Covalent inhibitors of KRas G12C
Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.
1. A method for treating a cancer mediated by a K-Ras G12C, H-Ras G12C or N-Ras G12C mutation, the method comprising administering an effective amount of a compound having the following structure (VI):
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, to a subject in need thereof, wherein:
A is CR 37b , N or NR 38a ;
B is CR 37c , N, NR 38b or S;
C is CR 37d , N, NR 38c or S;
G 3 and G 4 are each independently N or CR, wherein R is H, cyano, halo or C 1 -C 6 alkyl;
L 1a is a bond, —NH—, alkylene or heteroalkylene;
L 2 is a bond or alkylene;
R 32a and R 32b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, cyano, cyanoalkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32a is H, —OH, —NH 2 , —CO 2 H, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring;
R 33a and R 33b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, cyano, cyanoalkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33a is H, —OH, —NH 2 , —CO 2 H, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;
R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 aminoalkyl, heterocyclyl or aryl;
R 38a , R 38b and R 38c are each independently H, C 1 -C 6 alkyl or aryl;
n 3 and n 4 are each independently 1, 2 or 3;
m is 0 or 1;
is a single or double bond such that all valences are satisfied; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.
2. The method of claim 1 , wherein the compound has one of the following structures (VIa), (VIb), (VIc), (VId), (VIe), (VIf) or (VIg):
3. The method of claim 1 , wherein the compound has one of the following structures (VIa′), (VIb′), (VIc′), (VId′), (VIe′), (VIf′) or (VIg′):
wherein:
Q is C(═O)—, NR 34 C(═O)—, —S(═O) 2 — or —NR 34 S(═O) 2 —;
R 34 is H, C 1 -C 6 alkyl or hydroxylalkyl;
is a carbon-carbon double bond or a carbon-carbon triple bond; and
R 35 and R 36 are each independently H, cyano, C 1 -C 6 alkyl, aminoalkyl, alkylaminoalkyl, or hydroxylalkyl or R 35 and R 36 join to form a carbocyclic or heterocyclic ring when is a double bond; or R 35 is absent and R 36 is H, C 1 -C 6 alkyl, aminoalkyl, alkylaminoalkyl or hydroxylalkyl when is a triple bond.
4. The method of claim 1 , wherein G 3 is N and G 4 is CR.
5. The method of claim 1 , wherein G 3 is CR and G 4 is N.
6. The method of claim 1 , wherein G 3 is N and G 4 is N.
7. The method of claim 1 , wherein n 3 is 2 and n 4 is 2.
8. The method of claim 1 , wherein n 3 is 1 and n 4 is 1.
9. The method of claim 1 , wherein n 3 is 2 and n is 1.
10. The method of claim 1 , wherein R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, —OH, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, heterocyclyl or aryl.
11. The method of claim 10 , wherein R 37a , R 37b , R 37c , R 37d and R 37e are each independently H, —OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl.
12. The method of claim 1 , wherein R 37a or R 37e is aryl.
13. The method of claim 12 , wherein aryl is phenyl.
14. The method of claim 12 , where the aryl is substituted with one or more halo substituents.
15. The method of claim 14 , wherein the halo substituents are selected from fluoro and chloro.
16. The method of claim 1 , wherein R 37a is heteroaryl.
17. The method of claim 16 , wherein the heteroaryl is thiophenyl.
18. The method of claim 1 , wherein R 37a or R 37e , or both, is halo.
19. The method of claim 18 , wherein halo is chloro, bromo or iodo.
20. The method of claim 1 , wherein R 37a or R 37e has one of the following structures:
21. The method of claim 1 , wherein R 38a , R 38b and R 38c are each independently H or aryl.
22. The method of claim 21 , wherein R 38a , R 38b and R 38c are each independently H.
23. The method of claim 1 , wherein R 38c is aryl.
24. The method of claim 23 , wherein the aryl is substituted with one or more halo substituents.
25. The method of claim 24 , wherein halo is chloro.
26. The method of claim 3 , wherein Q is —C(═O)—.
27. The method of claim 3 , wherein each of R 35 and R 36 are H.
28. The method of claim 1 , wherein E has one of the following structures:
29. The method of claim 1 , wherein L 1a is a bond.
30. The method of claim 1 , wherein L 2 is a bond.
31. The method of claim 1 , wherein at least one of R 32a , R 32b , R 33a , or R 33b is H.
32. The method of claim 1 , wherein each of R 32a , R 32b , R 33a or R 33b is H.
33. The method of claim 1 , wherein the compound has one of the following structures:
34. The method of claim 1 , wherein the compound is formulated in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
35. The method of claim 34 , wherein the pharmaceutical composition is formulated for oral administration.
36. The method of claim 34 , wherein the pharmaceutical composition is formulated for injection.
37. The method of claim 1 , further comprising administering an additional anticancer agent to the subject.
38. The method of claim 1 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.