Inhibitors of KRAS G12C and methods of using the same

• US 10,640,504 B2
• Filed: 09/07/2018
• Issued: 05/05/2020
• Est. Priority Date: 09/08/2017
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: 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.
• Primary Examiner(s): Jarrell, Noble E
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US16/125,359
• Publication Number:
  US 20190077801A1
• Time in Patent Office: 606 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

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.

Claims

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

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

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 R¹ is CH₃.

8. The compound of claim 1 wherein R¹ is CH(CH₃)₂.

9. The compound of claim 1 wherein R² is CH₃.

10. The compound of claim 1 wherein R² is CH(CH₃)₂.

11. The compound of claim 1 wherein R⁵ is halo.

12. The compound of claim 11 wherein R⁵ is F.

13. The compound of claim 1 wherein R⁵ is —

OH.

14. The compound of claim 1 wherein R⁵ is —

NH₂.

15. The compound of claim 1 wherein R³ is

16. The compound of claim 15 wherein R³ is

17. The compound of claim 15 wherein R³ is

18. The compound of claim 15 wherein R³ is

19. The compound of claim 1 wherein R⁴ is halo.

20. The compound of claim 19 wherein R⁴ is Cl.

21. The compound of claim 19 wherein R⁴ is F.

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

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

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

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 R¹ is CH₃.

29. The compound of claim 22 wherein R¹ is CH(CH₃)₂.

30. The compound of claim 22 wherein R² is CH₃.

31. The compound of claim 22 wherein R² is CH(CH₃)₂.

32. The compound of claim 22 wherein R⁵ is halo.

33. The compound of claim 32 wherein R⁵ is F.

34. The compound of claim 22 wherein R⁵ is —

OH.

35. The compound of claim 22 wherein R⁵ is —

NH₂.

36. The compound of claim 22 wherein R³ is

37. The compound of claim 36 wherein R³ is

38. The compound of claim 36 wherein R³ is

39. The compound of claim 36 wherein R³ is

40. The compound of claim 22 wherein R⁴ is halo.

41. The compound of claim 22 wherein R⁴ is Cl.

42. The compound of claim 22 wherein R⁴ is F.

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

43. A compound having a structure selected from:

71. A pharmaceutical composition comprising the compound of claim 43 and a pharmaceutically acceptable excipient.

44. A compound having a structure selected from:

47. The compound of claim 44 having a structure

48. The compound of claim 44 having a structure

49. The compound of claim 44 having a structure

50. The compound of claim 44 having a structure

51. The compound of claim 44 having a structure

52. The compound of claim 44 having a structure

53. The compound of claim 44 having a structure

54. The compound of claim 44 having a structure

55. The compound of claim 44 having a structure

56. The compound of claim 44 having a structure

57. The compound of claim 44 having a structure

58. The compound of claim 44 having a structure

59. The compound of claim 44 having a structure

60. The compound of claim 44 having a structure

61. The compound of claim 44 having a structure

62. The compound of claim 44 having a structure

63. The compound of claim 44 having a structure

64. The compound of claim 44 having a structure

65. The compound of claim 44 having a structure

66. The compound of claim 44 having a structure

67. The compound of claim 44 having a structure

68. The compound of claim 44 having a structure

69. The compound of claim 44 having a structure

70. The compound of claim 44 having a structure