IP Library › Granted Patent US 11,939,328
Granted Patent B2
US 11,939,328 · App. 18/046,303 · Granted Mar 26, 2024

Quinoline compounds as inhibitors of KRAS

Inventors: Qinda Ye (Claymont, DE); Matthew McCammant (West Chester, PA); Artem Shvartsbart (Wilmington, DE); Wenyu Zhu (Wilmington, DE); Bin Hu (Garnet Valley, PA); Chao Qi (Wilmington, DE); Xiaozhao Wang (Mt. Laurel, NJ); Wenqing Yao (Wilmington, DE); Alexander Sokolsky (Wilmington, DE)
Assignee: Incyte Corporation
C07D471/04A61P35/00
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Quick Facts
Patent No.
US 11,939,328
App. No.
18/046,303
Granted
Mar 26, 2024
Kind
B2
Abstract

Disclosed are compounds of Formula I, methods of using the compounds for inhibiting KRAS activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with KRAS activity such as cancer.

Claims (35)

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

2. The compound of claim 1 that is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

3. The compound of claim 1 that is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

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

5. The compound of claim 4 that is methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

6. The compound of claim 4 that is a pharmaceutically acceptable salt of methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

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

8. The compound of claim 7 that is methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

9. The compound of claim 7 that is a pharmaceutically acceptable salt of methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate.

10. A compound that is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-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]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 that is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-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]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

12. The compound of claim 10 that is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-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]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

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

14. The compound of claim 13 that is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

15. The compound of claim 13 that is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

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

17. The compound of claim 16 that is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

18. The compound of claim 16 that is a pharmaceutically acceptable salt of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile.

19. A pharmaceutical composition comprising the compound of claim 1 , and at least one pharmaceutically acceptable carrier or excipient.

20. A pharmaceutical composition comprising the compound of claim 2 , and at least one pharmaceutically acceptable carrier or excipient.

21. A pharmaceutical composition comprising the compound of claim 3 , and at least one pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical composition comprising the compound of claim 4 , and at least one pharmaceutically acceptable carrier or excipient.

23. A pharmaceutical composition comprising the compound of claim 5 , and at least one pharmaceutically acceptable carrier or excipient.

24. A pharmaceutical composition comprising the compound of claim 6 , and at least one pharmaceutically acceptable carrier or excipient.

25. A pharmaceutical composition comprising the compound of claim 7 , and at least one pharmaceutically acceptable carrier or excipient.

26. A pharmaceutical composition comprising the compound of claim 8 , and at least one pharmaceutically acceptable carrier or excipient.

27. A pharmaceutical composition comprising the compound of claim 9 , and at least one pharmaceutically acceptable carrier or excipient.

28. A pharmaceutical composition comprising the compound of claim 10 , and at least one pharmaceutically acceptable carrier or excipient.

29. A pharmaceutical composition comprising the compound of claim 11 , and at least one pharmaceutically acceptable carrier or excipient.

30. A pharmaceutical composition comprising the compound of claim 12 , and at least one pharmaceutically acceptable carrier or excipient.

31. A pharmaceutical composition comprising the compound of claim 13 , and at least one pharmaceutically acceptable carrier or excipient.

32. A pharmaceutical composition comprising the compound of claim 14 , and at least one pharmaceutically acceptable carrier or excipient.

33. A pharmaceutical composition comprising the compound of claim 15 , and at least one pharmaceutically acceptable carrier or excipient.

34. A pharmaceutical composition comprising the compound of claim 16 , and at least one pharmaceutically acceptable carrier or excipient.

35. A pharmaceutical composition comprising the compound of claim 17 , and at least one pharmaceutically acceptable carrier or excipient.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2023
From: YE, QINDA; MCCAMMANT, MATTHEW; POLICARPO, ROCCO; SHVARTSBART, ARTEM; ZHU, WENYU; ROACH, JEREMY; HOANG, GIA; HU, BIN; LI, GENCHENG; SUSICK, ROBERT; POLAM, PADMAJA; ZHANG, FENGLEI; QI, CHAO; WANG, XIAOZHAO; YAO, WENQING; SOKOLSKY, ALEXANDER; YIN, HAOLIN; ZHAO, LE; CARLSEN, PETER
To: INCYTE CORPORATION
Reel/Frame 062490/0182 →
Continuity (5)
Provisional Application 63368563 · Jul 15, 2022
Provisional Application 63363270 · Apr 20, 2022
Provisional Application 63279464 · Nov 15, 2021
Provisional Application 63255610 · Oct 14, 2021
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