INHIBITORS OF KRAS G12C AND METHODS OF USING THE SAME

• US 20190077801A1
• Filed: 09/07/2018
• Published: 03/14/2019
• 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.
• Granted Patent: US 10,640,504 B2
• Time in Patent Office: 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.

72. A method of inhibiting KRAS G12C in a cell, comprising contacting the cell with the compound of claim 43 or the pharmaceutically acceptable salt thereof.

73. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 43 or the pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

75. The method of claim 73 or the pharmaceutically acceptable salt thereof, further comprising administering to the subject a therapeutically effective amount of an additional pharmaceutically active compound.

76. The method of claim 75, wherein the additional pharmaceutically active compound is carfilzomib.

77. The method of claim 76, wherein the additional pharmaceutically active compound is cytarabine.

78. A use of the compound of claim 43 or the pharmaceutically acceptable salt thereof for treating cancer in a subject.

79. The compound of claim 78, wherein the cancer is a hematologic malignancy.

80. The compound of claim 43 or the pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

81. The compound of claim 80, wherein the cancer is a hematologic malignancy.

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