (50 ml) were stirred at room temperature followed by addition of Hunig's Base (0.508 ml, 2.91 mmol) for 20 minutes. The reaction crude was purified by reverse phase chromatography (C18, 360 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled and evaporated in vacuo to afford a colorless solid as methyl (12S,13S,9S,12S)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-12-((5-fluoro-1H-indol-3-yl)methyl)-4,10,13-trioxo-2-oxa-5,11-diaza-1(3,1)-pyrrolidina-7(1,3)-benzenacyclo-tridecaphane-12-carboxylate. LCMS calc.=787.30; found=788.55 and 810.55 (M+Na+).
Step I (12S,13S,9S,12S)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-12-((5-fluoro-1H-indol-3-yl)methyl)-4,10,13-trioxo-2-oxa-5,11-diaza-1(3,1)-pyrrolidina-7(1,3)-benzenacyclotridecaphane-12-carboxylic Acid (10)
To the solution of Intermediate 9 in THE (10 mL), MeOH (5 ml), and water (4 ml) at 0° C. was added lithium hydroxide (2M, 0.685 mL, 1.371 mmol). The resulting solution was stirred at 0° C. for 4 h then quenched by addition of HCl (1M, 1.371 mL, 1.371 mmol). Volatiles were evaporated in vacuo. To the pot residue at 0° C. was added acetone (20 mL), sodium carbonate (24.22 mg, 0.228 mmol) and FMOC-OSU (51.4 mg, 0.152 mmol). The reaction was stirred at 0° C. for 3 h. Volatiles were evaporated on rotary evaporator. The resulting aqueous mixture was acidified to pH 4 followed by DCM extraction. The combined organic extracts were evaporated under reduced pressure. The pot residue was purified by reverse-phase chromatography (C18, 43 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled and evaporated in vacuo to afford a colorless solid as (12S,13S,9S,12S)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-12-((5-fluoro-1H-indol-3-yl)methyl)-4,10,13-trioxo-2-oxa-5,11-diaza-1(3,1)-pyrrolidina-7(1,3)-benzenacyclotridecaphane-12-carboxylic acid. LCMS calc.=773.29; found=774.52.
Preparation of Intermediate 20
Step A: Preparation of Intermediate Compound 11
To (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (5.6 g, 15.94 mmol) and tert-butyl 4-(2-aminoethyl)benzylcarbamate hydrochloride (4.80 g, 16.73 mmol) in DMF (159 ml) at 0° C. was added HATU (7.27 g, 19.12 mmol) and N,N-diisopropylethylamine (8.33 ml, 47.8 mmol), the reaction mixture was warmed up to ambient temperature (about 25° C.) and stirred for 4.5 h, then diluted with H2O (100 mL), extracted with EtOAc (3×200 mL)), washed with brine (3×200 mL). The ethylacetate extract was dried over MgSO4, filtered, concentrated and purified by silica gel column using EtOAc/hexanes as eluting solvents to give intermediate 11. LC/MS: (M+1)+: 584.5.
Step B: Preparation of Intermediate Compound 12
To the mixture of 11 (9.48 g, 16.24 mmol) in CH2Cl2 (81 ml) was added hydrochloride (4N in 1,4-dioxane, 16.24 ml, 65.0 mmol) in CH2Cl2 (81 ml), the resulting mixture was stirred at ambient temperature overnight, then the mixture was concentrated on rotary evaporator to give 12. LC/MS: (M+1)+: 484.2.
Step C: Preparation of Intermediate Compound 13
To the suspension of 12 (4.15 g, 7.98 mmol) and 4-(tert-butoxy)-4-oxobutanoic acid (1.460 g, 8.38 mmol) in DMF (45 ml) was added HATU (3.64 g, 9.58 mmol), the resulting mixture was stirred at ambient temperature for 50 min, then partitioned between EtOAc (500 mL) and brine (200 mL). The organic phase was washed with brine (2×200 mL), dried over Na2SO4, concentrated and the residue was purified on a silica gel column using EtOAc/hexane as eluting solvents to give 13. LC/MS: (M+1)+: 640.4.
Step D: Preparation of Intermediate Compound 14
To the solution of 13 (4.49 g, 7.02 mmol) in CH2Cl2 (20 ml) was added TFA (21.63 ml, 281 mmol), the solution was stirred at ambient temperature for 1 h, then concentrated on a rotary evaporator. The residue was azotropically concentrated from toluene, then dissolved in acetonitrile/water (100 mL, 1:1) and lyophilized. The residue was partitioned between EtOAc (400 mL) and HCl (pH4, 200 mL), the organic phase was washed with HCl (pH 4, 200 mL×3), brine, dried over Na2SO4, concentrated to give 14. LC/MS: (M+1)+: 584.2.
Step E: Preparation of Intermediate Compound 15
To the solution of 14 (3.7 g, 6.34 mmol) in MeOH (50 ml) was added TMS-diazomethane (22.19 ml, 44.4 mmol) dropwise, after completion of the reaction, the reaction was quenched dropwise with acetic acid (ca. 0.2 mL), then concentrated and the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give 15. LC/MS: (M+1)+: 598.3.
Step F: Preparation of Intermediate Compound 16
To the solution of 15 (2.83 g, 4.73 mmol) in acetonitrile (25 ml) was added piperidine (1.403 ml, 14.20 mmol) dropwise, the resulting solution was stirred at rt for 30 min, then concentrated and the residue was treated with acetonitrile (30 mL) and concentrated again. The cycle was repeated twice to give 16 as a crude. LC/MS: (M+1)+: 376.2
Step G: Preparation of Intermediate Compound 17
To the solution of 16 (1.778 g, 4.74 mmol) and Fmoc-L-Tyr(Me)-OH (2.175 g, 5.21 mmol) in DMF (35 ml) was added HATU (2.071 g, 5.45 mmol) and DIEA (1.654 ml, 9.47 mmol), the resulting solution was stirred at ambient temperature for 40 min, then partitioned between EtOAC (200 ML) and brine (150 mL), the organic phase was further washed with brine (2×150 mL), dried over Na2SO4, concentrated and the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give 17. LC/MS: (M+1)+: 775.2.
Step H: Preparation of Intermediate Compound 18
To the solution of 17 (3.36 g, 4.34 mmol) in acetonitrile (30 ml) was added piperidine (1.288 ml, 13.01 mmol), the resulting solution was stirred at ambient temperature for 30 min, then concentrated and the residue was treated with acetonitrile (30 mL) and concentrated again and further concentrated under high vacuum to give 18 as a crude. LC/MS: (M+1)+: 553.2.
Step I: Preparation of Intermediate Compound 19
To the solution of 18 (2.396 g, 4.34 mmol) in DMF (40 ml) was added Fmoc-L-Thr(tBu)-OH (1.895 g, 4.77 mmol), HATU (1.896 g, 4.99 mmol), and DIEA (1.514 ml, 8.67 mmol), the resulting solution was stirred at ambient temperature for 1 h, then partitioned between EtOAc (200 mL) and brine (100 mL), the aqueous phase was extracted with EtOAc (150 mL), the combined organic phase was washed with brine (2×200 mL), dried over Na2SO4, concentrated and the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give 19. LC/MS: (M+1)+: 932.2.
Step J: Preparation of Intermediate Compound 20
To the solution of 19 (0.155 g, 0.166 mmol) in acetonitrile (2 ml) was added piperidine (0.049 ml, 0.499 mmol), the resulting solution was stirred at ambient temperature for 1 hour, then concentrated and the residue was re-suspended in acetonitrile (10 mL) and concentrated, the cycle was repeated once and the residue was dried under high vacuum to give 20 as a crude product. LC/MS: (M+1)+: 710.3.
Preparation of Intermediate 29 Via Intermediate 25
Intermediate 29 was prepared by joining together intermediates 10 and 20, prepared above, and further derivatizing as detailed in the following Schemes
Preparation of Intermediate 25
Step A: Preparation of Intermediate Compound 22
To the solution of Intermediate 10 (0.104 g, 0.134 mmol) and Intermediate 20 (0.118 g, 0.166 mmol) in DMF (3 ml) at 0° C. was added HATU (0.054 g, 0.141 mmol) and DIEA (0.047 ml, 0.269 mmol), the resulting solution was stirred at 0° C. for 4 h. The reaction solution was partitioned between EtOAc (200 mL) and brine (100 mL), the organic phase was further washed with brine (2×100 mL), dried over Na2SO4, concentrated and the residue was purified on silica gel column using MeOH/DCM as eluting solvents to give 22. LC/MS: (M+1)+: 1465.9.
Step B: Preparation of Intermediate Compound 23
To the solution of 22 (0.196 g, 0.134 mmol) in acetonitrile (5 ml) was added piperidine (0.150 ml, 1.515 mmol), the resulting solution was stirred at rt for 40 min. then concentrated and the residue was resuspended in acetonitrile (5 mL) and concentrated again. The cycle was repeated once, the final residue was further dried under high vacuum for 1 h to give 23 as a crude product. LC/MS: (M+1)+: 1243.6.
Step C: Preparation of Intermediate Compound 25
To the solution of 23 (197 mg, 0.158 mmol) and 24 (67.6 mg, 0.158 mmol) in DMF (4 ml) at 0° C. was added HATU (66.3 mg, 0.174 mmol) and DIEA (0.055 ml, 0.317 mmol), the resulting solution was stirred at 0° C. for 4 h. The solution was purified on reverse phase MPLC (C18 column) using acetonitrile (0.05% TFA)/water (0.05% TFA) as eluting solvents to give 25. LC/MS: (M+1)+: 1651.6
Step D: Preparation of Intermediate Compound 26
To the solution of 25 (163 mg, 0.099 mmol) in acetonitrile (4 ml) was added piperidine (0.078 ml, 0.789 mmol), the resulting solution was stirred at ambient temperature for 1 hour, then the solution was concentrated and the residue was treated with acetonitrile (5 mL) and concentrated again, the cycle was repeated once again, the final residue was further dried under high vacuum for 1 h to give 26 as a crude product. LC/MS: (M+1)+: 1429.5
Step E: Preparation of Intermediate Compound 27
To the solution of 26 (141 mg, 0.099 mmol) and Z-L-Ala-OH (22.02 mg, 0.099 mmol) in DMF (4 ml) was added HATU (41.3 mg, 0.108 mmol) and DIEA (0.034 ml, 0.197 mmol), the resulting solution was stirred at ambient temperature for 1 hour, then directly purified on reverse phase MPLC (C18 column) using acetonitrile (0.05% TFA)/water (0.05% TFA) as eluting solvents to give 27. LC/MS: (M+1)+: 1634.2.
Step F: Preparation of Intermediate Compound 28
To the solution of 27 (160 mg, 0.098 mmol) in a mixture solvent of THE (6 ml), methanol (2 ml), and Water (2 ml) was added at 0° C. LiOH (0.4 ml, 0.400 mmol) dropwise, the resulting solution was stirred at 0° C. for 2 h, the volatile was evaporated on rotary evaporator at ambient temperature, the aqueous was acidified to pH 4 at 0° C., then extracted with 30% IPA/DCM (3×70 mL), the combined organic phase was dried over Na2SO4, concentrated to give 28. LC/MS: (M+1)+: 1620.8.
Step G: Preparation of Intermediate Compound 29
To the solution of 28 (159 mg, 0.098 mmol) in MeOH (15 ml) was added 10% Pd/C (20.88 mg, 0.020 mmol), the resulting mixture was hydrogenated via H2 balloon at rt for 5 h. The mixture was filtered through celite, the filtrate was concentrated and the residue was purified on reverse phase C18 column using acetonitrile (0.05% TFA)/water (0.05% TFA) as gradient to give product as TFA salt which was dissolved in acetonitrile (25 mL) and water (15 mL), to the solution at 0° C. was added HCl (5.00 ml, 0.5 mmol) dropwise, the resulting solution was stirred at 0° C. for 5 min, then lyophilized to give 29. LC/MS: (M+1)+: 1487.2.
Example 2 Preparation of Ex-B04
Ex-B04 was prepared by derivatizing intermediate Int-30, the penultimate intermediate to compound Ex-B03 prepared in Example 1, with intermediate Int 32, prepared in accordance with the following Scheme:
Step A: Preparation of Intermediate Compound 32A
To the solution of tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propanoate (5 g, 16.82 mmol) in acetonitrile (10 ml) was added trimethylamine (33% in ethanol, 11.46 ml, 50.5 mmol), the resulting solution was heated at 50° C. overnight. The solution was concentrated to give 2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)-N,N,N-trimethylethanaminium bromide (32A). LC/MS: (M)+: 276.5.
Step B: Preparation of Intermediate 32
To the solution of 2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)-N,N,N-trimethylethanaminium bromide (32A, 5.99 g, 16.81 mmol) in CH2Cl2 (20 ml) was added HCl (4N in dioxane) (21.01 ml, 84 mmol), the resulting solution was stirred at rt overnight. The solution was concentrated to give 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethylethanaminium bromide (32). LC/MS: (M)+: 220.1
Preparation of Ex-B04
To the solution of Int 30 (74.1 mg, 0.055 mmol) and Int 32 (19.79 mg, 0.066 mmol) in DMF (5 ml) was added HATU (25.06 mg, 0.066 mmol) and DIEA (0.029 ml, 0.165 mmol), the resulting solution was stirred at rt for 50 min. then purified on reverse phase HPLC using acetonitrile (0.1% formic acid)/water (0.1% formic acid) as mobile phase to yield Ex=B04. LC/MS: M+: 1514.2.
Example 3: Preparation of Ex-B01 and Ex-B02
Compounds Ex-B01 and Ex-B02 were prepared from Int. 36 (analogous to intermediate Int 29, described above) in an analogous manner to the preparation of compounds Ex-B03 and Ex-B04 detailed above from Intermediate Int 29 described above. Compound Ex-B02 was prepared from Ex-B01 in an analogous manner to that described above for Ex-B03 and Ex-B04 using intermediate 34, the preparation of which is described below.
Step E: Synthesis of Intermediate 35
Intermediate 23 (152 mg, 0.122 mmol), DMF (3 ml) and Intermediate 34 (60.8 mg, 0.122 mmol) were stirred in a methanol/ice bath followed by addition of Hunig's Base (0.043 ml, 0.244 mmol) and HATU (48.8 mg, 0.128 mmol) for one hour. The reaction mixture was purified by reverse phase chromatography (C18, 130 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid (0% to 100%). Related fractions were pooled and evaporated on a lyophilizer to afford a colorless solid as Int 35. LCMS calc.=1721.82; found=1724.32.
Step F: Synthesis of Intermediate 36
To the solution of 35 (176 mg, 0.102 mmol) in 1,4-dioxane (2 mL) and water (2 ml) at 0° C. was added lithium hydroxide (2M, 0.511 mL, 1.022 mmol) dropwise. The reaction was stirred at room temperature for 1 hour followed addition of HCl (1M, 1.022 mL, 1.022 mmol).
Volatiles were removed under reduced pressure to afford a colorless solid as crude Int 36, which was used as isolated in the following reaction. LCMS calc.=1485.73; found=1488.28.
Step G: Synthesis of Intermediate 37
Intermediate 36 (152 mg, 0.102 mmol), DMF (8 mL) and CH2Cl2 (8 mL) were stirred in a methanol/ice bath followed by addition of Hunig's Base (0.018 mL, 0.102 mmol) and HATU (10.83 mg, 0.028 mmol) for 3 hours. To the reaction mixture was added 5 mL of water and the crude reaction mixture was purified by reverse phase chromatography (C18, 130 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled to afford a colorless solid as Intermediate 37. LCMS calc.=1467.72; found=1490.26 (M+Na+).
Step H: Synthesis of Compound Ex-B01
Intermediate 37 (89.4 mg, 0.061 mmol), CH2Cl2 (1.5 mL) and TFA (0.5 mL, 6.49 mmol) were stirred at room temperature for 1 h. Volatiles were removed under reduced pressure. The pot residue was purified by reverse phase chromatography (C18, 130 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid mixture (0% to 100%). Related fractions were pooled and evaporated in vacuo to afford Ex-B01. LCMS calc.=1311.61; found=1315.99.
Step I: Synthesis of Compound Ex-B02
Ex-B01 (17.22 mg, 0.013 mmol), Intermediate 32, and DMF (1 mL) were stirred in a methanol/ice bath followed by addition of Hunig's Base (0.018 mL, 0.102 mmol) and HATU (10.83 mg, 0.028 mmol). Aliquot at 1 h indicated completion of reaction. The reaction crude was purified by reverse phase chromatography (C18, 130 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v formic acid mixture (0% to 65%). Related fractions were pooled to afford Ex-B02. LCMS calc.=1513.75; found=1518.10.
Preparation of Int 34
Step E1: Synthesis of Intermediate 34A
To FMOC-DAP(BOC)—OH (500 mg, 1.172 mmol) in DMF (5862 μl) was added D-alanine methyl ester HCl (164 mg, 1.172 mmol), HATU (490 mg, 1.290 mmol) and DIEA (614 μl, 3.52 mmol). The mixture was stirred at rt for 15 h. The reaction crude was purified by reverse phase chromatography (C18, 100 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v TFA mixture (0% to 80%) to afford I-methyl 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propanamido)-propanoate, 34A (495 mg, 0.968 mmol, 83% yield) as a white solid. LCMS calc.=511.56; found=512.26.
