Inhibitors of KRAS G12C mutant proteins

• US 10,723,738 B2
• Filed: 04/03/2019
• Issued: 07/28/2020
• Est. Priority Date: 09/29/2016
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Li, Liansheng, Feng, Jun, Long, Yun Oliver, Liu, Yuan, Ren, Pingda, Liu, Yi
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US16/374,356
• Publication Number:
  US 20200062761A1
• Time in Patent Office: 482 Days
• Field of Search: 514243
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 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, tautomer, stereoisomer or prodrug thereof, wherein B, W, X, Y, R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, G¹, G², m¹, m², L¹, L² and E are 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 the following structure (I):

2. The compound of claim 1, wherein the compound has the following structure (If):

3. The compound of claim 1, wherein the compound has the following structure (If″

);

4. The compound of claim 1, wherein R¹ is aryl.

5. The compound of claim 1, wherein R¹ is heteroaryl.

6. The compound of claim 1, wherein R¹ is substituted with one or more substituent selected from halo, hydroxyl, cyano, aminocarbonyl, formyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxylalkyl, C₁-C₆ alkoxyalkyl, C₁-C₆ aminoalkyl, aliphatic heterocyclyl, heteroaryl, heteroarylaminyl, aryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester and —

OC(═

O)R, wherein R is C₁-C₆ alkyl optionally substituted with amino.

7. The compound of claim 1, wherein R¹ is substituted with one or more substituent selected from hydroxyl, methyl, trifluoromethyl and fluoro.

8. The compound of claim 7, wherein R¹ is substituted with fluoro or trifluoromethyl.

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

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

C(═

O)—

.

11. The compound of claim 1, wherein each of R⁹ and R¹⁰ are H.

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

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

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

15. The compound of claim 1, wherein R^2a and R^2b are each independently H, halo, oxo or C₁-C₆ alkyl.

16. The compound of claim 1, wherein m¹ and m² are each 2.

17. The compound of claim 1, wherein G¹ and G² are N.

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

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

20. A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 19 to a subject in need thereof.

21. The method of claim 20, wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

22. The method of claim 20, further comprising administering an additional therapeutic agent for treatment of cancer to the subject.