Inhibitors of KRAS G12C mutant proteins

• US 10,647,703 B2
• Filed: 09/27/2016
• Issued: 05/12/2020
• 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): Stockton, Laura L
• Application Number:
  US15/763,798
• Publication Number:
  US 20180282307A1
• Time in Patent Office: 1,323 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

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 A, X, R^3a, R^3b, R^4a, R^4b, G¹, G², G³, G⁴, L¹, L², m¹, m², m³, m⁴, 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′

), (Ic′

), (Id′

), (Ie′

), (If′

) or (Ig′

);

2. The compound of claim 1, wherein the compound has one of the following structures (Ia″

), (Ib″

), (Ic″

), (Id″

), (Ie″

), (If″

) or, (Ig″

);

3. The compound of claim 1, wherein R² is H.

4. The compound of claim 1, wherein R¹ is fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methylsulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclopropyl or phenyl, wherein the cyclopropyl and phenyl are each independently optionally substituted with one or more substituents selected from C₁-C₆ alkyl, halo, hydroxyl and cyano.

5. The compound of claim 1, wherein R¹ is chloro or cyclopropyl.

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

CH₂C(═

O)—

.

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

C(═

O)—

.

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

9. The compound of claim 1, wherein

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

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

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

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