Heteroaryl-biphenylamines for the treatment of PD-L1 diseases

Abstract

Compounds useful as immunomodulators are provided. These compounds have the formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, where R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 and n is as defined herein. Methods for the preparation and use of such compounds, as well as pharmaceutical compositions containing such compounds, are also disclosed. TIFF2022551972000129.tif40155

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug or bioequivalent thereof: (In the formula: A is unsubstituted or halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 a 5- to 10-membered heteroaryl group substituted with 1-5 members independently selected from the group consisting of haloalkoxy, OH, and CN; X 1 is unsubstituted or C 1-2 Alkyl and CO 2 C substituted by 1 or 2 members independently selected from the group consisting of H 1-3 alkylene; R 2a and R 2b is H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -CO 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -C(O)NR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 NR a R b , -X 2 -SO 3 R a and -X 2 -Y, wherein each X 2 is C 1-6 alkylene, and any C 1-8 Alkyl or C 1-6 Alkylene is unsubstituted or substituted with OH, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl and CO 2 and each Y is substituted with 1 or 2 members independently selected from the group consisting of C 3-6 Cycloalkyl, C 4-8 and 5- to 6-membered heteroaryl, each of which is unsubstituted or selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , -C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl, SO 3 H and CO 2 or substituted with 1 to 4 substituents independently selected from the group consisting of H; Or, R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring having 0-2 additional heteroatom ring vertices selected from O, N, and S; Here, R 2a and R 2b The ring formed by the combination of 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -CO 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -C(O)NR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 NR a R b , and −X 3 -SO 3 R a and wherein X is substituted with 1 to 4 substituents independently selected from the group consisting of 3 is a bond or C 1-6 alkylene; R 3 and R 4 are H, F, Cl, CN, CH 3 , OCH 3 , C.H. 2 CH 3 and CF 3 each independently selected from the group consisting of: The subscript n is 0, 1, 2, or 3; Each R 3a are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 2-3 independently selected from the group consisting of alkenyl and CN; R 6 , R 7 and R 8 are H, F, Cl, CN, CH 3 , OCH 3 , C.H. 2 CH 3 and CF 3 each independently selected from the group consisting of: Z is unsubstituted or is 1 to 3 R c a fused bicyclic heteroaryl ring substituted with Each R a is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H; Each R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is unsubstituted or selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl and CO 2 substituted by 1 or 2 members independently selected from H; And R a and R b when attached to the same nitrogen atom, may be optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which may be unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl or -CO 2 is substituted by H; Each R c is H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1 , -X 4 -CO 2 R a , -O-X 4 -CO 2 R a , -X 4 -OR a , -X 4 -NR a R b , -X 4 -C(O)NR a R b , -O-X 4 -C(O)NR a R b , -X 4 -SO 2 R a , -X 4 -SO 2 NR a R b , -X 4 -SO 3 R a , and −N(R a )-X 4 -CO 2 R a wherein each X is independently selected from the group consisting of 4 is a bond or C 1-6 alkylene, and each Y 1 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices c are combined to form a fused 5- or 6-membered heterocycle).