Step E2: Synthesis of Intermediate 34
NaOH (46.4 mg, 1.161 mmol) was added to a stirred mixture of I-methyl 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propanamido)-propanoate, 34A (495 mg, 0.968 mmol) in 0.8 M aq: CaCl2) (1.210 ml, 0.968 mmol) and 2-Propanol (15 ml)/Water (5 ml). The mixture was stirred at room temperature overnight. The reaction crude was purified by reverse phase chromatography (C18, 100 g cartridge). The column was eluted by an acetonitrile/water/0.1% v/v TFA mixture (0% to 80%) to afford I-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)3-((tert-butoxycarbonyl)amino)-propanamido)propanoic acid, Int 34. LCMS calc.=497.54; found=499.23.
Example 4 Preparation of Ex-C03 and Ex-C04
Compounds Ex-C03 and Ex-C04 were prepared in accordance with the following schemes in a manner analogous to the above-described example compounds using and intermediate Int 49 analogous to intermediate Int 10 described above:
Step A—Synthesis of Intermediate 41
To a solution of 40 (5.0 g, 11.38 mmol) and DIPEA (3.97 mL, 22.75 mmol) in acetone (25 mL) was added methyl iodide (1.423 mL, 22.75 mmol) and the reaction mixture was stirred at room temperature overnight. Upon stirring overnight, some precipitation was observed and the solids were filtered and triturated with acetone. The combined organic fractions were concentrated in vacuo. The residue was purified by column chromatography over silica gel (Isco 120 g), eluting with 0-40% EtOAc/hexanes to give Intermediate 41. UPLC Method A: tR=1.50 min; [M+23]+=476.37.
Step B—Synthesis of Intermediate 42
To a solution of Intermediate 41 (5.04 g, 11.11 mmol) in DCM (25 mL) was added piperidine (3.30 mL, 33.3 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography over silica gel (Isco 220 g), eluting with 0-40-100% EtOAc/hexanes to yield intermediate 42. UPLC Method A: tR=0.59 min; [M+1]+=232.19.
Step C—Synthesis of Intermediate 44
To a solution of intermediate 42 (20 mg, 0.062 mmol), DIPEA (0.033 mL, 0.186 mmol) and 43 (15.79 mg, 0.068 mmol) in DCM (1 mL) was added HATU (26.0 mg, 0.068 mmol) and the mixture was stirred at room temperature for 90 min. The mixture was quenched by the addition of water and extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isco 4 g), eluting with 0-50% EtOAc/isohexane to give intermediate 44. UPLC Method A: tR=1.34 min; [M+1]+=536.41.
Step D—Synthesis of Intermediate 45
To a solution of intermediate 44 (1.0 g, 1.867 mmol) in a 4:1 t-BuOAc/DCM (10 mL) was added methanesulfonic acid (0.485 mL, 7.47 mmol) and the mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated to half its volume and the crude mixture was used a such for the next step without any purification. UPLC Method A: tR=0.92 min; [M+1]+=436.23.
Step E—Synthesis of Intermediate 47
To a stirred mixture of 46 (1.929 g, 3.73 mmol) and DIPEA (1.956 mL, 11.20 mmol) in DCM (20 mL) was added HATU (1.420 g, 3.73 mmol) and the mixture was stirred at room temperature for 10 min. This mixture was added to a stirred solution of intermediate 45 (0.813 g, 1.867 mmol) in 2 mL DCM and the reaction was stirred at rt for 1 h. The reaction mixture was quenched by the addition of sat. NaHCO3 and extracted with DCM. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isco 120 g), eluting with 0-25% EtOAc:EtOH (3:1)/hexanes to give intermediate 47 as a yellow oil. UPLC Method C: tR=1.60 min; [M+1]+=934.36.
Step F—Synthesis of Intermediate 48
To a stirred solution of intermediate 47 (1.10 g, 1.178 mmol) in DCM (15 mL) was added TFA (2.72 mL, 35.3 mmol) and the reaction mixture was stirred at room temperature for 2 h. The excess TFA was concentrated in vacuo and diluted with 4 N HCl in 1,4-dioxane. The residue was left to stir for 5 min, concentrated in vacuo and dried which was then diluted with DMF (5 mL). To this mixture was added HATU (537 mg, 1.413 mmol) and the mixture was stirred at room temperature for 15 min followed by dilution with DCM (50 mL). DIPEA (1.028 mL, 5.89 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of sat. NaHCO3 and extracted with DCM. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isco 40 g), eluting with 0-40-50% EtOAc:EtOH (3:1)/hexanes to give intermediate 48 as a yellow gum. UPLC Method C: tR=1.26 min; [M+1]+=760.26.
Step G—Synthesis of Intermediate 49
To a solution of intermediate 48 (150 mg, 0.197 mmol) and 0.8 M CaCl2 (0.987 mL, 0.790 mmol) in 7:3 i-PrOH:H2O (1.5 mL) was added NaOH (9.48 mg, 0.237 mmol) and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of 1 N HCl until pH 6 and extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was used as such for the next step without further purification. UPLC Method C: tR=1.21 min; [M+1]+=746.12.
Compounds Ex-C03 and Ex-C04 were prepared in accordance with the following scheme:
Step H—Synthesis of Intermediate 50
To a solution of intermediate 49 (250 mg, 0.335 mmol), intermediate 20 (238 mg, 0.335 mmol) and DIPEA (0.176 mL, 1.006 mmol) was added HATU (140 mg, 0.369 mmol) and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of sat. NaHCO3 and extracted with DCM. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isco 40 g), eluting with 0-40-60-80-100% EtOAc:EtOH (3:1)/hexanes to give intermediate 50 as a white solid. UPLC Method C: tR=1.40 min; [M+1]+=1437.53.
Step I— Synthesis of Intermediate 51
To a solution of intermediate 50 (235 mg, 0.163 mmol) in CH3CN (1 mL) was added piperidine (0.081 mL, 0.817 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and dried. The product was used as such without further purification. UPLC Method C: tR=1.02 min; [M+1]+=1215.52.
Step J—Synthesis of Intermediate 52
To a solution of Fmoc-D-Ala-OH (53.5 mg, 0.172 mmol) and DIPEA (0.086 mL, 0.491 mmol) in DCM (2 mL) was added HATU (68.5 mg, 0.180 mmol) and the mixture was stirred at room temperature for 15 min. followed by the addition of intermediate 51 (199 mg, 0.164 mmol) in 2 mL DCM and was stirred for 2 h. The reaction mixture was quenched by the addition of sat. NaHCO3 and extracted with DCM. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isco 24 g), eluting with 0-40-60% EtOAc:EtOH (3:1)/hexanes to give intermediate 52 as a colorless oil. UPLC Method C: tR=1.39 min; [M+1]+=1509.7.
Step K—Synthesis of Intermediate 53
To a solution of intermediate 52 (207 mg, 0.137 mmol) in CH3CN (2 mL) was added piperidine (0.082 mL, 0.823 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and dried. The product was used as such without further purification. UPLC Method A: tR=1.01 min; [M/2+1]+=643.97.
Step L—Synthesis of Intermediate 54
To a solution of Fmoc-DAP(Boc)-OH (53.7 mg, 0.126 mmol) and DIPEA (0.066 mL, 0.378 mmol) in DCM (2 mL) was added HATU (52.7 mg, 0.139 mmol) and the mixture was stirred at room temperature for 15 min. followed by the addition of intermediate 53 (162 mg, 0.126 mmol) in 2 mL DCM and was stirred for 2 h. The reaction mixture was quenched by the addition of sat. NaHCO3 and extracted with DCM. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isco 24 g), eluting with 0-40-50-80-100% EtOAc:EtOH (3:1)/hexanes to give intermediate 54 as an off-white gum. UPLC Method A: tR=1.41 min; [M/2+1]+=848.69.
Step M—Synthesis of Intermediate 55
To a solution of intermediate 54 (23 mg, 0.014 mmol) in 2-propanol (3 mL) was added 2 N NaOH (0.068 mL, 0.136 mmol) and stirred for 2 h at 0° C. The mixture was purified by column chromatography over C18 (eluting with acetonitrile+0.05% TFA/water+0.05% TFA 20:80 to 100:0) to give intermediate 55 as a white solid after lyophilization. UPLC Method A: tR=1.04 min; [M/2+1]+=730.30.
Step N—Synthesis of Intermediate 56
To a solution of intermediate 55 (10 mg, 6.86 μmol) in DMF (1 mL) was added HATU (2.87 mg, 7.54 μmol) and the reaction was stirred at 0° C. for 15 followed by dilution with DCM (30 mL). DIPEA (5.99 μL, 0.034 mmol) was added and the reaction was stirred at room temperature for 2 h. The residue was purified by column chromatography over C18 (eluting with acetonitrile+0.05% TFA/water+0.05% TFA 20:80 to 100:0) to give intermediate 55 as a white solid after lyophilization. UPLC Method A: tR=1.19 min; [M/2+1]+=721.27.
Step O—Synthesis of Ex-C04
To a solution of intermediate 56 (9 mg, 6.25 μmol) in DCM (2 mL) was added 4.0 M HCl in 1,4-dioxane (0.156 mL, 0.625 mmol) and the mixture was stirred at room temperature for 3 h. The excess reagent was concentrated in vacuo and dried to yield Ex-C04. The product was used as such for the next step without further purification. UPLC Method A: tR=0.84 min; [M/2+1]+=643.19.
Step P—Synthesis of Ex-C03
To a solution of intermediate 32 (2.162 mg, 6.23 μmol) and DIPEA (6.53 μL, 0.037 mmol) in DCM (5 mL) was added HATU (2.61 mg, 6.85 μmol) and the mixture was stirred at room temperature for 15 min. followed by the addition of Compound 58 (8.0 mg, 6.23 μmol) in 2 mL DCM. The reaction was stirred at 0° C. for 2 h. The residue was purified by column chromatography over C18 (eluting with acetonitrile+0.05% TFA/water+0.05% TFA 20:80 to 100:0) to yield Ex-C03 after lyophilization. UPLC Method A: tR=0.85 min; [M/2+1]+=743.75.
Example 5
Compounds Ex-C05, Ex-C06 and Ex-C07 were prepared in accordance with the following schemes in a manner analogous to the above-described example compounds from intermediate Int 53, prepared above, in accordance with the following scheme:
Step E—Synthesis of Intermediate 59
To the solution of 53 (112 mg, 0.080 mmol) and (S)-2-(((benzyloxy)carbonyl)amino)-propanoic acid (25.7 mg, 0.115 mmol) in DMF (2 ml) was added HATU (42.6 mg, 0.112 mmol) and DIPEA (0.042 ml, 0.240 mmol). The resulting solution was stirred at ambient temperature for 2 hours, the reaction mixture was purified on reverse phase MPLC (150 g C18 column), eluting with Acetonitrile/Water+0.05% TFA (10-100% Acetonitrile in water) to give Int 59. LCMS anal. Calcd. For C84H108FN13O18: 1605.79; Found: 1607.31 (M+1)+, 803.73 (M+2)2+.
Step F—Synthesis of Intermediate 60
To a solution of 59 (0.124 g, 0.077 mmol) in a mixture solvent of THF (5 ml), MeOH (1.6 ml) and Water (1.6 ml) at 0° C. was added lithium hydroxide (0.4 ml, 0.400 mmol) dropwise, and the resulting solution was stirred at 0° C. for 2 hours. Reaction mixture volatiles were evaporated on rotary evaporator and the aqueous residue was acidified to pH 4 at 0° C., then extracted with 30% IPA/DCM (3×100 mL), the combined organic phase was dried over Na2SO4, concentrated, and the residue was purified on reverse phase MPLC (150 g C18 column), eluting with Acetonitrile/Water+0.05% TFA (10-100% Acetonitrile in water) to give Int 60. LCMS anal. Calcd. For C83H106FN13O18: 1591.78; Found: 1593.18 (M+1)+, 797.04 (M+2)2+.
Step G—Synthesis of Intermediate 61
To a solution of 60 (70 mg, 0.044 mmol) in MeOH (4 ml) was added Pd/C (10 mg, 9.40 μmol), the resulting mixture was hydrogenated for 1 hour at room temperature using a hydrogen balloon. The mixture was filtered through celite, washed with MeOH (3×50 ml), and the filtrate concentrated, then dissolved in acetonitrile (10 mL) and water (6.5 mL). The resulting solution was cooled to 0° C. and HCl (0.659 ml, 0.066 mmol) was added dropwise, with stirring. The resulting solution was stirred at 0° C. for 3 min, then lyophized to give product Int 61. LCMS anal. Calcd. For C75H100FN13O16: 1457.74; Found: 1459.05 (M+1)+, 730.04 (M+2)2+.
Step H—Synthesis of Ex-C05
To the solution of 61 (59.1 mg, 0.040 mmol) in DMF (5 ml) at r.t. was added HATU (18.04 mg, 0.047 mmol), the resulting solution was stirred at r.t. for 20 min, then added CH2Cl2 (140 ml) followed by addition of DIPEA (0.021 ml, 0.119 mmol), the resulting solution was stirred at ambient temperature for 0.5 h. Volatiles were removed under reduced pressure, and the resulting DMF solution was purified on reverse phase MPLC (130 g C18 column), eluting with Acetonitrile/Water+0.05% TFA (5-80% Acetonitrile in water) to give Ex-C05. LCMS anal. Calcd. For C75H98FN13O15: 1439.73; Found: 1440.49 (M+1)+, 720.89 (M+2)2+.
Step I—Synthesis of Ex-C06
To the solution of Ex-C05 (0.0295 g, 0.020 mmol) in CH2Cl2 (1.5 ml) at r.t. was added triisopropylsilane (0.025 mL, 0.123 mmol) and TFA (2.3 ml, 29.9 mmol), the resulting solution was stirred at rt for 0.5 h, then the solution was concentrated under reduced pressure and the residue was dissolved in DCM (1.5 mL) and treated with HCl (4N in Dioxane) (0.28 mL, 1.120 mmol), concentrated, and the residue was further dried under high vacuum overnight to give Ex-C06. The crude product was purified by preparative HPLC reverse phase (SunFire C-18, 19×150 mm), eluting with Acetonitrile/Water+0.1% formic acid (2-50% Acetonitrile in water). LCMS anal. Calcd. For C66H82FN13O13: 1283.61; Found: 1284.46 (M+1)+, 642.79 (M+2)2+.
Step J—Synthesis of Ex-07
To the solution of Ex-06 (26.4 mg, 0.02 mmol) and 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethylethanaminium bromide (32) (7.20 mg, 0.024 mmol) in DMF (2 ml) was added HATU (9.13 mg, 0.024 mmol) and DIPEA (10.48 μl, 0.060 mmol), the resulting solution was stirred at r.t. for 0.5 h, LCMS showed the reaction completed. The DMF solution was purified by preparative HPLC reverse phase (SunFire C-18, 19×150 mm), eluting with Acetonitrile/Water+0.1% formic acid (2-45% Acetonitrile in water) to yield Ex-07. LCMS anal. Calcd. For C76H102FN14O16+: 1485.76; Found: 1485.37 M+, 743.45 (M+1)2+
Example 9: Preparation of Ex-OT-03 and Ex-OT-04
Intermediate 122
Step A: Synthesis of Intermediate 120
To a solution of (S)-2-amino-3-(3-cyanophenyl)propanoic acid (2.00 g, 10.52 mmol) in THE (20 mL) and water (20 mL) was added NaHCO3 (2.65 g, 31.5 mmol) at 25° C. under nitrogen atmosphere. After Fmoc-OSu (3.90 g, 11.6 mmol) was added at 0° C., the reaction mixture was stirred at 25° C. for 16 h. The pH value of the reaction solution was adjusted to 4-5 with aqueous HCl (2 N). The aqueous phase was extracted with EA (2×200 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0˜2% MeOH in DCM to afford 5.20 g (90% yield) of 120 as an off-white solid. LCMS (ESI) calc'd for C25H20N2O4 [M+H]+: 413.1, found 413.2; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=7.6 Hz, 2H), 7.57-7.55 (m, 3H), 7.46-7.30 (m, 7H), 5.26 (d, J=7.7 Hz, 1H), 4.72-4.70 (m, 1H), 4.54-4.38 (m, 2H), 4.20 (t, J=6.8 Hz, 1H), 3.28-3.22 (m, 1H), 3.16-3.11 (m, 1H).
Step B: Synthesis of Intermediate 121
To a stirred solution of 120 (2.00 g, 3.64 mmol) in ETOAc (20 mL) and AcOH (20 mL) was added Pd—C (0.387 g, 0.364 mmol, dry) at 25° C. under nitrogen atmosphere. The reaction mixture was degassed with hydrogen for 3 times and stirred at 25° C. for 16 h under 2 atm. The solid was filtered out. The filtrate was concentrated under reduced pressure to afford a yellow solid. The crude product was washed with EA (80 mL) to afford 1.80 g (59% yield) of 121. LCMS (ESI) calc'd for C25H24N2O4 [M+H]+: 417.2, found 417.2; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=7.7 Hz, 2H), 7.67-7.58 (m, 2H), 7.41-7.20 (m, 8H), 4.26-4.03 (m, 4H), 3.96-3.93 (m, 2H), 3.06 (dd, J=14.0, 4.7 Hz, 1H), 2.88 (dd, J=14.0, 10.5 Hz, 1H).
