Inhibitors of KRAS G12C mutant proteins
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein A, B R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , m 1 , m 2 , L 1 , L 2 and E 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 the following structure (I):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
L 1 is a bond;
L 2 is a bond;
R″ is H or alkylcarbonylaminyl;
R 1 is aryl or heteroaryl;
R 2a and R 2b are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 7 )—, —NR 8 C(═O)—, —S(═O) 2 —or —NR 8 S(═O) 2 —;
R 7 is H, —OH, —CN or C 1 -C 6 alkyl;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxylalkyl; and
when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl,
wherein all valences are satisfied.
2. The compound of claim 1 , wherein R 1 is aryl.
3. The compound of claim 2 , wherein aryl is phenyl or naphthyl.
4. The compound of claim 1 , wherein R 1 is heteroaryl.
5. The compound of claim 4 , wherein heteroaryl is indazolyl.
6. The compound of claim 1 , wherein R 1 is substituted with one or more substituent selected from 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, heteroarylaminyl and aryl.
7. The compound of claim 1 , wherein R′ has one of the following structures:
8. The compound of claim 1 , wherein Q is —C(═O)—.
9. The compound of claim 1 , wherein at least one of R 9 or R 10 is H.
10. The compound of claim 9 , wherein each of R 9 and R 10 are H.
11. The compound of claim 1 , wherein
has one of the following structures:
12. The compound of claim 1 , wherein R 2a and R 2b are each independently H or halo.
13. The compound of claim 12 , wherein halo is chloro or fluoro.
14. The compound of claim 12 , wherein R 2a is chloro and R 2b fluoro.
15. The compound of claim 1 , wherein the compound has one of the following structures:
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 16 to a subject in need thereof.
18. A method for inhibiting activity of a KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS HRAS or NRAS G12C mutant protein with the compound of claim 1 .
19. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of claim 16 to a subject in need thereof, wherein the tumor comprises a G12C KRAS, HRAS or NRAS mutation.
20. The method of claim 17 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.