2. Compounds of formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt, prodrug or bioequivalent thereof: (In the formula: A is unsubstituted or halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 a 5- to 10-membered heteroaryl group substituted with 1 to 5 members independently selected from the group consisting of haloalkoxy and CN; X 1 is unsubstituted or C 1-2 Alkyl and CO 2 C substituted by 1 or 2 members independently selected from the group consisting of H 1-3 alkylene; R 2a and R 2b is H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -CO 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -C(O)NR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 NR a R b , -X 2 -SO 3 R a and -X 2 -Y, wherein each X 2 is C 1-6 alkylene, and any C 1-8 Alkyl or C 1-6 Alkylene is unsubstituted or substituted with OH, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl and CO 2 and each Y is substituted with one or two members independently selected from the group consisting of C 3-6 Cycloalkyl, C 4-8 and 5- to 6-membered heteroaryl, each of which is unsubstituted or selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl, SO 3 H and CO 2 or substituted with 1 to 4 substituents independently selected from the group consisting of H; Or, R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring having 0-2 additional heteroatom ring vertices selected from O, N, and S; Here, R 2a and R 2b The ring formed by the combination of 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -CO 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -C(O)NR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 NR a R b , and −X 3 -SO 3 R a and wherein X is substituted with 1 to 4 substituents independently selected from the group consisting of 3 is a bond or C 1-6 alkylene; R 3 and R 4 are F, Cl, CN, CH 3 , OCH 3 , C.H. 2 CH 3 and CF 3 each independently selected from the group consisting of: The subscript n is 0, 1, 2, or 3; Each R 3a are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 2-3 independently selected from the group consisting of alkenyl and CN; R 6 , R 7 and R 8 are H, F, Cl, CN, CH 3 , OCH 3 , C.H. 2 CH 3 and CF 3 each independently selected from the group consisting of: Z is unsubstituted or is 1 to 3 R c a fused bicyclic heteroaryl ring substituted with Each R a is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H; Each R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is unsubstituted or selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl and CO 2 substituted by 1 or 2 members independently selected from H; And R a and R b when attached to the same nitrogen atom, may be optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which may be unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl or -CO 2 is substituted by H; Each R c is H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1 , -X 4 -CO 2 R a , -O-X 4 -CO 2 R a , -X 4 -OR a , -X 4 -NR a R b , -X 4 -C(O)NR a R b , -O-X 4 -C(O)NR a R b , -X 4 -SO 2 R a , -X 4 -SO 2 NR a R b , -X 4 -SO 3 R a , and −N(R a )-X 4 -CO 2 R a wherein each X is independently selected from the group consisting of 4 is a bond or C 1-6 alkylene, and each Y 1 is C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices c are combined to form a fused 5- or 6-membered heterocycle).

3. 3. The compound of claim 1 or 2 having the formula (Ia), or a pharmaceutically acceptable salt thereof: 【Transformation 3】

4. The A is unsubstituted or halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a 5- or 6-membered heteroaryl group substituted with 1 to 3 members independently selected from the group consisting of alkoxy, OH, and CN.

5. The A is unsubstituted or halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a 6-membered heteroaryl group substituted with 1 to 3 members independently selected from the group consisting of alkoxy, OH, and CN.

6. 3. The compound of claim 1 or 2 having the formula (Ib), or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

7. The A is unsubstituted or CF 3 , OH, Et, CN, OCH 3 and F, or a pharmaceutically acceptable salt thereof.

8. A is a 6-membered heteroaryl group selected from the group consisting of pyridine, pyrimidine, pyrazine, and 1,2,4-triazine, each of which is unsubstituted or selected from the group consisting of CF 3 , OH, Et, CN, OCH 3 and F, or a pharmaceutically acceptable salt thereof.

9. 7. The compound of any one of claims 1 to 6, wherein Z is a fused bicyclic heteroaryl ring having a formula selected from the group consisting of: 【Transformation 5】

10. The -N(R 2a ) (R 2b 10. The compound of claim 1, wherein R is selected from the group consisting of: 【Transformation 6】

11. The -N(R 2a ) (R 2b 10. The compound of claim 1, wherein R is selected from the group consisting of: 【Transformation 7】

12. The -N(R 2a ) (R 2b 10. The compound of claim 1, wherein R is selected from the group consisting of: 【Transformation 8】

13. The Y is C 3-6 Cycloalkyl and C 4-8 heterocyclyl, each of which is unsubstituted or selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 ,C(O)NHOH,PO 3 H 2 , CO 2 C 1-8 Alkyl, SO 3 H and CO 2 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, substituted with 1 to 4 substituents independently selected from the group consisting of H.

14. A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl, each of which is unsubstituted or selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with one or two members independently selected from the group consisting of haloalkoxy, OH, and CN.

15. 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.

16. 2. The compound of claim 1, wherein the compound is selected from the compounds of Table 1.

17. 2. The compound of claim 1, selected from the group consisting of: 【Chemistry 9】

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. 20. The pharmaceutical composition of claim 18, further comprising one or more additional therapeutic agents.

20. 20. The pharmaceutical composition of claim 19, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anti-cancer agents, angiogenesis inhibitors, immunotherapeutic agents, anti-hormonal agents, anti-fibrotic agents, radiation therapy, radiation therapy agents, anti-neoplastic agents, and anti-proliferative agents.