Step C: Synthesis of Intermediate 122
Intermediate 121 (12.0 g, 14.41 mmol) was dissolved in MeOH (240 mL) and water (60 mL) at 25° C. The pH value of the solution was adjusted to 9 with NaHCO3 powder. To the reaction mixture were added sulfuric acid, 1-(azidosulfonyl)-2H-imidazol-1-ium salt (4.71 g, 17.29 mmol), copper(II) sulfate pentahydrate (0.719 g, 2.88 mmol), DMF (150 mL) and DMSO (60 mL) at 25° C. The pH value of the reaction mixture was adjusted to 9 with NaHCO3 powder. The reaction mixture was stirred at 25° C. for 16 h. The pH value of the reaction mixture was adjusted to 3 with aqueous HCl (1 N). The reaction solution was diluted with water (200 mL). The aqueous phase was extracted with EA (2×500 mL). The combined organic layer was washed with brine (3×100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with following condition: Column, Xbridge C18, 330 g; mobile phase: ACN in water (0.05% TFA), 30%-75% in 45 min; Detector, UV 254 nm. RT: 38 min. The fractions containing the desired product were combined and concentrated under reduced pressure to afford 6.44 g (95% yield) of 122 as an off-white solid. LCMS (ESI) calc'd for C25H22N4O4 [M+H]+: 443.2, found 443.3; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (d, J=7.5 Hz, 2H), 7.76 (d, J=8.4 Hz, 1H), 7.67-7.63 (m, 2H), 7.43-7.38 (m, 2H), 7.31-7.20 (m, 6H), 4.40 (s, 2H), 4.22-4.19 (m, 4H), 3.10 (dd, J=13.8, 4.4 Hz, 1H), 2.90 (dd, J=13.8, 10.5 Hz, 1H).
Intermediate
Step A: Synthesis of Intermediate 123
To a stirred solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (3.00 g, 22.88 mmol) in THE (150 mL) was added water (150 mL) and NaHCO3 (7.70 g, 92 mmol) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes. After Boc2O (7.50 g, 34.4 mmol) was added, the reaction mixture was stirred at 25° C. for 16 h. The resulting mixture was added sat'd aqueous NaHCO3 (50 mL) and washed with ethyl ether (2×100 mL). The separated organic phases were deserted. The pH value of the aqueous phase was adjusted to 3 with aqueous HCl (1 M). The aqueous solution was extracted with EA (6×200 mL). The organic layers were combined and concentrated under reduced pressure to afford 5.00 g (90% yield) of 123 as an off-white solid. LCMS (ESI) calc'd for C10H17NO5 [M+Na]+: 254.1, found 253.9. 1H NMR (300 MHz, CD3OD) δ 4.47-4.33 (m, 1H), 4.19-4.08 (m, 1H), 3.69-3.44 (m, 2H), 2.16-1.97 (m, 1H), 1.94-1.81 (m, 1H), 1.45 (d, J=13.3 Hz, 9H).
Step B: Synthesis of Intermediate 124
To a solution of 123 (1.15 g, 4.72 mmol) in THE (50 mL) were added DMF (10 mL) and NaH (660 mg, 16.50 mmol, 60% in mineral oil) at 0° C. under argon atmosphere. After the reaction mixture was stirred for 15 minutes, 3-bromoprop-1-yne (1.20 g, 10.09 mmol) was added at 0° C. After warming to 25° C., the reaction mixture was stirred for 16 h. The resulting mixture was added sat'd aqueous NaHCO3 (20 mL) and extracted with ethyl ether (2×60 mL). The separated organic phases were deserted. The pH value of the aqueous phase was adjusted to 4 with aqueous HCl (1 M). The aqueous solution was extracted with EA (5×100 mL). The organic layers were combined and concentrated under reduced pressure to afford 1.47 g (98% yield) of 124 as a yellow oil. LCMS (ESI) calc'd for C13H19NO5 [M+Na+CH3CN]+: 333.1, found 333.3. 1H NMR (300 MHz, CDCl3) δ 4.66-4.58 (m, 1H), 4.48-4.31 (m, 1H), 4.28-4.18 (m, 2H), 3.61-3.40 (m, 2H), 2.47 (t, J=2.4 Hz, 1H), 2.16-2.01 (m, 2H), 1.47 (d, J=17.3 Hz, 9H)
Step C: Synthesis of Intermediate 125
To a solution of 124 (7.14 g, 19.36 mmol) in DCM (40 mL) was added TFA (20 mL) at room temperature. The reaction solution was stirred at 25° C. for 16 h. The solvent was removed under reduced pressure to afford 8.00 g (95% yield) of 125 with 2,2,2-trifluoroacetic acid (1:1) as a brown oil, which was used in the next step without further purification. LCMS (ESI) calc'd for C10H12F3NO5 [M−CF3CO2−]+: 170.1, found 170.0.
Step D: Synthesis of Intermediate 126
To a stirred solution of 125 with 2,2,2-trifluoroacetic acid (1:1) (8.00 g, 18.36 mmol) in THE (150 mL) were added the aqueous NaHCO3 (295 mL, 148 mmol) and Fmoc-CI (7.20 g, 27.8 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting mixture was added sat'd aqueous NaHCO3 (20 mL) and extracted with ethyl ether (2×200 mL). The pH value of the aqueous phase was adjusted to 2 with aqueous HCl (1 M). The aqueous solution was extracted with EA (5×300 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography, eluted with gradient 1%-50% EA in PE. The fractions containing the desired product were combined and concentrated under reduced pressure to afford 5.92 g (78% yield) of 126 as an off-white solid. LCMS (ESI) calc'd for C23H21NO5 [M+H]+: 392.2, found 392.3. 1H NMR (300 MHz, CDCl3) δ 9.98 (br, 1H), 7.80-7.65 (m, 2H), 7.63-7.48 (m, 2H), 7.44-7.23 (m, 4H), 4.62-4.08 (m, 7H), 3.77-3.52 (m, 2H), 2.51-2.40 (m, 1H), 2.20-1.96 (m, 2H).
Preparation of Intermediates 128 and 129
Step A—Synthesis of Intermediate 127
Step A-1: Peptide was synthesized using Fmoc/t-Bu chemistry on Fmoc-rink amide MBHA resin (Midwest, 0.55 mmol/g) with a CEM Liberty Blue automated microwave peptide synthesizer. The peptide sequence was synthesized on a 0.15 mmol scale, using single-couplings of 3.3 equivalents of Fmoc protected amino acids as a 0.2M DMF solution along with 3.33 eq of 0.5M DIC and 3.33 eq of 1.0M Oxympure containing 10% DIEA. Fmoc deprotections were performed using 20% (V/V) piperidine in DMF. Linear peptide NT- was capped using 10% acetic anhydride in DMF.
The sequence of Fmoc protected amino acids used are:
1. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(((tert-butoxycarbonyl) amino)methyl) phenyl) propanoic acid
2. (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid
3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid
4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-threonine
5. (2S,3S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-(prop-2-yn-1-yloxy)pyrrolidine-2-carboxylic acid (Intermediate 126, see prep above)
6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro)-1H-indol-3-yl)propanoic acid
7. S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(azidomethyl)phenyl)propanoic acid (Intermediate 122, see prep above)
8. (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid
9. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid
10. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid
Step A-2: The peptidyl resin from Step A-1 was removed from the synthesizer to a vial, 10 ml of DMSO, N-ethyl-N-isopropylpropan-2-amine (0.15 g, 1.2 mmol), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.12 g, 0.6 mmol) was added and dissolved in 0.5 ml of water. The mixture was bubbled with N2 for 10 min, then copper(I) iodide (0.12 g, 0.6 mmol) was added and dissolved in 1 ml of DMSO. The vial was capped, and blanked with N2. The reaction was stirred at room temperature overnight. The resin was washed thoroughly with DMF, MeOH, DCM, and a solution mixture of 0.5% sodium diethyldithio carbamate and 0.5% DIEA in DMF. After isolation of the resin via filtration, the peptide was cleaved from solid support using 15 ml of TFA solution (v/v) (95% TFA: 2.5% triisopropylsilane: 2.5% water) for approximately 2 hours, at room temperature. The resin was filtered, and washed with 5 ml of TFA solution. Combined filtrate was concentrated, and precipitated in approximately 70 ml of cold ethyl ether (−78 C). Crude peptide pellet collected by centrifugation was washed in cold ethyl ether and centrifuged once more to provide Int-127, which was used crude in the next step.
LCMS anal. calcd. for C71H87FN16O16: 1439.6; Found: 1440.4 (M+1)+.
Step B—Synthesis of Ex-OT-02
Crude 127 (20 mg) was dissolved in 3 ml of DMF. HATU (0.021 mmol) and DIEA (0.042 mmol) were added, mixed and stirred at room temperature until reaction was complete. The mixture was concentrated in vacuo and purified using gradient elution on reverse phase (30×150 mm Sunfire Prep C18; 20-70% CH3CN/water w/ 0.1% TFA modifier over 40 min). The fractions were lyophilized to provide compound Ex-OT-03.
LCMS anal. calcd. for C71H85FN16O15 1421.56: Found: 1421.3 (M+1)+.
Compound Ex-OT-04 was prepared from Int 127 using analogous chemistry to that described herein for the preparation of Ex-C07 from Ex-C06. Ex-OT-04 was purified using LC/MS with the following data obtained: LCMS anal. calcd. for C75H96FN16O14+: 1464.7; Found: 1463.4 (M)+.
Example 10 Preparation of Ex-OT-05
The compound was prepared in accordance with the following schemes and experimental description:
Step A—Synthesis of Intermediate Compound 130
Step A-1: The Peptide was Synthesized Using Fmoc/t-Bu Chemistry on Fmoc-MBHA Resin
Spiraltide resin (CEM, 0.19 mmol/g) with a CEM Liberty Blue automated microwave peptide synthesizer. The peptide sequence was synthesized on a 0.20 mmol scale, using single-couplings of 5 equivalents of Fmoc protected amino acids as a 0.2M DMF solution along with 5 eq of 0.5M DIC and 5 eq of 1.0M Oxympure containing 10% DIEA. Fmoc deprotections were performed using 20% (V/V) piperidine in DMF.
The sequence of Fmoc protected amino acids used are:
1. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(((tert-butoxycarbonyl) amino)methyl) phenyl) propanoic acid
2. (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid
3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid
4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-threonine
5. (2S,3S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-(prop-2-yn-1-yloxy)pyrrolidine-2-carboxylic acid (Intermediate 133)
6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro)-1H-indol-3-yl)propanoic acid
7. S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(azidomethyl)phenyl)propanoic acid (Intermediate 129)
Step A-2: The peptidyl resin was removed from Step A-1 from the synthesizer to a vial. 10 ml of DMSO, N-ethyl-N-isopropylpropan-2-amine (0.2 g, 1.6 mmol), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.32 g, 1.6 mmol) were added and dissolved in 0.5 ml of water. The mixture was bubbled with N2 for 10 min, then added copper(I) iodide (0.16 g, 0.8 mmol) dissolved in 1 ml of DMSO. The vial was capped, and blanked with N2. The reaction was stirred at room temperature overnight. Then the resin was washed thoroughly with DMF, MeOH, DCM, and a solution mixture of 0.5% sodium diethyldithio carbamate and 0.5% DIEA in DMF.
Step A-3: The sequence assembly of peptidyl resin from Step A-2 was continued on CEM Liberty Blue automated microwave peptide synthesizer using the same protocol as Step A-1. The sequence of Fmoc protected amino acids used are:
1. (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid
2. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)amino)propanoic acid
3. 4-(tert-butoxy)-4-oxobutanoic acid
Step A-4: The resin was removed from Step A-3 from the synthesizer. 5% NH2NH2 in DMF 5 min, two time, was added to remove iVDde group on the side chain, followed by thorough wash with DMF, DCM, and Methanol. 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethylethanaminium (Int XXX) (0.4 mmol, 0.088 mg), HATU (0.4 mmol, 152 mg), and DIEA (0.8 mmol, 0.2 ml of 2M) were added. The mixture was mixed well and stirred at room temperature until the reaction was complete. The completed resin was cleaved by 15 ml of 95% TFA:2.5% TIS: 2.5% water for 2 hours, at room temperature. Another 5 ml of TFA solution was used to wash the peptidyl resin. After filtering, combined TFA solutions were condensed on a rotary evaporator, and precipitated in approximately 70 ml of cold ethyl ether (−78 C). Crude peptide pellet collected by centrifugation was washed in cold ethyl ether and centrifuged once more to provide 130 which was used crude in the next step. LCMS anal. calcd. for C79H104FN16O19+ 1600.79; Found: 1600.4 (M)+.
Step B—Synthesis of Compound Ex-OT-05
Crude 131 (50 mg) was dissolved in 4.5 ml of DMF. HATU (0.054 mmol) and DIEA (0.1 mmol), were added, mixed and stirred at room temperature until reaction was complete. The mixture was concentrated in vacuo and directly purified using gradient elution on reverse phase (30×150 mm Sunfire Prep C18; 5-65% CH3CN/water w/ 0.1% TFA modifier over 40 min). The fractions were lyophilized to provide compound Ex-OT-05. LCMS anal. calcd. for C79H102FN16O18+: 1582.78; Found: 1582.4 (M)+.
Example 11 Preparation of Ex-OT-06
Example Compound Ex-OT-06 was prepared in accordance with the following schemes and synthetic procedures:
Preparation of Int 135
Step A—Synthesis of Intermediate 132
A solution of 1.00 g (3.49 mmol) of tert-butyl 4-(2-aminoethyl)benzylcarbamate hydrochloride was dissolved in 30 ml of acetone, and the resulting solution treated with 0.59 g (6.97 mmol) of sodium bicarbonate in 10 ml water. A white precipitate formed immediately. An additional 20 ml of acetone was added and the reaction cleared. Approx. 1 hr later, a precipitate was formed. The suspension was stirred for 3 h, at which no SM was detected by LC-MS analysis. The mixture was stored at 4° C. overnight. The reaction mixture was concentrated to remove acetone, was acidified to pH 3-4 with 50 ml of 1M HCl.
The reaction was extracted with 2×40 ml of EtOAc. The combined extracts were washed with brine and concentrated to give a white powder. A large peak was present in the LC-MS for the desired product (MS=472.2), and the crude product was used as is in the next reaction.
Step B—Synthesis of Intermediate 133
A solution of 1.42 g (3.00 mmol) of 132 was dissolved in 2 ml TFA/2 ml dicholormethane. After 1 h, the reaction was complete by LC-MS analysis (MS product=372.2), and was conc. in vacuo to give the crude product as an oil, used immediately in the next step.
Step C— Synthesis of Intermediate 134
A solution of 1.00 g (2.68 mmol) of intermediate 133 in 2 ml of DMF was treated with 1.60 g (4.21 mmol) of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) in 2 ml of DMF and 5 ml (10.00 mmol) of DIEA. After 5 min, this mixture was added to a solution of 0.60 g (3.44 mmol) of 4-(tert-butoxy)-4-oxobutanoic acid in 1 ml DMF. The resulting solution was stirred for 30 min., at which point LC-MS analysis indicated completion of the reaction. The reaction was concentrated in vacuo to give the crude desired product (MS=528.30) which was used as is in the next reaction.
Step 4—Synthesis of intermediate 135
To a solution of 1.42 g (2.68 mmol) of intermediate 134 in 2 ml DMF was added 33.5 ml of 4M HCl/dioxane. The resulting solution was stirred overnight. The reaction was diluted with 1 volume of EtOAc/1 volume water. The layers were separate, the aqueous layer reextracted with 1 volume of EtOAc, and the EtOAc extracts combined and concentrated. The crude product was purified via prep HPLC using the following conditions: column: Sunfire C18 50×150, 5 u
Mobile phases: A=0.1% TFA in water, B=0.1% TFA in acetonitrile
flow rate 85 ml/min
gradient: 1% for 10 min. 5-65% in 40 min
This provided 0.75 g (1.59 mmol) of pure desired product as a fluffy white amorphous powder after lyophilization, MS=472.2.
Preparation of Int 141
Step A-1: First, 2-Cl trityl chloride resin (0.25 mmol, 1.28 mmol/g, Rapp Polymer) was loaded manually in DCM with (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (0.18 g, 0.5 mmol) and 2M DIEA (1 mmol). Stirred at room temperature for 30 min. The resin was then washed thoroughly, then capped with 10 ml of DCM:Methanol: DIEA 85:15:5 for 30 min. This preloaded resin was then moved to CEM Liberty Blue automated peptide synthesizer (CEM Corp.) using Fmoc/tBu chemistry. The peptide sequence was synthesized on a 0.25 mmol scale, using single-couplings of 4 equivalents of Fmoc protected amino acids as a 0.2M DMF solution along with 3.6 eq of 0.45M HATU in DMF and 8 eq of 2M DIEA. Fmoc deprotections were performed using 20% (V/V) piperidine in DMF. The sequence of Fmoc protected amino acids used are:
1. (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid
2. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid
3. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-threonine
4. (2S,3S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-(prop-2-yn-1-yloxy)pyrrolidine-2-carboxylic acid (Intermediate 133)
5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-)-1H-indol-3-yl)propanoic acid
6. S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(azidomethyl)phenyl)propanoic acid (Intermediate 129)
7. (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid
8. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)amino)propanoic acid
9. 4-((4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)benzyl)amino)-4-oxobutanoic acid (Intermediate 135, see prep above)
Step A-2: The peptidyl resin was removed from Step A-1 from the synthesizer, Boc anhydride (1.0 mmol, 0.24 g) and DIEA (1.0 mmol, 1 ml of 2M) were added in DMF, stirred at room temperature for 30 min. The resin was washed thoroughly, and 5% NH2NH2 in DMF 5 min was added, two times, to remove iVDde group on the side chain, followed by a thorough wash with DMF, DCM, and methanol, added 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethylethanaminium (IntXXX) (0.4 mmol, 0.088 mg), HATU (0.4 mmol, 152 mg), and DIEA (0.8 mmol, 0.2 ml of 2M). The mixture was mixed well and stirred at room temperature until reaction complete.
