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): (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein A, R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , G 3 , G 4 , m 1 , m 2 , m 3 , m 4 , 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 one of the following structures (Ia), (Ib), (Id), or (Ie):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
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;
R 1 and R 2 are each independently H, halo, hydroxyl, cyano, aminylcarbonyl, 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, heteroaryl or aryl, provided that at least one of R 1 or R 2 is not H;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or one R 3a and one R 3b join to form a carbocyclic or heterocyclic ring, and each remaining R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or one R 3b joins with one R 4b to form a carbocyclic or heterocyclic ring, and each R 3a and each remaining R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or one R 4a and one R 4b join to form a carbocyclic or heterocyclic ring, and each remaining R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or one R 4b joins with one R 3b to form a carbocyclic or heterocyclic ring, and each R′ and each remaining R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
L 1 is a bond or alkylene;
L 2 is a bond or a one or two carbon alkylene optionally substituted with oxo;
m 1 , m 2 , m 3 and m 4 are each independently 1, 2 or 3; and
E has the following structure:
wherein:
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; and
R 9 and R 10 are each independently H, cyano, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl,
wherein each C 1 -C 6 alkyl, C 2 -C 6 alkynyl, alkylene, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 aminoalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl, aminylcarbonylalkyl heterocyclyl, carbocyclyl, heteroaryl and aryl is optionally substituted with one or more substituents.
2. The compound of claim 1 , wherein m 1 is 2, m 2 is 2, m 3 is 1 and m 4 is 1.
3. The compound of claim 1 , wherein R 1 and R 2 are each independently fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methyl sulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluorethyl, cyclobutyl, cyclopropyl or phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halo, hydroxyl and cyano.
4. The compound of claim 1 , wherein R 1 is chloro, and R 2 is chloro or cyclopropyl.
5. The compound of claim 1 , wherein L 2 is a bond.
6. The compound of claim 1 , wherein L 2 is —CH 2 C(═O)—.
7. The compound of claim 1 , wherein Q is —C(═O)—.
8. The compound of claim 1 , wherein at least one of R 9 or R 10 is H.
9. The compound of claim 1 , wherein each of R 9 and R 10 are H.
10. The compound of claim 1 , wherein E has one of the following structures:
11. The compound of claim 1 , wherein L 1 is a bond.
12. The compound of claim 1 , wherein each R 3a , R 3b , R 4a and R 4b are H.
13. The compound of claim 1 , wherein G 1 , G 2 and G 4 are N.
14. The compound of claim 1 , wherein the compound has one of the following structures:
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
16. The compound of claim 1 , wherein the compound has structure (Ia).
17. The compound of claim 1 , wherein the compound has structure (Ia).
18. The compound of claim 1 , wherein the compound has structure (Id).
19. The compound of claim 1 , wherein the compound has structure (Ie).