Compounds that inhibit Mcl-1 protein

• US 10,500,213 B2
• Filed: 03/11/2019
• Issued: 12/10/2019
• Est. Priority Date: 03/30/2017
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Brown, Sean P., Li, Kexue, Li, Yunxiao, Stec, Markian M.
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US16/297,904
• Publication Number:
  US 20190201412A1
• Time in Patent Office: 274 Days
• Field of Search: 51421109
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 498/08 Bridged systems

Abstract

Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula I,

or a stereoisomer thereof; and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein may be used, for example, in the treatment of diseases or conditions, such as cancer.

Claims

1. A method of treating cancer, the method comprising:

administering to a patient in need thereof, a therapeutically effective amount of a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein the cancer is a hematologic malignancy and further wherein the compound is selected from;

2. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the patient.

4. The method of claim 1, wherein the cancer is multiple myeloma.

5. The method of claim 1, wherein the cancer is acute myelogenous leukemia.

6. The method of claim 1, wherein the cancer is non-Hodgkin'"'"'s lymphoma.

7. The method of claim 1, further comprising administering to the patient in need thereof a therapeutically effective amount of an additional pharmaceutically active compound.

8. The method of claim 7, wherein the additional pharmaceutically active compound is carfilzomib.

9. The method of claim 7, wherein the additional pharmaceutically active compound is venetoclax.

10. The method of claim 7, wherein the additional pharmaceutically active compound is cytarabine.

11. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

12. The method of claim 11, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

13. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

14. The method of claim 13, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

15. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

16. The method of claim 15, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

17. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

18. The method of claim 17, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

19. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

20. The method of claim 19, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

21. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

22. The method of claim 21, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

23. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

24. The method of claim 23, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

25. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

26. The method of claim 25, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

27. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

28. The method of claim 27, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

29. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

30. The method of claim 29, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

31. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

32. The method of claim 31, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

33. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

34. The method of claim 33, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

35. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

36. The method of claim 35, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

37. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

38. The method of claim 37, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

39. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

40. The method of claim 39, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

41. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

42. The method of claim 41, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

43. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

44. The method of claim 43, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

45. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt is administered to the patient, and the compound is

46. The method of claim 45, wherein the cancer is selected from multiple myeloma, acute myelogenous leukemia, or non-Hodgkin'"'"'s lymphoma.

3. A method of treating cancer, the method comprising:

administering to a patient in need thereof, a therapeutically effective amount of a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin'"'"'s lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia, and further wherein the compound is selected from;