Step A-3: To peptidyl resin from Step A-2, was added 10 ml of DMSO, N-ethyl-N-isopropylpropan-2-amine (1 ml of 2M, 2.0 mmol), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.2 g, 1.0 mmol) dissolved in 0.5 ml of water. The mixture was bubbled with N2 for 10 min, then copper(I) iodide (0.2 g, 1.0 mmol) dissolved in 1 ml of DMSO was added. The vial was capped, and blanked with N2. The reaction was stirred at room temperature overnight. The resin was then washed thoroughly with DMF, MeOH, DCM, and a solution mixture of 0.5% sodium diethyldithio carbamate and 0.5% DIEA in DMF.
Step A-4: To peptidyl resin from Step A-3, added 15 ml of 95% TFA:2.5% TIS: 2.5% water, and the mixture was stirred at room temperature for 2 hours. Another 5 ml of TFA solution was used to wash the peptidyl resin. After filtering, combined TFA solutions were condensed on a rotary evaporator, and precipitated in approximately 70 ml of cold ethyl ether (−78 C). Crude peptide pellet collected by centrifugation was washed in cold ethyl ether and centrifuged once more, redissolved in 50% acetonitrile/water (modified with 0.1% TFA) and water, lyophilized. This mixture was purified using gradient elution on reverse phase (30×150 mm Sunfire Prep C18; 5-65% CH3CN/water w/ 0.1% TFA modifier over 40 min). The fractions were lyophilized to provide Int-141, which was used in the next step. LCMS anal. calcd. for C78H104FN16O17+1556.8; Found: 1556.3 (M)+
Step B—Synthesis of Intermediate Ex-OT-06
Int-141 (20 mg) was dissolved in 2.0 ml of DMF. Added HATU (0.04 mmol) and DIEA (0.08 mmol), mixed and stirred at room temperature until reaction was complete. The mixture was concentrated in vacuo and directly purified using gradient elution on reverse phase (30×150 mm Sunfire Prep C18; 5-65% CH3CN/water w/ 0.1% TFA modifier over 40 min). The fractions were lyophilized to provide Ex-OT-06. LCMS anal. calcd. for C78H102FN16O16+ 1538.8; Found: 1539.4 (M)+
Example 12 Preparation of Example Compound Ex-C01
Step A—Synthesis of Intermediate 137
The peptide was synthesized manually using Fmoc/t-Bu chemistry on PS Rink-Amide resin (loading 0.47 mmol/g). Up to Thr, the peptide sequence was synthesized on a CEM Liberty Blue synthesizer on a 0.3 mmol scale, using single-couplings of Fmoc protected amino acid, with DIC and OXYME as activators in DMF at 90° C. Then, peptide synthesis was continued manually using single-couplings of 2 eq of Fmoc protected amino acid, 2 eq of HOAt and 2 eq of DIC, in DMF at r.t. Coupling reactions were monitored by Kaiser test. Couplings following secondary amines were monitored by chloranil test. Fmoc deprotections were performed using 20% (VNV) piperidine in DMF. Final acetylation was performed with 10 eq of Ac2O and monitored by Kaiser test.
The sequence of Fmoc protected amino acids and building blocks used are:
1. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)ethoxy)phenyl)propanoic acid
2. (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid
3. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-threonine
4. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid
5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid
6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)propanoic acid
7. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine (D-Ala)
8. (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine (Ala)
9. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(allyloxy)-4-oxobutanoic acid (Asp OAII)
At the end of the assembly the resin was dissolved in dry DCM. Phenilsilane (24 eq.) and Palladium Tetrakis (CAS: 14221-01-3, 0.25 eq) were added. Reaction was kept under stirring for 30 min at r.t. under N2 atmosphere (2 cycles of 30 min) and then washed with a 5% solution of Sodium diethyldithiocarbamate in DMF with 5% of DIPEA (200 ml). DDe removal was performed washing the resin with 100 mL of a 3% hydrazine monohydrate solution in DMF. Lactam formation was performed on solid phase: a solution of PyAOP (2.5 eq), HOAt (2.5 eq) and DIPEA (5 eq) in DMF was added to the resin. Reaction complete after 10-15 min (monitored by test cleavage). The resin was washed with DMF, MeOH, DCM, Et2O. The peptide was cleaved from solid support using 60 ml of TFA solution (v/v) (91% TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA, concentrated to dryness and lyophilized to afford 97 mg of 137.
LCMS anal. calcd. For C70H89FN14O17: 1417.56; found: 1418.9 (M+1)+.
Step B—Synthesis of Compound Ex-C01
Intermediate 137 (20 mg) was dissolved in DMF (2 mL). HATU (1 eq) and DIPEA (2 eq) were added. Reaction completed after 5 min, and was quenched with TFA, concentrated to dryness and purified by RP-HPLC (Dr. Maisch Reprosil Gold C18, 20×150 mm, 5 um, 100 A; 20% to 35% ACN/water+0.1% TFA modifier over 25 min). Collected fractions were lyophilized to provide Ex-C01 (3.0 mg).
LCMS anal. calcd. For C70H87FN14O16: 1399.55; found: 1399.9 (M+1)+.
Example 13 Preparation of Ex-C02
Ex-C02 was prepared in accordance with the following schemes and synthesis procedures:
Step A—Synthesis of Intermediate 139
The peptide was synthesized manually using Fmoc/t-Bu chemistry on a PS rink-amide resin (Novabiochem—loading: 0.35 mmol/g) —250 umol scale, using single-couplings of 3 equivalents of Fmoc protected amino acids as a 0.3M DMF solution along with 3 eq of HOAt as a 0.3 M DMF solution and 3 eq of DIC. Fmoc deprotections were performed using 20% (V/V) piperidine in DMF.
The sequence of Fmoc protected amino acids and building blocks used are:
1. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)ethoxy)phenyl)propanoic acid
2. (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid
3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid
4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-threonine
5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid
6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid
7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)propanoic acid
8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine
9. pentandioic acid
After the last coupling, resin was treated with 100 mL of a 3% NH2-NH2 solution in DMF for 10 minutes, in order to remove Dde group. Then, resin was washed several times with DMF.
Step B—Synthesis of Intermediate 140
Resin was treated with a solution of PyAOP (5 eq.), HOAt (5 eq.) and DIPEA (10 eq.) in DMF (5 ml) for 1 h, then dried and washed. Test cleavage confirmed the lactam formation. The resin was washed with DMF, MeOH, DCM, Et2O and dried under vacuum. The peptide was cleaved from solid support using 60 ml of TFA solution (v/v) (91% TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA, concentrated to dryness and lyophilized. Yield: 43%.
LCMS anal. calcd. for C66H83FN12O15: 1303.4; Found: 1303.9 (M+1)+.
Step C—Synthesis of Ex-C02
Intermediate 140 (0.030 g, 0.023 mmol) was dissolved in DMF in a final concentration of 10 mg/mL. HATU (1 eq.) and DIPEA (2 eq.) were added. After 5 min UPLC-MS confirmed the formation of the second lactam. The reaction mixture was quenched with TFA and purified by RP-HPLC (C18 Dr. Maisch Reprosil Gold Semi-Prep column, 20×150 mm, 5 um, 120 Å, 20% to 40% B in 20 min, A: H2O 0.1% TFA. B: ACN 0.1% TFA). Fractions collected and lyophilized provided 1.8 mg (Y=6%; Purity >95%) of Example Compound Ex-C02. LCMS anal. calcd. for C66H81FN12014: 1285.4; Found: 1286 (M+1)+
Activity Determination
Selected compounds of the invention were subjected to one or more of the following procedures to assay their activity for antagonism of PCSK9 activity.
The following is a description of the assays used to determine activity of compounds of the invention, and any comparator compounds reported, toward PCSK9 antagonism. Biotinylated PCSK9 was obtained by commercially
LDLR TR-FRET
The PCSK9 TR-FRET assay measures the interaction between PCSK9 and LDLR. A solution containing 40 nM biotinylated PCSK9+10 nM Lance ULight Streptavidin is made in 50 mM HEPES pH 7.4, 0.15 M NaCl, 5 mM CaCl2, 0.01% BSA, and 0.01% Surfactant P20. A separate solution containing 40 nM rhLDLR-6×His+10 nM Eu-W1024 anti-6×His is made in the same buffer system. An Echo is used to transfer 0.750 ul of compound to an assay plate followed by the addition of 15 ul of PCSK9+Ulight and 15 ul of LDLR+Eu. The final assay volume is 30.750 ul containing 20 nM PCSK9, 5 nM Ulight, 20 nM LDLR, and 5 nM Eu. The reaction is incubated at room temperature for at least two hours prior to fluorescence measurements using an Envision Multilabel Reader. IC50 values are determined by fitting data to a sigmoidal dose-response curve using nonlinear regression. Counts (B-counts) of the europium-labeled LDLR are followed to observe if compounds are adversely affecting LDLR. A fall off of the B-counts is likely indicates a false positive of inhibition.
Alexa FRET Standard TR-FRET
The PCSK9 Alexa FRET Standard assay measures the interaction between PCSK9 and an AlexaFluor647 (AF) tagged cyclic peptide, Reagent A (KD=83 nM). A solution containing 1 nM biotinylated PCSK9+2.5 nM Lance Streptavidin Europium (Strep-Eu) is made in 50 mM HEPES pH 7.4, 0.15 M NaCl, 5 mM CaCl2, 0.01% BSA, and 0.01% Surfactant P20. A separate solution containing 40 nM of the AlexaFluor tagged cyclic peptide is made in the same buffer system. An Echo is used to transfer 0.750 ul of compound to an assay plate followed by the addition of 15 ul of PCSK9+Stept-Eu and 15 ul of AF peptide. The final assay volume is 30.750 ul containing 0.5 nM PCSK9, 1.25 nM Strep-Eu, and 20 nM AF cyclic peptide. The reaction is incubated at room temperature for at least two hours prior to fluorescence measurements using an Envision Multilabel Reader. IC50 values are determined by fitting data to a sigmoidal dose-response curve using nonlinear regression. Ki is then calculated from the Ic50 and the KD of AF cyclic peptide. Counts (B-counts) of the europium-labeled PCSK9 are followed to observe if compounds are adversely PCSK9. A fall off of the B-counts is likely indicates a false positive of inhibition. Data from this procedure is reported as “A=‘numerical value’ (nanomolar)”
Reagent A was prepared in accordance with the following method:
Step A—Synthesis of Intermediate Compound t-A
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/tBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g−1. The assembly was performed using single-couplings using 4 eq of Fmoc protected amino acid 0.2M in DMF, 4 eq of 0.5M HATU in DMF, 4 eq of 2M DIPEA (double coupling for Tyr). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF.
The sequence of Fmoc protected aminoacids and building blocks used are:
1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine
2. (S)-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid
3. (((9H-fluoren-9-yl)methoxy)carbonyl)-L-tyrosine
4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine
5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid
6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid
7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid
8. (((9H-fluoren-9-yl)methoxy)carbonyl)glycine
9. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine
10. 3-(tritylthio)propanoic acid
At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et20. The peptide was cleaved from solid support using 50 ml of TFA solution (v/v) (91% TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (399 mg), which was used as crude in the next step. LCMS anal. calcd. C61H75F2N15O13S2: 1328.48, found: 1328.2 (M+1)+
Step B—Synthesis of Intermediate Compound Int-B: As Described for Reagent B
Purified by RP-HPLC (Waters Deltapak C4, double cartidge, 40×100 mm, 15 □m, 300 A; 15% to 35% ACN/water+0.1% TFA modifier over 20 min). Collected fractions lyophilized to afford 35 mg of Intermediate Compound Int-B. LCMS anal. calcd. for C69H81F2N15O13S2: 1430.62; found: 1430.9 (M+1)+.
Step C—Synthesis of Compound Reagent A: As Described for Reagent B
LCMS anal. calcd. for C105H122F2N17O26S63−: 2268.58; 1135.8 (M+2)2+
Alexa FRET Plus TR-FRET
The PCSK9 Alexa FRET Plus assay measures the interaction between PCSK9 and an AlexaFluor647 (AF) tagged cyclic peptide, Reagent B (KD=35 nM). A solution containing 1 nM biotinylated PCSK9+2.5 nM Lance Streptavidin Europium (Strep-Eu) is made in 50 mM HEPES pH 7.4, 0.15 M NaCl, 5 mM CaCl2, 0.01% BSA, and 0.01% Surfactant P20. A separate solution containing 1920 nM of the AlexaFluor tagged cyclic peptide is made in the same buffer system. An Echo is used to transfer 0.075 ul of compound plus 0.675 ul of DMSO to each well of an assay plate followed by the addition of 15 ul of PCSK9+Stept-Eu and 15 ul of AF peptide. The final assay volume is 30.750 ul containing 0.5 nM PCSK9, 1.25 nM Strep-Eu, and 960 nM AF cyclic peptide. The reaction is incubated at room temperature for at least two hours prior to fluorescence measurements using an Envision Multilabel Reader. IC50 values are determined by fitting data to a sigmoidal dose-response curve using nonlinear regression. Ki is then calculated from the IC50 and the KD of AF cyclic peptide. Counts (B-counts) of the europium-labeled PCSK9 are followed to observe if compounds are adversely affecting PCSK9. A fall off of the B-counts is likely indicates a false positive of inhibition. Data from this procedure is reported as “P=‘numerical value’ (nanomolar)”
Reagent B was prepared by the following procedure.
Step A—Synthesis of Intermediate Compound Int-A
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/tBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g−1. The assembly was performed using single-couplings using 4 eq of Fmoc protected amino acid 0.2M in DMF, 4 eq of 1M Oxyme in DMF, 4 eq of 0.5M N,N-diisopropylcarbodiimide (DIC) (double coupling for Y01). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF.
The sequence of Fmoc protected amino acids and building blocks used are:
1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine
2. (S)-1((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid
3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid
4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine
5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid
6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid
7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid
8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine
9. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine
10. 3-(tritylthio)propanoic acid
At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et20. The peptide was cleaved from solid support using 50 ml of TFA solution (v/v) (91% TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (300 mg), which was used as crude in the next step. LCMS anal. calcd. C63H79F2N15O13S2: 1356.53, found: 1356.9 (M+1)+.
Step B—Synthesis of Intermediate Compound Int-B
Crude Int-A (0.22 mmol) was redissolved in 24 ml of DMF. 6 ml of 1M aqueous solution of sodium bicarbonate was added to raise the pH to 7. Then 0.26 mmol of 1,3-bis(bromomethyl)benzene (0.1M in DMF) were added dropwise. Reaction was left under stirring at room temperature for 20 min, quenched with TFA (pH to 3-4) and then concentrated in vacuo to provide crude Int-B, which was purified by RP-HPLC (Waters XBridge, C18, 50×150 mm, 5 μm, 130 A; 25% to 40% ACN/water+0.1% TFA modifier over 20 min). Collected fractions were lyophilized to afford 35 mg of Intermediate Compound Int-B. LCMS anal. calcd. for C71H85F2N15O13S2: 1458.67; found: 1458.8 (M+1)+.
Step C—Synthesis of Compound Reagent B
Intermediate Compound Int-B (15 mg) was dissolved in 0.2 ml of dry DMSO. Then 15 mg of ALEXAFLUOR 647NHS Ester (A37566, Life technology) dissolved in 1.5 ml of dry DMSO were added. 20 uL of dry DIPEA were added. Reaction was left under stirring at room temperature for 12 h under Nitrogen atmosphere in the dark. Quenched with TFA (pH to 3-4) and purified by RP-HPLC (Dr Maish, Reprosil Gold C18, 250×20 mm, 120 Å, 10 μm; 20% to 35% of 0.1% TFA in ACN/0.1% TFA in H2O, over 20 min, then 35% to 40% over 5 min at 20 mL/min flow rate). Collected fractions were lyophilized to afford 16.1 mg of Compound Reagent B. LCMS anal. for C107H126F2N17O26S63−:2296.64; found: 1150.6 (M+2)2+
Activity data obtained by one or both of the above-described procedures is reported for selected example compounds of the invention in the following format: Example No.: A (standard TR Fret)=‘numerical value’; P (Alexa Fret plus standard TR Fret)=‘numerical value’/, note that all values reported are nanomolar.
The following compounds were assessed using the protocol described above with the results shown:
Ex-B01: A=2.04; Plus=1.24/Ex-B02: A=4.02; Plus=2.19/Ex-B03: A<1.26; Plus=0.008/Ex-B04: A<1.26; Plus=0.020/Ex-C01: A=27.8/Ex-C02: A=150.9/Ex-C03: A=18.4/Ex-C04: A=4.24/Ex-C05: A<1.26; Plus=4.37/Ex-C06: A=15.9/Ex-C07: A=7.17/Ex-OT-03: A<1.26; Plus=0.32/Ex-OT-04: A<1.26; Plus=0.32/Ex-OT-05: A<1.26; Plus=0.19/Ex-OT-06: A<1.26; Plus=0.29/
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17253815
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merck sharp & dohme corp.
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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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Apr 20th, 2022 03:02PM
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Apr 20th, 2022 03:02PM
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Merck
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:mrk
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Merck
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Apr 19th, 2022 12:00AM
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Jul 3rd, 2015 12:00AM
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https://www.uspto.gov?id=US11309497-20220419
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Materials for organic electroluminescent devices
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The present invention describes dibenzofuran and dibenzothiophene derivatives, in particular for use as triplet matrix materials in organic electroluminescent devices. The invention furthermore relates to a process for the preparation of the compounds according to the invention and to electronic devices comprising same.
