Covalent inhibitors of KRAS
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 R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5 , L 1 , L 2 , L 3 , E, m 1 , m 2 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.
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.