Inhibitors of KRAS G12C mutant proteins

• US 10,730,867 B2
• Filed: 09/27/2016
• Issued: 08/04/2020
• Est. Priority Date: 09/28/2015
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Li, Liansheng, Feng, Jun, Long, Yun Oliver, Ren, Pingda, Liu, Yi
• Primary Examiner(s): Pihonak, Sarah
• Application Number:
  US15/763,806
• Publication Number:
  US 20180273523A1
• Time in Patent Office: 1,407 Days
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein A, R^3a, R^3b, R^4a, R^4b, G¹, G², G³, G⁴, m¹, m², m³, m⁴, 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 one of the following structures (Ia), (Ib), (Id), or (Ie):

2. The compound of claim 1, wherein m¹ is 2, m² is 2, m³ is 1 and m⁴ is 1.

3. The compound of claim 1, wherein R¹ and R² are each independently fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methyl sulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluorethyl, cyclobutyl, cyclopropyl or phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from C₁-C₆alkyl, halo, hydroxyl and cyano.

4. The compound of claim 1, wherein R¹ is chloro, and R² is chloro or cyclopropyl.

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

6. The compound of claim 1, wherein L² is —

CH₂C(═

O)—

.

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

C(═

O)—

.

8. The compound of claim 1, wherein at least one of R⁹ or R¹⁰ is H.

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

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

11. The compound of claim 1, wherein L¹ is a bond.

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

13. The compound of claim 1, wherein G¹, G² and G⁴ are N.

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

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

16. The compound of claim 1, wherein the compound has structure (Ia).

17. The compound of claim 1, wherein the compound has structure (Ia).

18. The compound of claim 1, wherein the compound has structure (Id).

19. The compound of claim 1, wherein the compound has structure (Ie).