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11309497
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1. An organic electroluminescent device comprising in the emissive layer a mixture of a phosphorescent emitter and a compound of the formula (1),
where the following applies to the symbols used:
A is on each occurrence, identically or differently, CR1;
Y1 is O or S;
L is on each occurrence, identically or differently, a single bond or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, which may be substituted by one or more radicals R1;
HetAr is a group of the formula (2), (3) or (4),
where the dashed bond represents the linking of this group;
X is on each occurrence, identically or differently, CR2 or N, with the proviso that at least one symbol X stands for N;
N1 is a group of formula (6),
where the dashed bond represents the linking of this group;
precisely two adjacent groups W together stand for a group of the formula (7), and the remaining groups W stand, identically or differently on each occurrence, for CR1 or N,
where the dashed bonds indicate the linking of this group;
Y2 are, identically or differently on each occurrence, O, NR4, S, C(R4)2, Si(R4)2, BR4 or C═O, where the radical R4 which is bonded to N is not equal to H for the groups of formulae (7) and (8);
R1 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, a straight-chain alkyl group having 1 to 20 C atoms or a branched or cyclic alkyl group having 3 to 20 C atoms, each of which may be substituted by one or more radicals R5, where one or more H atoms may be replaced by D, F, or CN or, an aromatic ring system having 5 to 40 aromatic ring atoms, which may in each case be substituted by one or more radicals R5;
R2, R4 are selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, a straight-chain alkyl group having 1 to 20 C atoms or a branched or cyclic alkyl group having 3 to 20 C atoms, each of which may be substituted by one or more radicals R5, where one or more H atoms may be replaced by D, F, or CN or, an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms, which may in each case be substituted by one or more radicals R5; two adjacent substituents R4 may form an aliphatic or aromatic ring system, which may be substituted by one or more radicals R5;
R5 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, an aliphatic hydrocarbon radical having 1 to 20 C atoms or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, in which one or more H atoms may be replaced by D, F, Cl, Br, I or CN and which may be substituted by one or more alkyl groups, each having 1 to 4 carbon atoms; two or more adjacent substituents R5 here may form an aliphatic ring system with one another.
2. The device according to claim 1 wherein the compound is of the formula (1a),
where symbols used have the meanings given in claim 1 and n stands, identically or differently on each occurrence, for 0, 1, 2 or 3.
3. The device according to claim 1 of one of the formulae (1b) to (1g),
where the symbols used have the meanings given in claim 1.
4. The device according to claim 1, wherein the groups of the formulae (2), (3) and (4) are selected from the groups of the formulae (2-1) to (2-10), (3-1) and (4-1),
where the dashed bond represents the linking of these groups and R2 has the meanings claim 1.
5. The device according to claim 1, wherein the group of the formula (6) is selected from the groups of the formula (6-2),
where R1 has the meanings given in claim 1 and wherein
two adjacent groups W together stand for a group of the formula (7a) and the other two groups W stand for CR1,
where Y2 and R1 have the meanings given in claim 1;
m is, identically or differently on each occurrence, 0, 1, 2, 3 or 4.
6. The device according to claim 1, wherein the group of the formula (6) is selected from the groups of the formulae (6-2a) to (6-2f),
where the symbols and indices used have the meanings given in claim 1;
m is, identically or differently on each occurrence, 0, 1, 2, 3 or 4.
7. The device according to claim 1, wherein Y2 stand, identically or differently on each occurrence, for O, C(R4)2 or NR4, where the radical R4 which is bonded to the nitrogen is not equal to H.
8. The device according to claim 2 wherein the compound is of the formula (1a), where the symbols used have the meanings given in claim 1 and n stands, identically or differently on each occurrence, for 0, 1, 2 or 3, and wherein N1 is selected from the groups of the formula (6-2),
where R1 has the meanings given in claim 1 and wherein
two adjacent groups W together stand for a group of the formula (7a) and the other two groups W stand for CR1,
where Y2 and R1 have the meanings given in claim 1;
m is, identically or differently on each occurrence, 0, 1, 2, 3 or 4.
9. A compound of formula (1),
where the following applies to the symbols used:
A is on each occurrence, identically or differently, CR1;
Y1 is O or S;
L is on each occurrence, identically or differently, a single bond or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, which may be substituted by one or more radicals R1;
HetAr is a group of the formula (2), (3) or (4),
where the dashed bond represents the linking of this group;
X is on each occurrence, identically or differently, CR2 or N, with the proviso that at least one symbol X stands for N;
N1 is a group of formula (6),
where the dashed bond represents the linking of this group;
precisely two adjacent groups W together stand for a group of the formula (7), and the remaining groups W stand, identically or differently on each occurrence, for CR1 or N,
where the dashed bonds indicate the linking of this group;
Y2 are, identically or differently on each occurrence, O, NR4, S, C(R4)2, Si(R4)2, BR4 or C═O, where the radical R4 which is bonded to N is not equal to H for the groups of formulae (7) and (8);
R1 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, a straight-chain alkyl group having 1 to 20 C atoms or a branched or cyclic alkyl group having 3 to 20 C atoms, each of which may be substituted by one or more radicals R5, where one or more H atoms may be replaced by D, F, or CN or, an aromatic ring system having 5 to 40 aromatic ring atoms, which may in each case be substituted by one or more radicals R5;
R2, R4 are selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, a straight-chain alkyl group having 1 to 20 C atoms or a branched or cyclic alkyl group having 3 to 20 C atoms, each of which may be substituted by one or more radicals R5, where one or more H atoms may be replaced by D, F, or CN or, an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms, which may in each case be substituted by one or more radicals R5, two adjacent substituents R4 may form an aliphatic or aromatic ring system, which may be substituted by one or more radicals R5;
R5 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, an aliphatic hydrocarbon radical having 1 to 20 C atoms or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, in which one or more H atoms may be replaced by D, F, Cl, Br, I or CN and which may be substituted by one or more alkyl groups, each having 1 to 4 carbon atoms; two or more adjacent substituents R5 here may form an aliphatic ring system with one another.
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9
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a national stage application (under 35 U.S.C. § 371) of PCT/EP2015/001353, filed Jul. 3, 2015, which claims benefit of European Application No. 14002642.8, filed Jul. 29, 2014, both of which are incorporated herein by reference in their entirety.
The present invention describes dibenzofuran and dibenzothiophene derivatives, in particular for use as triplet matrix materials in organic electroluminescent devices. The invention furthermore relates to a process for the preparation of the compounds according to the invention and to electronic devices comprising these compounds.
BACKGROUND OF THE INVENTION
The structure of organic electroluminescent devices (OLEDs) in which organic semiconductors are employed as functional materials is described, for example, in U.S. Pat. Nos. 4,539,507, 5,151,629, EP 0676461 and WO 98/27136. The emitting materials employed are frequently organometallic complexes which exhibit phosphorescence instead of fluorescence. For quantum-mechanical reasons, an up to four-fold increase in energy and power efficiency is possible using organometallic compounds as phosphorescence emitters. In general, there is still a need for improvement, for example with respect to efficiency, operating voltage and lifetime, in the case of OLEDs, in particular also in the case of OLEDs which exhibit triplet emission (phosphorescence). The properties of phosphorescent OLEDs are not determined only by the triplet emitters employed. In particular, the other materials used, such as, for example, matrix materials, are also of particular importance here. Improvements in these materials may thus also result in significant improvements in the OLED properties.
In accordance with the prior art, inter alia carbazole derivatives (for example in accordance with WO 2014/015931), indolocarbazole derivatives (for example in accordance with WO 2007/063754 or WO 2008/056746) or indenocarbazole derivatives (for example in accordance with WO 2010/136109 or WO 2011/000455), in particular those which are substituted by electron-deficient heteroaromatic compounds, such as triazine, are used as matrix materials for phosphorescent emitters. Furthermore, bisdibenzofuran derivatives (for example in accordance with EP 2301926), for example, are used as matrix materials for phosphorescent emitters. WO 2013/077352 discloses triazine derivatives in which the triazine group is bonded to a dibenzofuran group via a divalent arylene group. These compounds are described as hole-blocking materials. Use of these materials as host for phosphorescent emitters is not disclosed.
In general, there is still a need for improvement in the case of materials for use as matrix materials, in particular with respect to the lifetime, but also with respect to the efficiency and the operating voltage of the device.
BRIEF SUMMARY OF THE INVENTION
The object of the present invention is the provision of compounds which are suitable for use in a phosphorescent or fluorescent OLED, in particular as matrix material. In particular, it is an object of the present invention to provide matrix materials which are suitable for red-, yellow- and green-phosphorescent OLEDs and optionally also for blue-phosphorescent OLEDs and which result in a long lifetime, good efficiency and a low operating voltage.
Surprisingly, it has been found that electroluminescent devices which comprise compounds of the following formula (1) have improvements over the prior art, in particular on use as matrix material for phosphorescent dopants.
DETAILED DESCRIPTION OF THE INVENTION
The present invention therefore relates to a compound of the following formula (1),
where the following applies to the symbols used:
A is on each occurrence, identically or differently, CR1 or N, where a maximum of two groups A per ring stand for N;
Y1 is O or S;
L is a single bond or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, which may be substituted by one or more radicals R1;
HetAr is a group of the following formula (2), (3) or (4),
where the dashed bond represents the linking of this group;
X is on each occurrence, identically or differently, CR2 or N, with the proviso that at least one symbol X stands for N;
N1 is a group of the following formula (5) or (6),
where the dashed bond represents the linking of this group, and A in formula (6) has the meanings given above;
Ar1 is on each occurrence, identically or differently, an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, which may be substituted by one or more radicals R3;
W is on each occurrence, identically or differently, CR1 or N, where a maximum of two groups W stand for N, or precisely two adjacent groups W together stand for a group of the following formula (7) or (8), and the remaining groups W stand, identically or differently on each occurrence, for CR1 or N,
where the dashed bonds indicate the linking of this group, and A has the meanings given above;
Y2, Y3 are, identically or differently on each occurrence, O, NR4, S, C(R4)2, Si(R4)2, BR4 or C═O, where the radical R4 which is bonded to N is not equal to H;
R1, R2, R3, R4 are selected on each occurrence, identically or differently, from the group consisting of H, D, F, Cl, Br, I, CN, NO2, N(Ar2)2, N(R5)2, C(═O)Ar2, C(═O)R5, P(═O)(Ar2)2, P(Ar2)2, B(Ar2)2, Si(Ar2)3, Si(R5)3, a straight-chain alkyl, alkoxy or thioalkyl group having 1 to 20 C atoms or a branched or cyclic alkyl, alkoxy or thioalkyl group having 3 to 20 C atoms or an alkenyl group having 2 to 20 C atoms, each of which may be substituted by one or more radicals R5, where one or more non-adjacent CH2 groups may be replaced by R5C═CR5, Si(R5)2, C═O, C═NR5, P(═O)(R5), SO, SO2, NR5, O, S or CONR5 and where one or more H atoms may be replaced by D, F, Cl, Br, I, CN or NO2, an aromatic or heteroaromatic ring system having 5 to 40 aromatic ring atoms, which may in each case be substituted by one or more radicals R5, an aryloxy or heteroaryloxy group having 5 to 40 aromatic ring atoms, which may be substituted by one or more radicals R5, or an aralkyl or heteroaralkyl group having 5 to 40 aromatic ring atoms, which may be substituted by one or more radicals R5; two adjacent substituents R1 or two adjacent substituents R3 here may optionally form an aliphatic ring system, which may be substituted by one or more radicals R5, and two adjacent substituents R4 may form an aliphatic or aromatic ring system, which may be substituted by one or more radicals R5;
Ar2 is on each occurrence, identically or differently, an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, which may be substituted by one or more non-aromatic radicals R5; two radicals Ar2 which are bonded to the same N atom, P atom or B atom here may also be bridged to one another by a single bond or a bridge selected from N(R5), C(R5)2, O or S;
R5 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, an aliphatic hydrocarbon radical having 1 to 20 C atoms or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, in which one or more H atoms may be replaced by D, F, Cl, Br, I or CN and which may be substituted by one or more alkyl groups, each having 1 to 4 carbon atoms; two or more adjacent substituents R5 here may form an aliphatic ring system with one another.
Adjacent substituents in the sense of the present invention are substituents which are bonded to carbon atoms which are linked directly to one another or which are bonded to the same carbon atom.
The formulation that two or more radicals may form a ring with one another is, for the purposes of the present application, intended to be taken to mean, inter alia, that the two radicals are linked to one another by a chemical bond. This is illustrated by the following scheme:
Furthermore, however, the above-mentioned formulation is also intended to be taken to mean that, in the case where one of the two radicals represents hydrogen, the second radical is bonded at the position at which the hydrogen atom was bonded, with formation of a ring.
A condensed aryl group in the sense of the present invention is a group in which two or more aromatic groups are condensed, i.e. annellated, onto one another via a common edge, such as, for example, in naphthalene. By contrast, for example, fluorene is not a condensed aryl group in the sense of the present invention, since the two aromatic groups in fluorene do not have a common edge.
An aromatic ring system in the sense of this invention contains 6 to 40 C atoms in the ring system. An aromatic ring system in the sense of this invention is intended to be taken to mean a system which does not necessarily contain only aryl or heteroaryl groups, but instead in which, in addition, a plurality of aryl or heteroaryl groups may be connected by a non-aromatic unit (preferably less than 10% of the atoms other than H), such as, for example, a C, N or O atom. Thus, for example, systems such as fluorene, 9,9′-spirobifluorene, 9,9-diarylfluorene, triarylamine, etc., are also intended to be taken to be aromatic ring systems in the sense of this invention, as are systems in which two or more aryl groups are connected, for example, by a short alkyl group. Furthermore, aromatic rings linked to one another by a single bond, i.e. oligoarylenes or oligoheteroarylenes, such as, for example, biphenyl, terphenyl or quaterphenyl, are referred to as aromatic ring systems in the sense of this application.
For the purposes of the present invention, an aliphatic hydrocarbon radical or an alkyl group or an alkenyl or alkynyl group, which may contain 1 to 40 C atoms and in which, in addition, individual H atoms or CH2 groups may be substituted by the above-mentioned groups, is preferably taken to mean the radicals methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 2-methylbutyl, n-pentyl, s-pentyl, neopentyl, cyclopentyl, n-hexyl, neohexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, 2-ethylhexyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, ethenyl, propenyl, butenyl, pentenyl, cyclopentenyl, hexenyl, cyclohexenyl, heptenyl, cycloheptenyl, octenyl, cyclooctenyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl or octynyl. An alkoxy group having 1 to 40 C atoms is preferably taken to mean methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, 2-methylbutoxy, n-hexoxy, cyclohexyloxy, n-heptoxy, cycloheptyloxy, n-octyloxy, cyclooctyloxy, 2-ethyhexyloxy, pentafluoroethoxy or 2,2,2-trifluoroethoxy. A thioalkyl group having 1 to 40 C atoms is taken to mean, in particular, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, n-pentylthio, s-pentylthio, n-hexylthio, cyclohexylthio, n-heptylthio, cycloheptylthio, n-octylthio, cyclooctylthio, 2-ethylhexylthio, trifluoromethylthio, pentafluoroethylthio, 2,2,2-trifluoroethylthio, ethenylthio, propenylthio, butenylthio, pentenylthio, cyclopentenylthio, hexenylthio, cyclohexenylthio, heptenylthio, cycloheptenylthio, octenylthio, cyclooctenylthio, ethynylthio, propynylthio, butynylthio, pentynylthio, hexynylthio, heptynylthio or octynylthio. In general, alkyl, alkoxy or thioalkyl groups in accordance with the present invention may be straight-chain, branched or cyclic, where one or more non-adjacent CH2 groups may be replaced by the above-mentioned groups; furthermore, one or more H atoms may also be replaced by D, F, Cl, Br, I, CN or NO2, preferably F, Cl or CN, further preferably F or CN, particularly preferably CN.
An aromatic or heteroaromatic ring system having 5-40 aromatic ring atoms is taken to mean, in particular, groups derived from benzene, naphthalene, anthracene, benzanthracene, phenanthrene, pyrene, chrysene, perylene, fluoranthene, naphthacene, pentacene, benzopyrene, biphenyl, biphenylene, terphenyl, triphenylene, fluorene, spirobifluorene, dihydrophenanthrene, dihydropyrene, tetrahydropyrene, cis- or trans-indenofluorene, cis- or trans-indenocarbazole, cis- or trans-indolocarbazole, truxene, isotruxene, spirotruxene, spiroisotruxene, furan, benzofuran, isobenzofuran, dibenzofuran, thiophene, benzothiophene, isobenzothiophene, dibenzothiophene, pyrrole, indole, isoindole, carbazole, pyridine, quinoline, isoquinoline, acridine, phenanthridine, benzo-5,6-quinoline, benzo-6,7-quinoline, benzo-7,8-quinoline, phenothiazine, phenoxazine, pyrazole, indazole, imidazole, benzimidazole, naphthimidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, oxazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, benzothiazole, pyridazine, hexaazatriphenylene, benzopyridazine, pyrimidine, benzopyrimidine, quinoxaline, 1,5-diazaanthracene, 2,7-diazapyrene, 2,3-diazapyrene, 1,6-diazapyrene, 1,8-diazapyrene, 4,5-diazapyrene, 4,5,9,10-tetraazaperylene, pyrazine, phenazine, phenoxazine, phenothiazine, fluorubin, naphthyridine, azacarbazole, benzocarboline, phenanthroline, 1,2,3-triazole, 1,2,4-triazole, benzotriazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole, 1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, purine, pteridine, indolizine and benzothiadiazole or groups derived from a combination of these systems.
In a preferred embodiment of the invention, a maximum of one group A per ring stands for N and the other groups A stand for CR1. A particularly preferably stands for CR1, so that the compound of the formula (1) is a compound of the following formula (1a),
where the symbols used have the meanings given above and n stands, identically or differently on each occurrence, for 0, 1, 2 or 3.
