Inhibitors of KRAS G12C and methods of using the same

Patent metadata

Field	Value
Publication number	US-10640504-B2
Application number	US-201816125359-A
Country	US
Kind code	B2
Filing date	Sep 7, 2018
Priority date	Sep 8, 2017
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.

First claim

What is claimed:

1. A compound having a structure of formula (I)

wherein
A is independently N or CH;
W is independently N or CH;
wherein one or both of A and W is N;
R 1 and R 2 are independently a branched or a linear C 1-6 alkyl;
R 3 is phenyl substituted by 1 or 2 R 5 substituents;
R 5 is independently selected from one or more halo, —OH, or NH 2 ;
R 4 is halo; or
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

2. The compound of claim 1 having a structure of formula (Ia)

or
a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein A is N.

4. The compound of claim 1 wherein A is CH.

5. The compound of claim 1 wherein W is N.

6. The compound of claim 1 wherein W is CH.

7. The compound of claim 1 wherein R 1 is CH 3 .

8. The compound of claim 1 wherein R 1 is CH(CH 3 ) 2 .

9. The compound of claim 1 wherein R 2 is CH 3 .

10. The compound of claim 1 wherein R 2 is CH(CH 3 ) 2 .

11. The compound of claim 1 wherein R 5 is halo.

12. The compound of claim 11 wherein R 5 is F.

13. The compound of claim 1 wherein R 5 is —OH.

14. The compound of claim 1 wherein R 5 is —NH 2 .

15. The compound of claim 1 wherein R 3 is

16. The compound of claim 15 wherein R 3 is

17. The compound of claim 15 wherein R 3 is

18. The compound of claim 15 wherein R 3 is

19. The compound of claim 1 wherein R 4 is halo.

20. The compound of claim 19 wherein R 4 is Cl.

21. The compound of claim 19 wherein R 4 is F.

22. A compound having a structure of formula (II)

wherein
A is independently N or CH;
W is independently N or CH;
wherein one or both A and W is N;
R 1 and R 2 are independently a branched or a linear C 1-6 alkyl;
R 3 is phenyl substituted by one or two R 5 substituents;
R 5 is independently selected from one or more halo, —OH, or NH 2 ; and
R 4 is halo; or
or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

23. The compound of claim 22 having a structure of formula (IIa)

or
a stereoisomer thereof; a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof.

24. The compound of claim 22 wherein A is N.

25. The compound of claim 22 wherein A is CH.

26. The compound of claim 22 wherein W is N.

27. The compound of claim 22 wherein W is CH.

28. The compound of claim 22 wherein R 1 is CH 3 .

29. The compound of claim 22 wherein R 1 is CH(CH 3 ) 2 .

30. The compound of claim 22 wherein R 2 is CH 3 .

31. The compound of claim 22 wherein R 2 is CH(CH 3 ) 2 .

32. The compound of claim 22 wherein R 5 is halo.

33. The compound of claim 32 wherein R 5 is F.

34. The compound of claim 22 wherein R 5 is —OH.

35. The compound of claim 22 wherein R 5 is —NH 2 .

36. The compound of claim 22 wherein R 3 is

37. The compound of claim 36 wherein R 3 is

38. The compound of claim 36 wherein R 3 is

39. The compound of claim 36 wherein R 3 is

40. The compound of claim 22 wherein R 4 is halo.

41. The compound of claim 22 wherein R 4 is Cl.

42. The compound of claim 22 wherein R 4 is F.

43. A compound having a structure selected from:

or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

44. A compound having a structure selected from:

or a pharmaceutically acceptable salt.

45. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

46. A pharmaceutical composition comprising the compound of claim 22 and a pharmaceutically acceptable excipient.

47. The compound of claim 44 having a structure

or the pharmaceutically acceptable salt thereof.

48. The compound of claim 44 having a structure

or the pharmaceutically acceptable salt thereof.

49. The compound of claim 44 having a structure

Assignees

• Amgen Inc

Inventors

• Lanman Brian Alan
• Booker Shon
• Goodman Clifford
• Reed Anthony B
• Low Jonathan D
• Wang Hui-Ling
• Chen Ning
• Minatti Ana Elena
• Wurz Ryan
• Cee Victor J

Classifications

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K38/07

  Tetrapeptides · CPC title