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 compound having one of the following structures:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
2. A pharmaceutical composition comprising a compound of claim 1 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
3. The compound of claim 1 , having one of the following structures:
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
6. A pharmaceutical composition comprising the compound of claim 5 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
7. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
8. A pharmaceutical composition comprising the compound of claim 7 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
9. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
14. A pharmaceutical composition comprising the compound of claim 13 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
15. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising the compound of claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising the compound of claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
20. A pharmaceutical composition comprising the compound of claim 19 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
21. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising the compound of claim 21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
23. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising the compound of claim 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
25. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
26. A pharmaceutical composition comprising the compound of claim 25 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
27. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising the compound of claim 27 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
29. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising the compound of claim 29 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
31. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
32. A pharmaceutical composition comprising the compound of claim 31 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
33. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
34. A pharmaceutical composition comprising the compound of claim 33 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
35. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising the compound of claim 35 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
37. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
38. A pharmaceutical composition comprising the compound of claim 37 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
39. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
40. A pharmaceutical composition comprising the compound of claim 39 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
41. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
42. A pharmaceutical composition comprising the compound of claim 41 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
43. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
44. A pharmaceutical composition comprising the compound of claim 43 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
45. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
46. A pharmaceutical composition comprising the compound of claim 45 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
47. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
48. A pharmaceutical composition comprising the compound of claim 47 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
49. The compound of claim 1 , having the following structure:
or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof.
50. A pharmaceutical composition comprising the compound of claim 49 , or an atropisomer thereof, or a pharmaceutically acceptable salt of the compound or atropisomer thereof, and a pharmaceutically acceptable carrier.
51. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
52. A pharmaceutical composition comprising the compound of claim 51 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
53. The compound of claim 1 , having the following structure:
or a pharmaceutically acceptable salt thereof.
54. A pharmaceutical composition comprising the compound of claim 53 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.