In a preferred embodiment of the invention, the index n in formula (1a) is, identically or differently on each occurrence, 0, 1 or 2, particularly preferably, 0 or 1 and very particularly preferably equal to 0.
Preferred embodiments of the formula (1a) are the compounds of the following formulae (1b) to (1f),
where the symbols used have the meanings given above.
A particularly preferred embodiment is the compound of the following formula (1g),
where the symbols used have the meanings given above.
Preferred embodiments of the group HetAr are described below.
Preferred embodiments of the groups of the formulae (2), (3) and (4) are the groups of the following formulae (2-1) to (2-10), (3-1) and (4-1),
where the dashed bond represents the linking of these groups and R2 has the meanings given above.
Preference is given to the groups of the formulae (2-1) to (2-3) and particular preference is given to the group of the formula (2-1).
Preferred embodiments of the above-mentioned groups are the groups of the following formulae (2-1a) to (4-1a),
where the dashed bond represents the linking of these groups and R2 represents a substituent in accordance with the definition given above other than hydrogen.
The substituent R2 on the group HetAr is preferably, identically or differently on each occurrence, H or an aromatic or heteroaromatic ring system having 6 to 24 aromatic ring atoms, which may be substituted by one or more radicals R5. R2 in the groups of the formulae (2-1a) to (4-1a) here is not equal to hydrogen. The aromatic or heteroaromatic ring system preferably has 6 to 18 aromatic ring atoms. It is particularly preferably an aromatic ring system having 6 to 12 aromatic ring atoms or a heteroaromatic ring system having 6 to 13 aromatic ring atoms, each of which may be substituted by one or more radicals R5, but is preferably unsubstituted. Examples of suitable groups R2 are selected from the group consisting of phenyl, biphenyl, in particular ortho-, meta- or para-biphenyl, terphenyl, in particular branched terphenyl, quaterphenyl, in particular branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, each of which may be substituted by one or more radicals R5, but is preferably unsubstituted.
Examples of suitable groups R2 are the structures R2-1 to R2-18 shown below,
where Y2 and R5 have the meanings given above, and the dashed bond represents the bond to the heteroaryl group.
Preferred embodiments of the group N1 are shown below. As described above, the group N1 stands for a group of the formula (5) or (6).
In a preferred embodiment of the invention, the group Ar1 in the group of the formula (5) stands, identically or differently on each occurrence, for an aromatic or heteroaromatic ring system having 6 to 24 aromatic ring atoms, preferably having 6 to 18 aromatic ring atoms, particularly preferably for an aromatic ring system having 6 to 12 aromatic ring atoms or a heteroaromatic ring system having 6 to 13 aromatic ring atoms, each of which may be substituted by one or more radicals R3, but is preferably unsubstituted. Examples of suitable groups Ar1 are selected from the group consisting of phenyl, biphenyl, in particular ortho-, meta- or para-biphenyl, terphenyl, in particular branched terphenyl, quaterphenyl, in particular branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, each of which may be substituted by one or more radicals R3, but is preferably unsubstituted.
Particularly preferred groups Ar1 are the groups of the following formulae (Ar1-1) to (Ar1-20),
where Y2 and R3 have the meanings given above, and the dashed bond represents the bond to the nitrogen in formula (5).
In a preferred embodiment of the invention, R3 stands, identically or differently on each occurrence, for H, an alkyl group having 1 to 4 C atoms or an aromatic or heteroaromatic ring system having 5 to 14 aromatic ring atoms. R3 particularly preferably stands, identically or differently on each occurrence, for H or an alkyl group having 1 to 4 C atoms.
In the group of the formula (6), it is preferred if a maximum of one group A stands for N and the other groups A stand for CR1. Particularly preferably, all groups A in formula (6) stand for CR1. Particularly preferred groups of the formula (6) are thus the groups of the following formulae (6-1) and (6-2),
where R1 has the meanings given above and furthermore:
two adjacent groups W together stand for a group of the following formula (7a) or (8a) and the other two groups W stand for CR1 and preferably for CH,
where Y2, Y3 and R1 have the meanings given above;
m is, identically or differently on each occurrence, 0, 1, 2, 3 or 4.
In a preferred embodiment of the invention, the index m stands for 0, 1, 2 or 3, particularly preferably for 0, 1 or 2 and very particularly preferably for 0 or 1.
Preferred embodiments of the group of the formula (6-1) are the groups of the following formulae (6-1a) to (6-1f),
where Y2 has the meanings given above and preferably stands for NR4, O or S.
Preferred embodiments of the group of the formula (6-2) are the groups of the following formulae (6-2a) to (6-2f),
where the symbols and indices used have the meanings given above.
In a further preferred embodiment of the invention, Y2 and Y3 stand, identically or differently on each occurrence, for O, C(R4)2 or NR4, where the radical R4 bonded to the nitrogen is not equal to H, particularly preferably for C(R4)2 or NR4, where the radical R4 bonded to the nitrogen is not equal to H, and very particularly preferably for C(R4)2.
If Y2 or Y3 stands for NR4, it is preferred if this radical R4 stands on each occurrence, identically or differently, for an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may in each case be substituted by one or more radicals R5, particularly preferably for an aromatic or heteroaromatic ring system having 6 to 18 aromatic ring atoms, which may be substituted by one or more radicals R5. Examples of suitable substituents R4 are selected from the group consisting of phenyl, biphenyl, in particular ortho-, meta- or para-biphenyl, terphenyl, in particular branched terphenyl, quaterphenyl, in particular branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl, 4,6-diphenyl-1,3,5-triazinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, where the carbazolyl group is substituted on the nitrogen atom by a radical R5 other than H or D. These groups may each be substituted by one or more radicals R5, but are preferably unsubstituted. Suitable structures R4 are the same structures as depicted above for R2-1 to R2-18.
If Y2 stands for C(R4)2, it is preferred if these radicals R4 stand on each occurrence, identically or differently, for a straight-chain alkyl group having 1 to 10 C atoms or a branched or cyclic alkyl group having 3 to 10 C atoms or an alkenyl group having 2 to 10 C atoms, each of which may be substituted by one or more radicals R5, where one or more non-adjacent CH2 groups may be replaced by O and where one or more H atoms may be replaced by D or F, or for an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may in each case be substituted by one or more radicals R5; the two substituents R4 here may optionally form a monocyclic or polycyclic, aliphatic, aromatic or heteroaromatic ring system, which may be substituted by one or more radicals R5. Ring formation of the two substituents R4 forms a spiro system, for example a spirobifluorene or a derivative of a spirobifluorene, if the groups R4 stand for phenyl groups.
In a further preferred embodiment of the invention, L stands for a single bond or an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may be substituted by one or more radicals R1. L particularly preferably stands, identically or differently on each occurrence, for a single bond or an aromatic ring system having 6 to 12 aromatic ring atoms or a heteroaromatic ring system having 6 to 13 aromatic ring atoms, each of which may be substituted by one or more radicals R1, but is preferably unsubstituted. L very particularly preferably stands for a single bond. Examples of suitable aromatic or heteroaromatic ring systems L are selected from the group consisting of phenylene, biphenyl, fluorene, pyridine, pyrimidine, triazine, dibenzofuran, dibenzothiophene and carbazole, each of which may be substituted by one or more radicals R1, but is preferably unsubstituted.
If the compounds according to the invention contain substituents R1, these are then preferably selected from the group consisting of H, D, F, CN, N(Ar2)2, C(═O)Ar2, P(═O)(Ar2)2, a straight-chain alkyl or alkoxy group having 1 to 10 C atoms or a branched or cyclic alkyl or alkoxy group having 3 to 10 C atoms or an alkenyl group having 2 to 10 C atoms, each of which may be substituted by one or more radicals R5, where one or more non-adjacent CH2 groups may be replaced by O and where one or more H atoms may be replaced by D or F, an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may in each case be substituted by one or more radicals R5, or an aralkyl or heteroaralkyl group having 5 to 25 aromatic ring atoms, which may be substituted by one or more radicals R1; two substituents R1 which are bonded to adjacent carbon atoms here may optionally form a monocyclic or polycyclic, aliphatic ring system, which may be substituted by one or more radicals R5.
The substituents R1 are particularly preferably selected from the group consisting of H, D, F, CN, N(Ar2)2, a straight-chain alkyl group having 1 to 8 C atoms, preferably having 1, 2, 3 or 4 C atoms, or a branched or cyclic alkyl group having 3 to 8 C atoms, preferably having 3 or 4 C atoms, or an alkenyl group having 2 to 8 C atoms, preferably having 2, 3 or 4 C atoms, each of which may be substituted by one or more radicals R5, but is preferably unsubstituted, or an aromatic or heteroaromatic ring system having 6 to 24 aromatic ring atoms, preferably having 6 to 18 aromatic ring atoms, particularly preferably having 6 to 13 aromatic ring atoms, which may in each case be substituted by one or more non-aromatic radicals R5, but is preferably unsubstituted; two substituents R1 which are bonded to adjacent carbon atoms here may optionally form a monocyclic or polycyclic, aliphatic ring system, which may be substituted by one or more radicals R5, but is preferably unsubstituted.
The substituents R1 are very particularly preferably selected from the group consisting of H or an aromatic or heteroaromatic ring system having 6 to 18 aromatic ring atoms, preferably having 6 to 13 aromatic ring atoms, which may in each case be substituted by one or more non-aromatic radicals R5, but is preferably unsubstituted. Examples of suitable substituents R1 are selected from the group consisting of phenyl, biphenyl, in particular ortho-, meta- or para-biphenyl, terphenyl, in particular branched terphenyl, quaterphenyl, in particular branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, each of which may be substituted by one or more radicals R5, but is preferably unsubstituted. Suitable structures R1 here are the same structures as depicted above for R2-1 to R2-18.
In a further preferred embodiment of the invention, R5 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, an aliphatic hydrocarbon radical having 1 to 10 C atoms, preferably having 1, 2, 3 or 4 C atoms, or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, preferably having 5 to 13 aromatic ring atoms, which may be substituted by one or more alkyl groups, each having 1 to 4 carbon atoms, but is preferably unsubstituted.
If the compound according to the invention is substituted by aromatic or heteroaromatic groups, it is preferred if these contain no aryl or heteroaryl groups having more than two aromatic six-membered rings condensed directly onto one another. The substituents particularly preferably contain absolutely no aryl or heteroaryl groups having six-membered rings condensed directly onto one another. This preference is due to the low triplet energy of such structures. Condensed aryl groups having more than two aromatic six-membered rings condensed directly onto one another which are nevertheless also suitable in accordance with the invention are phenanthrene and triphenylene, since these also have a high triplet level.
The preferences mentioned above may occur individually or together. It is preferred if the preferences mentioned above occur together.
Preference is thus given to compounds of the above-mentioned formula (1a) for which:
L is on each occurrence, identically or differently, a single bond or an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may be substituted by one or more radicals R1;
HetAr is a group of one of the above-mentioned formulae (2-1) to (2-10), (3-1) or (4-1);
N1 is a group of the following formula (5), (6-1) or (6-2),
two adjacent groups W together stand for a group of the following formula (7a) or (8a) and the other two groups W stand for CR1 and preferably for CH,
Ar1 is on each occurrence, identically or differently, an aromatic or heteroaromatic ring system having 6 to 24 aromatic ring atoms, preferably having 6 to 18 aromatic ring atoms, which may be substituted by one or more radicals R3;
Y2, Y3 are, identically or differently on each occurrence, O, NR4 or C(R4)2, where the radical R4 which is bonded to N is not equal to H;
R1 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, N(Ar2)2, C(═O)Ar2, P(═O)(Ar2)2, a straight-chain alkyl or alkoxy group having 1 to 10 C atoms or a branched or cyclic alkyl or alkoxy group having 3 to 10 C atoms or an alkenyl group having 2 to 10 C atoms, each of which may be substituted by one or more radicals R5, where one or more non-adjacent CH2 groups may be replaced by O and where one or more H atoms may be replaced by D or F, an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may in each case be substituted by one or more radicals R5, or an aralkyl or heteroaralkyl group having 5 to 25 aromatic ring atoms, which may be substituted by one or more radicals R1; two substituents R1 which are bonded to adjacent carbon atoms here may optionally form a monocyclic or polycyclic, aliphatic ring system, which may be substituted by one or more radicals R5;
R2 is on each occurrence, identically or differently, H or an aromatic or heteroaromatic ring system having 6 to 24 aromatic ring atoms, in particular having 6 to 18 aromatic ring atoms, which may in each case be substituted by one or more radicals R5;
R3 is on each occurrence, identically or differently, H, an alkyl group having 1 to 4 C atoms or an aromatic or heteroaromatic ring system having 5 to 14 aromatic ring atoms;
R4 is, for Y2 or Y3═NR4, an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, preferably having 6 to 18 aromatic ring atoms, which may in each case be substituted by one or more radicals R5;
and is, for Y2 or Y3═C(R4)2, on each occurrence, identically or differently, a straight-chain alkyl group having 1 to 10 C atoms or a branched or cyclic alkyl group having 3 to 10 C atoms or an alkenyl group having 2 to 10 C atoms, each of which may be substituted by one or more radicals R5, where one or more non-adjacent CH2 groups may be replaced by O and where one or more H atoms may be replaced by D or F, or an aromatic or heteroaromatic ring system having 5 to 24 aromatic ring atoms, which may in each case be substituted by one or more radicals R5; the two substituents R4 here may optionally form a monocyclic or polycyclic, aliphatic, aromatic or heteroaromatic ring system, which may be substituted by one or more radicals R5;
R5 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, an aliphatic hydrocarbon radical having 1 to 10 C atoms or an aromatic or heteroaromatic ring system having 5 to 30 aromatic ring atoms, which may be substituted by one or more alkyl groups, each having 1 to 4 carbon atoms;
n is on each occurrence, identically or differently, 0, 1, 2 or 3, preferably 0, 1 or 2;
m is, identically or differently on each occurrence, 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3;
the other symbols have the meanings given above.
Particular preference is given to the compounds of the above-mentioned formulae (1b) to (1g) for which:
L is on each occurrence, identically or differently, a single bond or an aromatic ring system having 6 to 12 aromatic ring atoms or a heteroaromatic ring system having 6 to 13 aromatic ring atoms, each of which may be substituted by one or more radicals R1, but is preferably unsubstituted;
HetAr is a group of one of the above-mentioned formulae (2-1a) to (2-10a), (3-1a) or (4-1a);
N1 is a group of the above-mentioned formulae (5), (6-1) or (6-2a) to (6-2f);
Ar1 is selected on each occurrence, identically or differently, from the group consisting of phenyl, biphenyl, terphenyl, quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, each of which may be substituted by one or more radicals R, but is preferably unsubstituted, and is in particular selected from the above-mentioned groups of the formulae (Ar1-1) to (Ar1-20);
Y2, Y3 are, identically or differently on each occurrence, NR4 or C(R4)2, where the radical R4 which is bonded to N is not equal to H, and are in particular C(R4)2;
R1 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, N(Ar2)2, a straight-chain alkyl group having 1 to 8 C atoms, preferably having 1, 2, 3 or 4 C atoms, or a branched or cyclic alkyl group having 3 to 8 C atoms, preferably having 3 or 4 C atoms, or an alkenyl group having 2 to 8 C atoms, preferably having 2, 3 or 4 C atoms, each of which may be substituted by one or more radicals R5, but is preferably unsubstituted, or an aromatic or heteroaromatic ring system having 6 to 24 aromatic ring atoms, preferably having 6 to 18 aromatic ring atoms, particularly preferably having 6 to 13 aromatic ring atoms, which may in each case be substituted by one or more non-aromatic radicals R5, but is preferably unsubstituted; two substituents R1 which are bonded to adjacent carbon atoms here may optionally form a monocyclic or polycyclic, aliphatic ring system, which may be substituted by one or more radicals R5, but is preferably unsubstituted; R1 is particularly preferably selected, identically or differently on each occurrence, from the group consisting of H or an aromatic or heteroaromatic ring system having 6 to 18 aromatic ring atoms, preferably having 6 to 13 aromatic ring atoms, which may in each case be substituted by one or more non-aromatic radicals R5, but is preferably unsubstituted;
R2 is selected, identically or differently on each occurrence, from the group consisting of phenyl, biphenyl, terphenyl, quaterphenyl, in particular branched quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, each of which may be substituted by one or more radicals R5, and is in particular selected from the groups of the above-mentioned structures R2-1 to R2-18;
R3 is H or an alkyl group having 1 to 4 C atoms;
R4 is, for Y2 or Y3═NR4, selected from the group consisting of phenyl, biphenyl, terphenyl, quaterphenyl, 1-, 2-, 3- or 4-fluorenyl, 1-, 2-, 3- or 4-spirobifluorenyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl, 4,6-diphenyl-1,3,5-triazinyl, 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or 4-dibenzothienyl and 1-, 2-, 3- or 4-carbazolyl, where the carbazolyl group is substituted on the nitrogen atom by a radical R5 other than H or D, where these groups may each be substituted by one or more radicals R5; particular preference is given to the structures R2-1 to R2-18 depicted above;
and is, for Y2 or Y3═C(R4)2, on each occurrence, Identically or differently, a straight-chain alkyl group having 1 to 5 C atoms or a branched or cyclic alkyl group having 3 to 8 C atoms or an alkenyl group having 2 to 8 C atoms, each of which may be substituted by one or more radicals R5, where one or more non-adjacent CH2 groups may be replaced by O and where one or more H atoms may be replaced by D or F, or an aromatic or heteroaromatic ring system having 6 to 18 aromatic ring atoms, which may in each case be substituted by one or more radicals R5; the two substituents R4 here may optionally form a monocyclic or polycyclic, aliphatic, aromatic or heteroaromatic ring system, which may be substituted by one or more radicals R5;
R5 is selected on each occurrence, identically or differently, from the group consisting of H, D, F, CN, an aliphatic hydrocarbon radical having 1, 2, 3 or 4 C atoms or an aromatic or heteroaromatic ring system having 5 to 13 aromatic ring atoms, which may be substituted by one or more alkyl groups, each having 1 to 4 carbon atoms, but is preferably unsubstituted;
n is on each occurrence, identically or differently, 0 or 1;
m is, identically or differently on each occurrence, 0, 1 or 2, preferably 0 or 1;
the other symbols have the meanings given above.
