Inhibitors of KRAS G12C mutant proteins

• US 10,280,172 B2
• Filed: 09/29/2017
• Issued: 05/07/2019
• 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:
  US15/721,021
• Publication Number:
  US 20180155348A1
• Time in Patent Office: 585 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 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 the following structure (I):

2. The compound of claim 1, wherein the compound has one of the following structures (Ic), (Id), (Ie), (Ig), (Ih) or (Im):

3. The compound of claim 2, wherein G¹ and G² are each N, m¹ and m² are each 2 and each R^3b and R^4b is H.

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 1, wherein R¹ has one of the following structures:

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

C(═

O)—

.

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

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

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

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

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

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

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

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

17. A compound having one of the following structures:

19. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable carrier.