Heterocyclic compounds as immunomodulators
Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.
1. A method of treating cancer, wherein the cancer is selected from the group consisting of lung cancer, hepatic cancer, melanoma, cancer of the bladder, cancer of the urethra, and renal cancer; said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from:
4,4′-(((((2-chloro-2′-methyl-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid);
4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid);
4-((2-((3′-(5-(2-(4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dichloro-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; and
4,4′-(((((2-chloro-2′-cyano-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid);
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound is 4,4′-(((((2-chloro-2′-methyl-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein the cancer is lung cancer.
4. The method of claim 3 , wherein the lung cancer is small cell lung cancer.
5. The method of claim 3 , wherein the lung cancer is non-small cell lung cancer.
6. The method of claim 2 , wherein the cancer is hepatic cancer.
7. The method of claim 6 , wherein the hepatic cancer is hepatocellular carcinoma.
8. The method of claim 2 , wherein the cancer is melanoma.
9. The method of claim 2 , wherein the cancer is cancer of the bladder.
10. The method of claim 2 , wherein the cancer is cancer of the urethra.
11. The method of claim 2 , wherein the cancer is renal cancer.
12. The method of claim 11 , wherein the renal cancer is renal cell carcinoma.
13. The method of claim 1 , wherein the compound is 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the cancer is lung cancer.
15. The method of claim 14 , wherein the lung cancer is small cell lung cancer.
16. The method of claim 14 , wherein the lung cancer is non-small cell lung cancer.
17. The method of claim 13 , wherein the cancer is hepatic cancer.
18. The method of claim 17 , wherein the hepatic cancer is hepatocellular carcinoma.
19. The method of claim 13 , wherein the cancer is melanoma.
20. The method of claim 13 , wherein the cancer is cancer of the bladder.
21. The method of claim 13 , wherein the cancer is cancer of the urethra.
22. The method of claim 13 , wherein the cancer is renal cancer.
23. The method of claim 22 , wherein the renal cancer is renal cell carcinoma.
24. The method of claim 1 , wherein the compound is 4-((2-((3′-(5-(2-(4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dichloro-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.
25. The method of claim 24 , wherein the cancer is lung cancer.
26. The method of claim 25 , wherein the lung cancer is small cell lung cancer.
27. The method of claim 25 , wherein the lung cancer is non-small cell lung cancer.
28. The method of claim 24 , wherein the cancer is hepatic cancer.
29. The method of claim 28 , wherein the hepatic cancer is hepatocellular carcinoma.
30. The method of claim 24 , wherein the cancer is melanoma.
31. The method of claim 24 , wherein the cancer is cancer of the bladder.
32. The method of claim 24 , wherein the cancer is cancer of the urethra.
33. The method of claim 24 , wherein the cancer is renal cancer.
34. The method of claim 33 , wherein the renal cancer is renal cell carcinoma.
35. The method of claim 1 , wherein the compound is 4,4′-(((((2-chloro-2′-cyano-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof.
36. The method of claim 35 , wherein the cancer is lung cancer.
37. The method of claim 36 , wherein the lung cancer is small cell lung cancer.
38. The method of claim 36 , wherein the lung cancer is non-small cell lung cancer.
39. The method of claim 35 , wherein the cancer is hepatic cancer.
40. The method of claim 39 , wherein the hepatic cancer is hepatocellular carcinoma.
41. The method of claim 35 , wherein the cancer is melanoma.
42. The method of claim 35 , wherein the cancer is cancer of the bladder.
43. The method of claim 35 , wherein the cancer is cancer of the urethra.
44. The method of claim 35 , wherein the cancer is renal cancer.
45. The method of claim 44 , wherein the renal cancer is renal cell carcinoma.
46. A method of treating a tumor expressing PD-L1, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from
4,4′-(((((2-chloro-2′-methyl-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid);
4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid);
4-((2-((3′-(5-(2-(4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dichloro-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid; and
4,4′-(((((2-chloro-2′-cyano-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid);
or a pharmaceutically acceptable salt thereof.
47. The method of claim 46 , wherein the compound is 4,4-((((2-chloro-2′-methyl-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof.
48. The method of claim 46 , wherein the compound is 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof.
49. The method of claim 46 , wherein the compound is 4-((2-((3′-(5-(2-(4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2′-dichloro-[1,1′-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.
50. The method of claim 46 , wherein the compound is 4,4′-(((((2-chloro-2′-cyano-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), or a pharmaceutically acceptable salt thereof.