Examples of suitable compounds according to the invention are the structures shown below.
The compounds according to the invention can be prepared by synthesis steps known to the person skilled in the art, such as, for example, bromination, Suzuki coupling, Ullmann coupling, Hartwig-Buchwald coupling, etc. A suitable synthesis process is depicted in general terms in Scheme 1 below.
The synthesis starts from 1-halodibenzofuran or -dibenzothiophene, which is converted into the corresponding boronic acid or a boronic acid derivative. In the next step, the group HetAr can be introduced by Suzuki coupling. The halogenation, for example using NBS, takes place selectively in the 8-position of the dibenzofuran or dibenzothiophene. In the final step, the group N1 can be introduced in this position, for example by a Hartwig-Buchwald coupling.
The general process shown for the synthesis of the compounds according to the invention is illustrative. The person skilled in the art will be able to develop alternative synthetic routes in the bounds of his general expert knowledge.
The present invention furthermore relates to a process for the synthesis of the compounds according to the invention, starting from 1-halodibenzofuran or 1-halodibenzothiophene, where the halogen is preferably bromine, characterised by the following steps:
(1) optionally conversion of the halogen group into a boronic acid or a boronic acid derivative;
(2) introduction of the group HetAr by a coupling reaction, in particular a Suzuki coupling;
(3) halogenation, in particular bromination, of the dibenzofuran or dibenzothiophene in the 8-position;
(4) introduction of the group N1 by a coupling reaction, in particular a Hartwig-Buchwald coupling.
For the processing of the compounds according to the invention from the liquid phase, for example by spin coating or by printing processes, formulations of the compounds according to the invention are necessary. These formulations can be, for example, solutions, dispersions or emulsions. It may be preferred to use mixtures of two or more solvents for this purpose. Suitable and preferred solvents are, for example, toluene, anisole, o-, m- or p-xylene, methyl benzoate, mesitylene, tetralin, veratrol, THF, methyl-THF, THP, chlorobenzene, dioxane, phenoxytoluene, in particular 3-phenoxytoluene, (−)-fenchone, 1,2,3,5-tetramethylbenzene, 1,2,4,5-tetramethylbenzene, 1-methylnaphthalene, 2-methylbenzothiazole, 2-phenoxyethanol, 2-pyrrolidinone, 3-methylanisole, 4-methylanisole, 3,4-dimethylanisole, 3,5-dimethylanisole, acetophenone, α-terpineol, benzothiazole, butyl benzoate, cumene, cyclohexanol, cyclohexanone, cyclohexylbenzene, decalin, dodecylbenzene, ethyl benzoate, indane, methyl benzoate, NMP, p-cymene, phenetole, 1,4-diisopropylbenzene, dibenzyl ether, diethylene glycol butyl methyl ether, triethylene glycol butyl methyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, diethylene glycol monobutyl ether, tripropylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, 2-isopropylnaphthalene, pentylbenzene, hexylbenzene, heptylbenzene, octylbenzene, 1,1-bis(3,4-dimethylphenyl)ethane or mixtures of these solvents.
The present invention therefore furthermore relates to a formulation comprising a compound according to the invention and at least one further compound. The further compound may be, for example, a solvent, in particular one of the above-mentioned solvents or a mixture of these solvents. However, the further compound may also be at least one further organic or inorganic compound which is likewise employed in the electronic device, for example an emitting compound, in particular a phosphorescent dopant, and/or a further matrix material. Suitable emitting compounds and further matrix materials are indicated below in connection with the organic electroluminescent device. This further compound may also be polymeric.
The compounds and mixtures according to the invention are suitable for use in an electronic device. An electronic device here is taken to mean a device which comprises at least one layer which comprises at least one organic compound. However, the component here may also comprise inorganic materials or also layers built up entirely from inorganic materials.
The present invention therefore furthermore relates to the use of the compounds or mixtures according to the invention in an electronic device, in particular in an organic electroluminescent device.
The present invention again furthermore relates to an electronic device comprising at least one of the compounds or mixtures according to the invention mentioned above. The preferences stated above for the compound also apply to the electronic devices.
The electronic device is preferably selected from the group consisting of organic electroluminescent devices (OLEDs, PLEDs), organic integrated circuits (O-ICs), organic field-effect transistors (O-FETs), organic thin-film transistors (O-TFTs), organic light-emitting transistors (O-LETs), organic solar cells (O-SCs), organic dye-sensitized solar cells, organic optical detectors, organic photoreceptors, organic field-quench devices (O-FQDs), light-emitting electrochemical cells (LECs), organic laser diodes (O-lasers) and “organic plasmon emitting devices” (D. M. Koller et al., Nature Photonics 2008, 1-4), preferably organic electroluminescent devices (OLEDs, PLEDs), in particular phosphorescent OLEDs.
The organic electroluminescent device comprises a cathode, an anode and at least one emitting layer. Apart from these layers, it may also comprise further layers, for example in each case one or more hole-injection layers, hole-transport layers, hole-blocking layers, electron-transport layers, electron-injection layers, exciton-blocking layers, electron-blocking layers and/or charge-generation layers. It is likewise possible for interlayers, which have, for example, an exciton-blocking function, to be introduced between two emitting layers. However, it should be pointed out that each of these layers does not necessarily have to be present. The organic electroluminescent device here may comprise one emitting layer or a plurality of emitting layers. If a plurality of emission layers are present, these preferably have in total a plurality of emission maxima between 380 nm and 750 nm, resulting overall in white emission, i.e. various emitting compounds which are able to fluoresce or phosphoresce are used in the emitting layers. Particular preference is given to systems having three emitting layers, where the three layers exhibit blue, green and orange or red emission (for the basic structure see, for example, WO 2005/011013). These can be fluorescent or phosphorescent emission layers or hybrid systems, in which fluorescent and phosphorescent emission layers are combined with one another.
The compound according to the invention in accordance with the embodiments indicated above can be employed in various layers, depending on the precise structure. Preference is given to an organic electroluminescent device comprising a compound of the formula (1) or in accordance with the preferred embodiments as matrix material for fluorescent or phosphorescent emitters, in particular for phosphorescent emitters, and/or in an electron-transport layer and/or in an electron-blocking or exciton-blocking layer and/or in a hole-transport layer, depending on the precise substitution. The preferred embodiments indicated above also apply to the use of the materials in organic electronic devices.
In a preferred embodiment of the invention, the compound of the formula (1) or in accordance with the preferred embodiments is employed as matrix material for a fluorescent or phosphorescent compound, in particular for a phosphorescent compound, in an emitting layer. The organic electroluminescent device here may comprise one emitting layer or a plurality of emitting layers, where at least one emitting layer comprises at least one compound according to the invention as matrix material.
If the compound of the formula (1) or in accordance with the preferred embodiments is employed as matrix material for an emitting compound in an emitting layer, it is preferably employed in combination with one or more phosphorescent materials (triplet emitters). Phosphorescence in the sense of this invention is taken to mean the luminescence from an excited state having spin multiplicity >1, in particular from an excited triplet state. For the purposes of this application, all luminescent transition-metal complexes and luminescent lanthanide complexes, in particular all iridium, platinum and copper complexes, are to be regarded as phosphorescent compounds.
The mixture comprising the compound of the formula (1) or in accordance with the preferred embodiments and the emitting compound comprises between 99 and 1% by vol., preferably between 98 and 10% by vol., particularly preferably between 97 and 60% by vol., in particular between 95 and 80% by vol., of the compound of the formula (1) or in accordance with the preferred embodiments, based on the entire mixture comprising emitter and matrix material. Correspondingly, the mixture comprises between 1 and 99% by vol., preferably between 2 and 90% by vol., particularly preferably between 3 and 40% by vol., in particular between 5 and 20% by vol., of the emitter, based on the entire mixture comprising emitter and matrix material.
A further preferred embodiment of the present invention is the use of the compound of the formula (1) or in accordance with the preferred embodiments as matrix material for a phosphorescent emitter in combination with a further matrix material. Particularly suitable matrix materials which can be employed in combination with the compounds of the formula (1) or in accordance with the preferred embodiments are aromatic ketones, aromatic phosphine oxides or aromatic sulfoxides or sulfones, for example in accordance with WO 2004/013080, WO 2004/093207, WO 2006/005627 or WO 2010/006680, triarylamines, carbazole derivatives, for example CBP (N,N-biscarbazolylbiphenyl) or the carbazole derivatives disclosed in WO 2005/039246, US 2005/0069729, JP 2004/288381, EP 1205527 or WO 2008/086851, indolocarbazole derivatives, for example in accordance with WO 2007/063754 or WO 2008/056746, indenocarbazole derivatives, for example in accordance with WO 2010/136109 and WO 2011/000455, azacarbazole derivatives, for example in accordance with EP 1617710, EP 1617711, EP 1731584, JP 2005/347160, bipolar matrix materials, for example in accordance with WO 2007/137725, silanes, for example in accordance with WO 005/111172, azaboroles or boronic esters, for example in accordance with WO 2006/117052, triazine derivatives, for example in accordance with WO 2010/015306, WO 2007/063754 or WO 2008/056746, zinc complexes, for example in accordance with EP 652273 or WO 2009/062578, diazasilole or tetraazasilole derivatives, for example in accordance with WO 2010/054729, diazaphosphole derivatives, for example in accordance with WO 2010/054730, bridged carbazole derivatives, for example in accordance with US 2009/0136779, WO 2010/050778, WO 2011/042107, WO 2011/088877 or in accordance with the unpublished application EP 11003232.3, triphenylene derivatives, for example in accordance with WO 2012/048781, or lactams, for example in accordance with WO 2011/116865 or WO 2011/137951. A further phosphorescent emitter which emits at shorter wavelength than the actual emitter may likewise be present in the mixture as co-host.
Preferred co-host materials are triarylamine derivatives, in particular monoamines, lactams, carbazole derivatives and indenocarbazole derivatives.
Suitable phosphorescent compounds (=triplet emitters) are, in particular, compounds which emit light, preferably in the visible region, on suitable excitation and in addition contain at least one atom having an atomic number greater than 20, preferably greater than 38 and less than 84, particularly preferably greater than 56 and less than 80, in particular a metal having this atomic number. The phosphorescent emitters used are preferably compounds which contain copper, molybdenum, tungsten, rhenium, ruthenium, osmium, rhodium, iridium, palladium, platinum, silver, gold or europium, in particular compounds which contain iridium or platinum. For the purposes of the present invention, all luminescent compounds which contain the above-mentioned metals are regarded as phosphorescent compounds.
Examples of the emitters described above are revealed by the applications WO 00/70655, WO 2001/41512, WO 2002/02714, WO 2002/15645, EP 1191613, EP 1191612, EP 1191614, WO 05/033244, WO 05/019373, US 2005/0258742, WO 2009/146770, WO 2010/015307, WO 2010/031485, WO 2010/054731, WO 2010/054728, WO 2010/086089, WO 2010/099852, WO 2010/102709, WO 2011/032626, WO 2011/066898, WO 2011/157339, WO 2012/007086, WO 2014/008982, WO 2014/023377, WO 2014/094962, WO 2014/094961 or WO 2014/094960. In general, all phosphorescent complexes as used in accordance with the prior art for phosphorescent OLEDs and as are known to the person skilled in the art in the area of organic electroluminescence are suitable, and the person skilled in the art will be able to use further phosphorescent complexes without inventive step.
In a further embodiment of the invention, the organic electroluminescent device according to the invention does not comprise a separate hole-injection layer and/or hole-transport layer and/or hole-blocking layer and/or electron-transport layer, i.e. the emitting layer is directly adjacent to the hole-injection layer or the anode, and/or the emitting layer is directly adjacent to the electron-transport layer or the electron-injection layer or the cathode, as described, for example, in WO 2005/053051. It is furthermore possible to use a metal complex which is identical or similar to the metal complex in the emitting layer as hole-transport or hole-injection material directly adjacent to the emitting layer, as described, for example, in WO 2009/030981.
It is furthermore possible to employ the compounds according to the invention in a hole-blocking or electron-transport layer. This applies, in particular, to compounds according to the invention which do not have a carbazole structure. These may preferably also be substituted by one or more further electron-transporting groups, for example benzimidazole groups.
In the further layers of the organic electroluminescent device according to the invention, it is possible to use all materials as usually employed in accordance with the prior art. The person skilled in the art will therefore be able, without inventive step, to employ all materials known for organic electroluminescent devices in combination with the compounds of the formula (1) or in accordance with the preferred embodiments.
Preference is furthermore given to an organic electroluminescent device, characterised in that one or more layers are applied by means of a sublimation process, in which the materials are vapour-deposited in vacuum sublimation units at an initial pressure of less than 10−5 mbar, preferably less than 10−6 mbar. However, it is also possible for the initial pressure to be even lower or higher, for example less than 10−7 mbar.
Preference is likewise given to an organic electroluminescent device, characterised in that one or more layers are applied by means of the OVPD (organic vapour phase deposition) process or with the aid of carrier-gas sublimation, in which the materials are applied at a pressure between 10−5 mbar and 1 bar. A special case of this process is the OVJP (organic vapour jet printing) process, in which the materials are applied directly through a nozzle and thus structured (for example M. S. Arnold et al., Appl. Phys. Lett. 2008, 92, 053301).
Preference is furthermore given to an organic electroluminescent device, characterised in that one or more layers are produced from solution, such as, for example, by spin coating, or by means of any desired printing process, such as, for example, ink-jet printing, LITI (light induced thermal imaging, thermal transfer printing), screen printing, flexographic printing, offset printing or nozzle printing. Soluble compounds, which are obtained, for example, by suitable substitution, are necessary for this purpose.
Also possible are hybrid processes, in which, for example, one or more layers are applied from solution and one or more further layers are applied by vapour deposition. Thus, it is possible, for example, to apply the emitting layer from solution and to apply the electron-transport layer by vapour deposition.
These processes are generally known to the person skilled in the art and can be applied by him without inventive step to organic electroluminescent devices comprising the compounds according to the invention.
The compounds according to the invention generally have very good properties on use in organic electroluminescent devices. In particular, the lifetime on use of the compounds according to the invention in organic electroluminescent devices is significantly better compared with similar compounds in accordance with the prior art. The other properties of the organic electroluminescent device, in particular the efficiency and the voltage, are likewise better or at least comparable. Furthermore, the compounds have a high glass transition temperature and high thermal stability.
The invention will now be explained in greater detail by the following examples, without wishing to restrict it thereby.
EXAMPLES
The following syntheses are carried out, unless indicated otherwise, under a protective-gas atmosphere in dried solvents. The solvents and reagents can be purchased, for example, from Sigma-ALDRICH or ABCR. The corresponding CAS numbers are also indicated in each case from the compounds known from the literature.
a) Synthesis of 6-bromo-2-fluoro-2′-methoxybiphenyl
200 g (664 mmol) of 1-bromo-3-fluoro-2-iodobenzene, 101 g (664 mmol) of 2-methoxyphenylboronic acid and 137.5 g (997 mmol) of sodium tetraborate are dissolved in 1000 ml of THF and 600 ml of water and degassed. 9.3 g (13.3 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1 g (20 mmol) of hydrazinium hydroxide are added. The reaction mixture is subsequently stirred at 70° C. under a protective-gas atmosphere for 48 h. The cooled solution is replenished with toluene, washed a number of times with water, dried and evaporated. The product is purified by column chromatography on silica gel with toluene/heptane (1:2). Yield: 155 g (553 mmol), 83% of theory.
The following compounds are prepared analogously:
Starting
Starting
material 1
material 2
Product
Yield
a1
[1000576-09-9]
77%
a2
[1379680-54-2]
74%
a3
[1199350-14-5]
76%
a4
[1114496-44-4]
71%
b) Synthesis of 6′-bromo-2′-fluorobiphenyl-2-ol
112 g (418 mmol) of 6-bromo-2-fluoro-2′-methoxybiphenyl are dissolved in 2 l of dichloromethane and cooled to 5° C. 41.0 ml (431 mmol) of boron tribromide are added dropwise to this solution over the course of 90 min., and stirring is continued overnight. Water is slowly added to the mixture, and the organic phase is washed three times with water, dried over Na2SO4, evaporated in a rotary evaporator and purified by chromatography. Yield: 104 g (397 mmol), 98% of theory.
The following compounds are prepared analogously:
Starting
material 1
Product
Yield
b1
92%
b2
90%
b3
93%
b4
94%
c) Synthesis of 1-bromodibenzofuran
111 g (416 mmol) of 6′-bromo-2′-fluorobiphenyl-2-ol are dissolved in 2 l of SeccoSolv® DMF (max. 0.003% of H2O) and cooled to 5° C. 20 g (449 mmol) of sodium hydride (60% suspension in paraffin oil) are added in portions to this solution, and the mixture is stirred for a further 20 min. after the addition is complete and then heated at 100° C. for 45 min. After cooling, 500 ml of ethanol are slowly added to the mixture, which is then evaporated to dryness in a rotary evaporator and purified by chromatography. Yield: 90 g (367 mmol), 88.5% of theory.
