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 compound having the following structure (V):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
R 1 is aryl;
R 30a and R 30b 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 30a and R 30b join to form a carbocyclic or heterocyclic ring; or R 30a 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 30b joins with R 31b to form a carbocyclic or heterocyclic ring;
R 31a and R 31b 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 31a and R 31b join to form a carbocyclic or heterocyclic ring; or R 31a 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 31b joins with R 30 b to form a carbocyclic or heterocyclic ring;
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;
L 1 heteroalkylene, heterocycloalkylene, heteroarylene, heteroalkylenecarbonyl, heterocycloalkylenecarbonyl or heteroarylenecarbonyl;
L 2 is a bond or alkylene;
G 1 , G 2 , G 3 and G 4 are each independently N or CR, where R is H, cyano, halo or C 1 -C 6 alkyl;
n 1 , n 2 , n 3 and n 4 are each independently 1, 2 or 3; 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 compound of claim 1 , wherein the compound has the following structure (Vb):
wherein:
L 1a is heteroalkylene, heterocycloalkylene or heteroarylene;
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.
3. The compound of claim 2 , wherein the compound is selected from the group consisting of (Vc), (Vd), (Ve) and (Vf):
4. The compound of claim 2 , wherein the compound is selected from the group consisting of (Vg), (Vh), (Vi) and (Vj):
5. The compound of claim 2 , wherein the compound is selected from the group consisting of (Vk), (Vl), (Vm), (Vn); (Vo) and (Vp):
6. The compound of claim 1 , wherein the aryl is naphthyl.
7. The compound of claim 1 , wherein the aryl is phenyl.
8. The compound of claim 1 , wherein the wherein the aryl is substituted with one or more substituents selected from the group consisting of halo, 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, aliphatic heterocyclyl, heteroaryl and aryl.
9. The compound of claim 8 , wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methylsulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluorethyl, cyclobutyl, cyclopropyl and phenyl, wherein the cyclopropyl, cyclibutyl and phenyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halo, hydroxyl and cyano.
10. The compound of claim 9 , wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, methyl, ethyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl and cyclobutyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halo, hydroxyl and cyano.
11. The compound of claim 10 , wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halo, hydroxyl and cyano.
12. The compound of claim 1 , wherein R 1 is selected from the group consisting of:
13. The compound of claim 2 , wherein Q is —C(═O)—.
14. The compound of claim 2 , wherein each of R 35 and R 36 are H.
15. The compound of claim 1 , wherein E is selected from the group consisting of:
16. The compound of claim 2 , wherein L 1a is heteroalkylene or heterocycloalkylene.
17. The compound of claim 16 , wherein L 1a is aminoalkylene or thioalkylene.
18. The compound of claim 17 , wherein L 1a is selected from the group consisting of:
19. The compound of claim 1 , wherein L 2 is a bond.
20. The compound of claim 1 , wherein each of R 30a , R 30b , R 31a , R 31b , R 32a , R 32b , R 33a and R 33b is H.
21. The compound of claim 1 , wherein at least one of R 30a , R 30b , R 31a , R 31b , R 32a , R 32b , R 33a and R 33b is hydroxylalkyl.
22. The compound of claim 1 , wherein at least one of R 30a , R 30b , R 31a , R 31b , R 32a , R 32b , R 33a and R 33b is C 1 -C 6 alkyl.
23. The compound of claim 1 , wherein the compound is selected from the group consisting of:
24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.