Covalent inhibitors of KRAS

Patent metadata

Field	Value
Publication number	US-11377441-B2
Application number	US-202016915942-A
Country	US
Kind code	B2
Filing date	Jun 29, 2020
Priority date	May 25, 2017
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

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, isotopic form or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5, L1, L2, L3, E, m1, m2 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.

First claim

The invention claimed is:

1. A method for treating cancer, the method comprising administering, to a subject in need thereof, an effective amount of a pharmaceutical composition comprising a compound having one of the following structures:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, wherein the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.

2. The method of claim 1 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

3. The method of claim 1 , wherein the method inhibits tumor metastasis.

4. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

5. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

6. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

9. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

12. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

15. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

18. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

21. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

24. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

26. The method of claim 1 , wherein the compound has following structure:

or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.

27. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

28. The method of claim 1 , wherein the compound has following structure:

or a pharmaceutically acceptable salt thereof.

Assignees

• Araxes Pharma Llc

Inventors

• Li Liansheng
• Feng Jun
• Wu Tao
• Liu Yuan
• Wang Yi
• Ren Pingda
• Liu Yi

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title