Granted Patent B2

US 12,448,399 · App. 18/424,488 · Granted Oct 21, 2025

Inventors: Jesus Raul Medina (Gilbertsville, PA); Hanqing Dong (Madison, CT)

Assignee: ARVINAS OPERATIONS, INC.

C07D519/00A61K31/519A61K31/55A61P35/00

Abstract

Claims (104)

1. A compound of Formula IVB:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 and R 2 are each independently selected from H, halo, C 1-6 alkyl, and C 2-6 alkynyl;

R 3 is selected from H, halo, and CN;

each Q L is independently CR L or N;

each R L is independently H, halo, or CN;

each p is 1, 2, 3, 4, 5, or 6; and

R 12 and R 13 are each independently selected from H, C 1-6 alkyl, and C 1-6 alkoxy.

2. The compound of claim 1 , each R L is independently H or halo.

3. The compound of claim 1 , wherein each Q L is independently CH or N.

4. The compound of claim 1 , wherein R 3 is halo.

5. The compound of claim 1 , wherein each p is 1, 2, 3, or 4.

6. The compound of claim 1 , wherein each p is 1, 2, or 3.

7. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

11. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 1 , wherein the cancer is characterized by a KRAS G12D mutation.

12. The method of claim 11 , wherein the cancer is selected from bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell tumor, carcinoma, cytoma, ependymoma, ganglioglioma, ganglioneuroma, gliobastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma peripheral neuroepithelioma, sarcoma, and schwannoma.

13. The method of claim 12 , wherein the leukemia is acute lymphoblastic leukemia.

14. A compound of Formula IB-i:

or a pharmaceutically acceptable salt thereof,

wherein:

Q 1 is selected from C(R 14 ) 2 , C(O), and NR 14 ;

R 1 is halo;

R 2 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, and C 1-6 haloalkyl;

R 5a and R 14 are each independently selected from H, halo, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;

each Q L is independently CR L or N;

each R L is independently H, halo, or CN; and

each p is independently 1, 2, 3, 4, 5, or 6.

15. The compound of claim 14 , wherein R 2 is selected from H, C 1-6 alkyl, and C≡CH.

16. The compound of claim 14 , wherein R 5a is selected from H, halo, and C 1-6 alkoxy.

17. The compound of claim 14 , wherein R 14 is H or C 1-6 alkyl.

18. The compound of claim 14 , wherein Q 1 is CH 2 or C(O).

19. The compound of claim 14 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 14 wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 14 wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.

23. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 14 wherein the cancer is characterized by a KRAS G12D mutation.

24. The method of claim 23 , wherein the cancer is selected from bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pineal cell tumor, carcinoma, cytoma, ependymoma, ganglioglioma, ganglioneuroma, gliobastoma, glioma, leukemia, lymphoma, medulloblastoma, melanoma, meningioma, myeloma, nephroblastoma, neuroblastoma, neurofibroma, oligodendroglioma peripheral neuroepithelioma, sarcoma, and schwannoma.

25. The method of claim 24 , wherein the leukemia is acute lymphoblastic leukemia.

26. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 14 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

28. A compound that is:

or a pharmaceutically acceptable salt thereof.

29. A compound that is:

or a pharmaceutically acceptable salt thereof.

30. A compound that is:

or a pharmaceutically acceptable salt thereof.

31. A compound that is:

or a pharmaceutically acceptable salt thereof.

32. A compound that is:

or a pharmaceutically acceptable salt thereof.

33. A compound that is:

or a pharmaceutically acceptable salt thereof.

34. A compound that is:

or a pharmaceutically acceptable salt thereof.

35. A compound that is:

or a pharmaceutically acceptable salt thereof.

36. A compound that is:

or a pharmaceutically acceptable salt thereof.

37. A compound that is:

or a pharmaceutically acceptable salt thereof.

38. A compound that is:

or a pharmaceutically acceptable salt thereof.

39. A compound that is:

or a pharmaceutically acceptable salt thereof.

40. A compound that is:

or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition comprising a compound of claim 28 , and a pharmaceutically acceptable carrier.

42. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 28 , wherein the cancer is characterized by a KRAS G12D mutation.

43. A pharmaceutical composition comprising a compound of claim 29 , and a pharmaceutically acceptable carrier.

44. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 29 , wherein the cancer is characterized by a KRAS G12D mutation.

45. A pharmaceutical composition comprising a compound of claim 30 , and a pharmaceutically acceptable carrier.

46. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 30 , wherein the cancer is characterized by a KRAS G12D mutation.

47. A pharmaceutical composition comprising a compound of claim 31 , and a pharmaceutically acceptable carrier.

48. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 31 , wherein the cancer is characterized by a KRAS G12D mutation.

49. A pharmaceutical composition comprising a compound of claim 32 , and a pharmaceutically acceptable carrier.

50. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 32 , wherein the cancer is characterized by a KRAS G12D mutation.

51. A pharmaceutical composition comprising a compound of claim 33 , and a pharmaceutically acceptable carrier.

52. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 33 , wherein the cancer is characterized by a KRAS G12D mutation.

53. A pharmaceutical composition comprising a compound of claim 34 , and a pharmaceutically acceptable carrier.

54. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 34 , wherein the cancer is characterized by a KRAS G12D mutation.

55. A pharmaceutical composition comprising a compound of claim 35 , and a pharmaceutically acceptable carrier.

56. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 35 , wherein the cancer is characterized by a KRAS G12D mutation.

57. A pharmaceutical composition comprising a compound of claim 36 , and a pharmaceutically acceptable carrier.

58. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 36 , wherein the cancer is characterized by a KRAS G12D mutation.

59. A pharmaceutical composition comprising a compound of claim 37 , and a pharmaceutically acceptable carrier.

60. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 37 , wherein the cancer is characterized by a KRAS G12D mutation.

61. A pharmaceutical composition comprising a compound of claim 38 , and a pharmaceutically acceptable carrier.

62. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 38 , wherein the cancer is characterized by a KRAS G12D mutation.

63. A pharmaceutical composition comprising a compound of claim 39 , and a pharmaceutically acceptable carrier.

64. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 39 , wherein the cancer is characterized by a KRAS G12D mutation.

65. A pharmaceutical composition comprising a compound of claim 40 , and a pharmaceutically acceptable carrier.

66. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound according to claim 40 , wherein the cancer is characterized by a KRAS G12D mutation.

Assignments (2)

Continuity (4)

References Cited (400)