21. A method for modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 18 to 20.

22. 21. A method of enhancing, stimulating, modulating and / or augmenting an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 18 to 20.

23. A method for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 18 to 20.

24. A method for treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 18 to 20.

25. 25. The method of any one of claims 21 to 24, wherein the subject is suffering from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infection, a viral infection, a fungal infection, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.

26. The disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovoma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, Sarcoma, sepsis, bile duct tumor, basal cell carcinoma, thymic neoplasm, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, tonsils Squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, head and neck cancer, gastrointestinal tract, cancer of the stomach, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, cancer of the endocrine system, urethral cancer, penile cancer, bladder cancer, kidney 25. The method of claim 24, wherein the tumor is selected from the group consisting of carcinoma, ureteral carcinoma, renal pelvic carcinoma, neoplasms of the central nervous system (CNS), angiogenic tumors, tumors of the spinal axis, brainstem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchial carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

27. 27. The method of any one of claims 21 to 26, further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.

28. 28. The method of claim 27, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anti-cancer agents, anti-angiogenesis inhibitors, immunotherapeutic agents, anti-hormonal agents, anti-fibrotic agents, radiation therapy, radiation therapy agents, anti-neoplastic agents, and anti-proliferative agents.

29. A process for preparing a compound of formula (II): 【Chemistry 10】 This process: (a) converting a compound having formula (2e1) to a compound having formula (2f1) with a borate reagent and a first catalyst: 【Chemistry 11】 (b) contacting a compound having formula (2f1) with a compound having formula (2g1) and a second catalyst under Suzuki conditions to produce a compound having formula (2h1); 【Chemistry 12】 (c) reacting a compound having formula (2h1) with HN(R 2a ) (R 2b ) and a hydride reagent to provide a compound having formula (II): 【Chemistry 13】 wherein in the above formulae (2e1), (2f1), (2g), (2h1), and (II), Z, R 2a , R 2b , R 3 , R 3a , subscript n, R 4 , R 5 , R 6 , R 7 , R 8 each having the meaning provided in claim 1; Each R' is H and C 1 -C 6 independently selected from the group consisting of alkyl; X is a member selected from the group consisting of Br and Cl; X' is a member selected from the group consisting of I, Br, and Cl; R s is a 6-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R s is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 are 0, 1, 2 or 3 substituents independently selected from the group consisting of haloalkoxy, OH, and CN.

30. A process for preparing a compound of formula (II): 【Chemistry 14】 This process: (a) contacting a compound having formula (2e1) with a compound having formula (2g'1) and a catalyst under Suzuki conditions to produce a compound having formula (2h1): 【Chemistry 15】 (b) reacting a compound having formula (2h1) with HN(R 2a ) (R 2b ) and a hydride reagent to provide a compound having formula (II): 【Chemistry 16】 wherein in the above formulae (2e1), (2g'1), (2h1), and (II), Z, R 2a , R 2b , R 3 , R 3a , subscript n, R 4 , R 5 , R 6 , R 7 , R 8 each having the meaning provided in claim 1; Each R' is H and C 1 -C 6 independently selected from the group consisting of alkyl; X is a member selected from the group consisting of I, Br, and Cl; R s is a 6-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R s is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 are 0, 1, 2 or 3 substituents independently selected from the group consisting of haloalkoxy, OH, and CN.

31. A process for preparing a compound of formula (II): 【Chemistry 17】 This process: (a) contacting a compound having formula (2j1) with a compound having formula (2k1) and a first catalyst under Suzuki conditions to produce a compound having formula (2h1): [Chemistry 18] (b) reacting a compound having formula (2h1) with HN(R 2a ) (R 2b ) and a hydride reagent to provide a compound having formula (II): 【Chemistry 19】 wherein in the above formulae (2j1), (2k1), (2h1), and (II), Z, R 2a , R 2b , R 3 , R 3a , subscript n, R 4 , R 5 , R 6 , R 7 , R 8 each having the meaning provided in claim 1; Each R and R' is H and C 1 -C 6 independently selected from the group consisting of alkyl; X is a member selected from the group consisting of I, Br, and Cl; R s is a 6-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R s is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 are 0, 1, 2 or 3 substituents independently selected from the group consisting of haloalkoxy, OH, and CN.

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