The following compounds are prepared analogously:
Starting
material 1
Product
Yield
c1
81%
c2
78%
c3
73%
c4
79%
d) Synthesis of dibenzofuran-1-boronic acid
180 g (728 mmol) of 1-bromodibenzofuran are dissolved in 1500 ml of dry THF and cooled to −78° C. 305 ml (764 mmol/2.5 M in hexane) of n-butyllithium are added over the course of about 5 min. at this temperature, and stirring is subsequently continued at −78° C. for 2.5 h. 151 g (1456 mmol) of trimethyl borate are added as rapidly as possible at this temperature, and the reaction mixture is allowed to come slowly to room temperature (about 18 h). The reaction solution is washed with water, and the precipitated solid and the organic phase are dried azeotropically with toluene. The crude product is washed by stirring with toluene/methylene chloride at about 40° C. and filtered off with suction. Yield: 146 g (690 mmol), 95% of theory.
The following compounds are prepared analogously.
Starting
material 1
Product
Yield
d1
81%
d2
78%
d3
73%
d4
[65642-94-6]
73%
e) Synthesis of 2-chloro-4-dibenzofuran-1-yl-6-phenyl-1,3,5-triazine
23 g (110.0 mmol) of dibenzofuran-1-boronic acid, 29.5 g (110.0 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine and 21 g (210.0 mmol) of sodium carbonate are suspended in 500 ml of ethylene glycol diamine ether and 500 ml of water. 913 mg (3.0 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(ii) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water each time and subsequently evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/heptane. The yield is 37 g (94 mmol), corresponding to 87% of theory.
The following compounds are prepared analogously:
Starting
Starting
material 1
material 2
Product
Yield
e1
[40734-24-5]
73%
e2
82%
e3
[3842-55-5]
73%
e4
[40734-4-5]
72%
e5
63%
e6
[1434286-69-7]
76%
f) Synthesis of 2-(8-bromodibenzofuran-1-yl)-4,6-diphenyl-1,3,5-triazine
70 g (190.0 mmol) of 2-dibenzofuran-1-yl-4,6-diphenyl-1,3,5-triazine are suspended in 2000 ml of aceetic acid (100%) and 2000 ml of sulfuric acid (95-98%). 34 g (190 mmol) of NBS are added to this suspension in portions, and the mixture is stirred in the dark for 2 h. Water/ice is then added, and the solid is separated off and rinsed with ethanol. The residue is recrystallised from toluene. The yield is 80 g (167 mmol), corresponding to 87% of theory.
The following compounds are prepared analogously.
Starting
material 1
Product
Yield
f1
80%
f2
41%
f3
52%
f4
64%
In the case of thiophene derivatives, nitrobenzene is employed instead of sulfuric acid and elemental bromine is employed instead of NBS:
f5
55%
f6
52%
g) Synthesis of 9-[9-(4,6-diphenyl-1,3,5-triazin-2-yl)dibenzofuran-2-yl]-3-phenyl-9H-carbazole
A degassed solution of 70 g (147 mmol) of 2-(8-bromodibenzofuran-1-yl)-4,6-diphenyl-1,3,5-triazine and 35.7 g (147 mmol) of 3-phenyl-9H-carbazole in 600 ml of toluene is saturated with N2 for 1 h. Firstly 2.09 ml (8.6 mmol) of P(tBu)3, then 1.38 g (6.1 mmol) of plladium(II) acetate are added to the solution, and 17.7 g (185 mmol) of NaOtBu in the solid state are subsequently added. The reaction mixture is heated under reflux for 1 h. After cooling to room temperature, the mixture is washed with 3×50 ml of toluene, dried over MgSO4, and the solvent is removed in vacuo. The cruse product is purified by chromatography on silica gel with heptane/ethyl acetate (20/1). The residue is recrystallised from toluene and finally sublimed in a high vacuum (p=5×10−6 mbar). The yield is 74.8 g (116 mmol), corresponding to 80% of theory.
The following compounds are prepared analogously:
Starting
Starting
material 1
material 2
Product
Yield
g1
[103012-26-6]
87%
g2
[1447708-58-5]
80%
g3
[1060735-14-9]
67%
g4
[1345202-03-0]
78%
g5
[1345202-03-0]
74%
g6
[1407183-86-7]
57%
g7
[1257220-47-5]
81%
g8
[1257220-47-5]
83%
g9
[1024598-06-8]
87%
g10
[1024598-06-8]
80%
g11
[1338919-70-2]
81%
g12
[103012-26-6]
88%
g13
[1439927-96-4]
73%
g14
[1373281-72-1]
79%
g15
[1316311-27-9]
84%
g16
[1260228-95-2]
59%
g17
[1199350-22-5]
62%
g18
[1257248-14-8]
72%
g19
[1255309-04-6]
69%
g20
[1345202-03-0]
72%
g21
[1316311-27-9]
62%
g22
[1361126-04-6]
65%
g23
[1247053-55-9]
61%
g24
[1246308-90-6]
73%
g25
[1246308-88-2]
80%
g26
[1257246-71-7]
69%
g27
[1219841-59-4]
71%
g28
[1247053-55-9]
72%
g29
[1246308-85-9]
63%
g30
[1259280-39-1]
72%
g31
[1430889-64-1]
82%
g32
[1255308-97-4]
63%
h) Biphenyl-4-yl-(9,9-dimethyl-9H-fluoren-2-yl)amine
24.0 g (142 mmol, 1.2 eq.) of 4-aminobiphenyl (CAS 92-67-1) are initially introduced in 950 ml of toluene together with 32.0 g (117 mmol, 1.0 eq.) of 2-bromo-9,9′-dimethylfluorene (CAS 28320-31-2) and saturated with argon for 30 minutes. 1.0 g (1.8 mmol, 0.02 eq.) of 1,1′-bis(diphenylphosphino)ferrocene (CAS 12150-46-8), 350 mg (1.6 mmol, 0.01 eq.) of palladium(II) acetate (CAS 3375-31-3) and 29 g (300 mmol, 2.6 eq.) of sodium tertbutoxide (CAS 865-48-5) are subsequently added, and the mixture is heated under reflux overnight. When the reaction is complete, the batch is diluted with 300 ml of toluene and extracted with water. The organic phase is dried over sodium sulfate, and the solvent is removed in a rotary evaporator. 50 ml of ethyl acetate are added to the brown oil, and the mixture is added to a mixture of heptane/ethyl acetate 20:1. The solid formed is filtered off with suction and washed with heptane. Drying gives 29 g (80 mmol, 69%) of the desired product h having an HPLC purity of 99.1%.
The following compounds are prepared analogously:
Starting
Starting
No.
material 1
material 2
Product
Yield
h1
92-67-1
2052-07-5
71%
h2
92-67-1
942615-32-9
61%
h3
92-67-1
955959-84-9
78%
h4
92-67-1
22439-61-8
82%
h5
118951-68-1
2052-07-5
62%
h6
108714-73-4
942615-32-9
47%
h7
95-53-4
90-11-9
92%
h8
92-67-1
171408-76-7
75%
h9
92-67-1
1153-85-1
84%
h10
90-41-5
1225053-54-2
62%
The following compounds are prepared analogously to the procedure Indicated above under g):
Starting
Starting
material 1
material 2
Product
Yield
g33
85%
g34
86%
g35
83%
g36
80%
g37
82%
g38
81%
g39
87%
g40
86%
g41
85%
g42
75%
g43
81%
g44
79%
g45
85%
g46
79%
g47
78%
g48
76%
g49
80%
g50
74%
Production of the OLEDs
The data of various OLEDs are presented in the following Examples V1 to E20 (see Tables 1 and 2).
Pre-Treatment for Examples V1-E20:
Glass plates coated with structured ITO (indium tin oxide) in a thickness of 50 nm are coated with 20 nm of PEDOT:PSS (poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate), purchased as CLEVIOS™ P VP AI 4083 from Heraeus Precious Metals GmbH, Germany, applied by spin coating from aqueous solution) for improved processing. These coated glass plates form the substrates to which the OLEDs are applied.
The OLEDs have in principle the following layer structure: substrate/hole-transport layer (HTL) I/optional interlayer (IL)/electron-blocking layer (EBL)/emission layer (EML)/optional hole-blocking layer (HBL)/electron-transport layer (ETL)/optional electron-injection layer (EIL) and finally a cathode. The cathode is formed by an aluminium cathode with a thickness of 100 nm. The precise structure of the OLEDs is shown in Table 1. The materials required for the production of the OLEDs are shown in Table 3.
All materials are applied by thermal vapour deposition in a vacuum chamber. The emission layer here always consists of at least one matrix material (host material) and an emitting dopant (emitter), which is admixed with the matrix material or materials in a certain proportion by volume by coevaporation. An expression such as IC1:IC3:TEG1 (55%:35%:10%) here means that material IC1 is present in the layer in a proportion by volume of 55%, IC3 is present in the layer in a proportion of 35% and TEG1 is present in the layer in a proportion of 10%. Analogously, the electron-transport layer may also consist of a mixture of two materials.
The OLEDs are characterised by standard methods. For this purpose, the electroluminescence spectra, the current efficiency (measured in cd/A), the power efficiency (measured in lm/W) and the external quantum efficiency (EQE, measured in percent) as a function of the luminous density, calculated from current/voltage/luminous density characteristic lines (IUL characteristic lines), assuming Lambert emission characteristics, and the lifetime are determined. The electroluminescence spectra are determined at a luminous density of 1000 cd/m2, and the CIE 1931 x and y colour coordinates are calculated therefrom. The expression U1000 in Table 2 denotes the voltage required for a luminous density of 1000 cd/m2. CE1000 and PE1000 denote the current and power efficiencies achieved at 1000 cd/m2. Finally, EQE1000 denotes the external quantum efficiency at an operating luminous density of 1000 cd/m2. The lifetime LT is defined as the time after which the luminous density drops to a certain proportion L1 from the initial luminous density on operation at constant current. An expression of L0; j0=4000 cd/m2 and L1=70% in Table 2 means that the lifetime indicated in column LT corresponds to the time after which the initial luminous density drops from 4000 cd/m2 to 2800 cd/m2. Analogously, L0; j0=20 mA/cm2, L1=80% means that the luminous density on operation at 20 mA/cm2 drops to 80% of its initial value after time LT.
The data of the various OLEDs are summarised in Table 2. Examples V1-V5 are OLEDs comparative examples in accordance with the prior art, Examples E1-E20 show data of OLEDs according to the invention.
Some of the examples are explained in greater detail below in order to illustrate the advantages of the compounds according to the invention.
Use of Mixtures According to the Invention in the Emission Layer of Phosphorescent OLEDs
On use as matrix materials in phosphorescent OLEDs, the materials according to the invention give rise to significant improvements over the prior art with respect to the lifetime of the components. Use of compounds EG1 to EG4 according to the invention in combination with the green-emitting dopant TEG1 enables an increase in the lifetime by over 200% compared with the prior art to be observed (comparison of Examples V1 with E1 and V2 with E2 as well as V3 with E3 and V4, V5 with E4).
TABLE 1
Structure of the OLEDs
HTL
IL
EBL
EML
HBL
ETL
EIL
Ex.
Thickness
Thickness
Thickness
Thickness
Thickness
Thickness
Thickness
V1
SpA1
HATCN
SpMA1
SdT1:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
V2
SpA1
HATCN
SpMA1
SdT2:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
V3
SpA1
HATCN
SpMA1
SdT3:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
V4
SpA1
HATCN
SpMA1
SdT4:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
V5
SpA1
HATCN
SpMA1
SdT5:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E1
SpA1
HATCN
SpMA1
EG1:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E2
SpA1
HATCN
SpMA1
EG2:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E3
SpA1
HATCN
SpMA1
EG3:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E4
SpA1
HATCN
SpMA1
EG4:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E5
SpA1
HATCN
SpMA1
EG5:TER1
—
ST2:LiQ
—
90 nm
5 nm
130 nm
(92%:8%)
(50%:50%)
30 nm
40 nm
E6
SpA1
HATCN
SpMA1
EG6:TER1
—
ST2:LiQ
—
90 nm
5 nm
130 nm
(92%:8%)
(50%:50%)
30 nm
40 nm
E7
SpA1
HATCN
SpMA1
EG7:TEG1
—
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
(50%:50%)
30 nm
40 nm
E8
SpA1
HATCN
SpMA1
EG8:TEG1
—
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
(50%:50%)
30 nm
40 nm
E9
SpA1
HATCN
SpMA1
EG9:IC3:TEG1
IC1
ST2:LiQ
—
70 nm
5 nm
90 nm
(45%:45%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E10
SpA1
HATCN
SpMA1
EG10:IC3:TEG1
IC1
ST2:LiQ
—
70 nm
5 nm
90 nm
(45%:45%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E11
SpA1
HATCN
SpMA1
EG11:IC3:TEG1
IC1
ST2:LiQ
—
70 nm
5 nm
90 nm
(45%:45%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E12
SpA1
HATCN
SpMA1
IC1:TEG1
—
EG8
LiQ
70 nm
5 nm
90 nm
(90%:10%)
40 nm
3 nm
30 nm
E13
SpA1
HATCN
SpMA1
IC1:TEG1
IC1
EG9:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E14
SpA1
HATCN
SpMA1
EG14:IC3:TEG1
IC1
ST2:LiQ
—
70 nm
5 nm
90 nm
(65%:25%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E15
SpA1
HATCN
SpMA1
IC1:TEG1
EG15
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E16
HATCN
SpMA1
SpMA2
EG16:L1:TEY1
—
ST1
LiQ
5 nm
70 nm
15 nm
(45%:45%:10%)
45 nm
3 nm
25 nm
E17
SpA1
HATCN
SpMA1
EG17:TEG1
ST2
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E18
SpA1
HATCN
SpMA1
EG18:IC3:TEG1
IC1
ST2:LiQ
—
70 nm
5 nm
90 nm
(45%:45%:10%)
10 nm
(50%:50%)
30 nm
30 nm
E19
HATCN
SpMA1
SpMA2
EG16:L1:TEY1
—
ST1
LiQ
5 nm
70 nm
15 nm
(45%:45%:10%)
45 nm
3 nm
25 nm
E20
SpA1
HATCN
SpMA1
IC1:TEG1
EG20
ST2:LiQ
—
70 nm
5 nm
90 nm
(90%:10%)
10 nm
(50%:50%)
30 nm
30 nm
TABLE 2
Data of the OLEDs
U1000
CE1000
PE1000
EQE
CIE x/y at
L1
LT
Ex.
(V)
(cd/A)
(lm/W)
1000
1000 cd/m2
L0; j0
%
(h)
V1
3.6
51
44
13.7%
0.33/0.63
20
mA/cm2
80
95
V2
4.2
50
37
14.3%
0.33/0.62
20
mA/cm2
80
10
V3
4.3
55
40
14.7%
0.33/0.64
20
mA/cm2
80
15
V4
3.5
48
43
12.8%
0.32/0.64
20
mA/cm2
80
190
V5
3.7
59
50
15.7%
0.33/0.64
20
mA/cm2
80
125
E1
3.5
40
36
11.6%
0.33/0.62
20
mA/cm2
80
290
E2
4.3
51
37
14.5%
0.33/0.62
20
mA/cm2
80
20
E3
4.4
55
39
15.0%
0.33/0.63
20
mA/cm2
80
35
E4
3.6
41
36
11.9%
0.32/0.63
20
mA/cm2
80
300
E5
4.4
13
9
12.4%
0.66/0.34
4000
cd/m2
80
340
E6
4.6
11
8
11.4%
0.67/0.34
4000
cd/m2
80
370
E7
3.4
59
55
15.9%
0.33/0.63
20
mA/cm2
80
115
E8
3.6
56
49
15.2%
0.33/0.62
20
mA/cm2
80
125
E9
3.4
62
57
16.5%
0.34/0.63
20
mA/cm2
80
240
E10
3.5
60
54
16.1%
0.33/0.63
20
mA/cm2
80
350
E11
3.6
57
50
15.5%
0.33/0.63
20
mA/cm2
80
290
E12
3.3
64
61
17.1%
0.33/0.63
20
mA/cm2
80
125
E13
3.7
62
53
16.5%
0.34/0.63
20
mA/cm2
80
165
E14
3.3
60
57
16.7%
0.32/0.63
20
mA/cm2
80
270
E15
3.5
59
53
16.0%
0.34/0.63
20
mA/cm2
80
145
E16
2.9
75
81
22.4%
0.44/0.55
50
mA/cm2
90
85
E17
3.4
41
37
11.7%
0.33/0.63
20
mA/cm2
80
140
E18
3.5
60
53
16.3%
0.33/0.63
20
mA/cm2
80
260
E19
2.8
77
86
23.1%
0.45/0.55
50
mA/cm2
90
100
E20
3.7
59
50
15.8%
0.33/0.63
20
mA/cm2
80
155
TABLE 3
Structural formulae of the materals for the OLEDs
HATCN
SpA1
SpMA1
LiQ
SpMA2
TER1
L1
TEY1
IC1
ST2
IC3
TEG1
SdT1
SdT2
SdT3
SdT4
SdT5
EG1
EG2
EG3
EG4
EG5
EG6
EG7
EG8
EG9
EG10
EG11
E12
EG13
EG14
EG15
EG16
EG17
EG18
EG19
EG20
|
15329099
|
merck patent gmbh
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
|
|
Apr 20th, 2022 03:01PM
|
Apr 20th, 2022 03:01PM
|
Merck
|
Health Care
|
Pharmaceuticals & Biotechnology
|