Inhibitors of RAS and methods of use thereof

• US 10,377,743 B2
• Filed: 10/06/2017
• Issued: 08/13/2019
• Est. Priority Date: 10/07/2016
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Li, Liansheng, Feng, Jun, Liu, Yuan, Ren, Pingda, Liu, Yi, Wu, Tao, Wang, Yi
• Primary Examiner(s): Seaman, D Margaret M
• Application Number:
  US15/727,422
• Publication Number:
  US 20180127396A1
• Time in Patent Office: 676 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07B 2200/09 Geometrical isomers
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R″, Q, W, X, Y, Z, n¹, n² and are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

Claims

1. A compound having one of the following structures (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Ibb), (Icc), (Idd), (Tee), (Iff), (Igg), (Ihh), (Iii) or (Ijj):

2. The compound of claim 1, wherein R¹ is optionally substituted aryl.

3. The compound of claim 2, wherein R¹ is optionally substituted phenyl or optionally substituted naphthyl.

4. The compound of claim 1, wherein R¹ is optionally substituted heteroaryl.

5. The compound of claim 4, wherein R¹ comprises nitrogen.

6. The compound of claim 4, wherein R¹ is optionally substituted indazolyl, optionally substituted indolyl, optionally substituted benzimidazolyl, optionally substituted benzotriazolyl or optionally substituted quinolinyl.

7. The compound of claim 1, wherein R¹ is optionally substituted heterocyclyl.

8. The compound of claim 7, wherein R¹ is optionally substituted piperidinyl or optionally substituted pyrrolidinyl.

9. The compound of claim 1, wherein R¹ is substituted with one or more substituents.

10. The compound of claim 9, wherein R¹ is substituted with halo, amino, hydroxyl, C₁-C₆ alkyl, cyano, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —

OC(═

O)R or C₁-C₆ alkylcarbonyloxy, or combinations thereof, wherein R is C₁-C₆ alkyl.

11. The compound of claim 9, wherein R¹ is substituted with fluoro, chloro, amino, hydroxyl, cyano, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.

12. The compound of claim 1, wherein R¹ has one of the following structures:

13. The compound of claim 1, wherein R^2a is chloro, fluoro, cyano, hydroxyl, methyl, —

C(═

O)NH₂ or trifluoromethyl and R^2b and R^2c are each H.

14. The compound of claim 1, wherein, R^2b is chloro, fluoro, cyano, hydroxyl, methyl, —

C(═

O)NH₂ or trifluoromethyl and R^2a and R^2c are each H.

15. The compound of claim 1, wherein, R^2c is chloro, fluoro, cyano, hydroxyl, methyl, —

C(═

O)NH₂ or trifluoromethyl and R^2b and R^2b are each H.

16. The compound of claim 1, wherein each R^3a, R^3b, R^4a and R^4b is H.

17. The compound of claim 1, wherein at least one occurrence of R^3a, R^3b, R^4a or R^4b is C₁-C₆ alkyl.

18. The compound of claim 17, wherein C₁-C₆ alkyl is methyl.

19. The compound of claim 1, wherein Q is —

C(═

O)—

.

20. The compound of claim 1, wherein each of R⁵ and R⁶ are H.

21. The compound of claim 1, wherein

22. The compound of claim 1, wherein

23. The compound of claim 1, wherein L² is a bond.

24. The compound of claim 1, wherein L is absent.

25. The compound of claim 1, wherein L is —

O—

, —

NH—

, —

NHC(═

O)—

, —

NHS(═

O)₂—

or —

S(═

O)₂—

.

26. The compound of claim 1, having one of the following structures:

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

28. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 to a subject in need thereof.

29. The method of claim 28, wherein the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.

30. The method of claim 28, wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

31. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 to a subject in need thereof.