Quinoline compounds as KRAS inhibitors

Abstract

Disclosed are compounds of formula I, methods of using the compounds to inhibit KRAS activity, and pharmaceutical compositions comprising such compounds, which are useful for treating, preventing, or ameliorating diseases or disorders associated with KRAS activity, such as cancer.

Claims

1. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

3. A pharmaceutically acceptable salt of the compound according to claim 1, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

4. A compound which is methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, wherein the compound is methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

6. A pharmaceutically acceptable salt of the compound according to claim 4, which is a pharmaceutically acceptable salt of methyl(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

7. A compound which is methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein the compound is methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

9. A pharmaceutically acceptable salt of the compound according to claim 7, which is a pharmaceutically acceptable salt of methyl(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridine-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinoline-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

10. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

12. A pharmaceutically acceptable salt of the compound according to claim 10, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

13. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

15. A pharmaceutically acceptable salt of the compound according to claim 13, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

16. A compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, wherein the compound is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

18. A pharmaceutically acceptable salt of the compound according to claim 16, which is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propanenitrile.

19. A pharmaceutical composition comprising the compound described in Claim 1 or a pharmaceutically acceptable salt thereof, the compound described in Claim 2 or a pharmaceutically acceptable salt of the compound described in Claim 3, and at least one pharmaceutically acceptable carrier or excipient.

20. A pharmaceutical composition comprising the compound described in claim 4 or a pharmaceutically acceptable salt thereof, the compound described in claim 5 or a pharmaceutically acceptable salt of the compound described in claim 6, and at least one pharmaceutically acceptable carrier or excipient.

21. A pharmaceutical composition comprising the compound according to claim 7 or a pharmaceutically acceptable salt thereof, the compound according to claim 8 or a pharmaceutically acceptable salt of the compound according to claim 9, and at least one pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical composition comprising the compound according to claim 10 or a pharmaceutically acceptable salt thereof, the compound according to claim 11 or a pharmaceutically acceptable salt of the compound according to claim 12, and at least one pharmaceutically acceptable carrier or excipient.

23. A pharmaceutical composition comprising the compound according to claim 13 or a pharmaceutically acceptable salt thereof, the compound according to claim 14 or a pharmaceutically acceptable salt of the compound according to claim 15, and at least one pharmaceutically acceptable carrier or excipient.

24. A pharmaceutical composition comprising the compound according to claim 16 or a pharmaceutically acceptable salt thereof, the compound according to claim 17 or a pharmaceutically acceptable salt of the compound according to claim 18, and at least one pharmaceutically acceptable carrier or excipient.

25. A pharmaceutical agent for treating a disease or disorder related to the activity of KRAS, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, a compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of a compound according to any one of claims 3, 6, 9, 12, 15, and 18.

26. A pharmaceutical agent for treating a disease or disorder related to the activity of a G12D mutation in the KRAS protein, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, the compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of the compound according to any one of claims 3, 6, 9, 12, 15, and 18.

27. ​​The pharmaceutical product according to claim 26, wherein the disease or disorder is an immunological or inflammatory disorder.

28. The pharmaceutical product according to claim 27, wherein the immunological or inflammatory disorder is Ras-associated lymphoproliferative disorder or juvenile myelomonocytic leukemia caused by a somatic mutation of KRAS.

29. A pharmaceutical agent for treating cancer in a patient, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4, 7, 10, 13, and 16, a compound according to any one of claims 2, 5, 8, 11, 14, and 17, or a pharmaceutically acceptable salt of a compound according to any one of claims 3, 6, 9, 12, 15, and 18.

30. The pharmaceutical product according to claim 29, wherein the cancer is selected from carcinoma, hematological carcinoma, sarcoma, and glioblastoma.

31. The pharmaceutical product according to claim 29, wherein the cancer is a hematological cancer selected from myeloproliferative neoplasm, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma.

32. The pharmaceutical product according to claim 29, wherein the cancer is a carcinoma selected from carcinomas of the pancreas, colon, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid.

33. The pharmaceutical product according to claim 29, wherein the cancer is characterized by a KRAS protein having a G12D mutation.

34. The pharmaceutical product according to claim 29, wherein the cancer is pancreatic cancer.

35. The pharmaceutical product according to claim 29, wherein the cancer is pancreatic ductal adenocarcinoma.

36. The pharmaceutical product according to claim 29, wherein the cancer is colorectal cancer.

37. The pharmaceutical product according to claim 29, wherein the cancer is a type of colorectal cancer.

38. The pharmaceutical product according to claim 29, wherein the cancer is lung cancer.

39. The pharmaceutical product according to claim 29, wherein the cancer is non-small cell lung cancer.

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