Compounds that inhibit Mcl-1 protein

• US 10,632,128 B2
• Filed: 08/22/2019
• Issued: 04/28/2020
• Est. Priority Date: 03/30/2017
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Harrington, Paul E., Ashton, Kate, Brown, Sean P., Kaller, Matthew R., Kohn, Todd J., Lanman, Brian Alan, Li, Kexue, Li, Yunxiao, Low, Jonathan D., Minatti, Ana Elena, Pickrell, Alexander J., Stec, Markian M., Taygerly, Joshua
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US16/547,747
• Publication Number:
  US 20190381064A1
• Time in Patent Office: 250 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 compound of Formula I′

;

2. The compound of claim 1, wherein the compound of Formula I′

has the Formula I′

a;

3. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein b is a double bond.

4. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Z is C.

5. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Z is N.

6. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein Q is O.

7. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein W is CR^WAR^WB.

8. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^WA and R^WB are both H.

9. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is halo.

10. The compound of claim 9, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R¹ is Cl.

11. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R² is H.

12. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H or —

C_1-6 alkyl.

13. The compound of claim 12, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is —

CH₃.

14. The compound of claim 12, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R³ is H.

15. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ selected from H, —

C_1-6alkyl, —

C_1-6alkylhalo, —

C_1-6alkyl-O—

C_1-6alkyl, or —

(CH₂CH₂O)_nR^a, wherein the —

C_1-6alkyl is unsubstituted or substituted with —

OH, (═

O), phenyl, —

O—

SiR^aR^bR^c, —

NR^aR^b, a 3- to 12-membered cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, N or S.

16. The compound of claim 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is H.

17. The compound of claim 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —

C_1-6alkyl.

18. The compound of claim 1, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —

CH₃.

19. The compound of claim 1, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁴ is —

CH₂CH₂OCH₃.

20. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is H or —

C_1-6 alkyl.

21. The compound of claim 20, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁵ is —

CH₃.

22. The compound of claim 1, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁶ is H or —

C_1-6 alkyl.

23. The compound of claim 22, wherein or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, R⁶ is H.

24. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein each of R^4A, R^5A, R^6A, R^7A and R^8A is independently selected from H, OH, halo, or —

C_1-6alkyl.

25. The compound of claim 24, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein each of R^4A, R^5A, R^6A, R^7A and R^8A is H.

26. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is independently selected from H, —

C_1-6alkyl, —

C_2-6alkenyl, or —

C_1-6alkyl-O—

C_1-6alkyl or —

C_1-6haloalkyl.

27. The compound of claim 26, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is H.

28. The compound of claim 26, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —

CH₃.

29. The compound of claim 26, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R⁹ is —

CH₂CH₃.

30. The compound of claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein R^9A is selected from H, C_1-6haloalkyl, C_1-6alkyl, —

C_2-6alkenyl —

(CH₂CH₂O)_nR^a, —

SO₂R^a, —

C(═

O)R^a, —

C(═

O)OR^a, —

C(═

O)NR^aR^b, —

NR^aR^b, —

N═

N═

N, —

C_1-6alkyl-O—

C_1-6alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═

O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═

O or SO₂.

31. The compound of claim 30, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 3- to 12-membered monocyclic heterocycloalkyl R^9A group can be unsubstituted or substituted with 1, 2, 3 or 4 R¹⁰ substituents independently selected from OH, halo, —

NR^cR^d, —

C_1-6alkyl, —

C₂-C₆ alkenyl, —

C₂-C₆alkynyl, —

OC_1-6alkyl, —

C_1-6alkyl-OH, —

C_1-6alkyl-O—

C_1-6alkyl, C_1-6haloalkyl, —

O-haloC_1-6alkyl, —

SO₂R^c, —

CN, —

C(═

O)NR^cR^d, —

C(═

O)R^c, —

OC(═

O)R^a, —

C(═

O)OR^c, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, or heterocycloalkyl group have from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═

O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═

O or SO₂.

32. The compound of claim 31, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt of the stereoisomer thereof, wherein the 1, 2, 3 or 4 R¹⁰ substituents are independently selected from —

C_1-6alkyl or a 3- to 12-membered monocyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

33. The compound of claim 30, wherein R^9A is independently selected from —

N═

N═

N,

34. The compound of claim 1, wherein the compound of Formula I′

has Formula II′

;

35. The compound of claim 1, wherein the compound of Formula I′

has Formula II′

a;

36. The compound of claim 1, wherein the compound of Formula I′

has Formula IV′

;

37. The compound of claim 1, wherein the compound of Formula I′

has Formula IV′

a;

38. The compound of claim 1, wherein the compound has a structure selected from:

39. The compound of claim 38 or the pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound is

41. The compound of claim 40 or the pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

43. A pharmaceutical composition comprising the compound of claim 38 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

44. A pharmaceutical composition comprising the compound of claim 40 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

45. The compound of claim 1, wherein the compound is

46. The compound of claim 1, wherein the compound is

47. The compound of claim 1, wherein the compound is

48. The compound of claim 1, wherein the compound is

49. The compound of claim 1, wherein the compound is