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 B, W, X, Y, 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 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, prodrug or stereoisomer thereof, wherein:
W is N;
X is N;
Y is C;
B is a 6-membered heteroaryl comprising one ring nitrogen;
G 1 and G 2 are each independently N or CH;
L 1 is a bond;
L 2 is a bond or alkylene;
R 1 is aryl or heteroaryl;
R 2a and R 2b are each independently H, oxo, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl;
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, aminocarbonylalkyl or aminocarbonyl; 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, aminocarbonylalkyl or aminocarbonyl; 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, aminocarbonylalkyl or aminocarbonyl; 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, aminocarbonylalkyl or aminocarbonyl; or one R 4b joins with one R 3b to form a carbocyclic or heterocyclic ring, and each R 4a 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;
R 5 is H or C 1 -C 6 alkyl;
m 1 and m 2 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, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxylalkyl; or R 9 and R 10 join to form a carbocyclic or heterocyclic ring,
wherein all valences are satisfied.
2. The compound of claim 1 , wherein the compound has the following structure (If):
wherein R′ is H or C 1 -C 6 alkyl.
3. The compound of claim 1 , wherein the compound has the following structure (If″):
4. The compound of claim 1 , wherein R 1 is aryl.
5. The compound of claim 1 , wherein R 1 is heteroaryl.
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, aryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester and —OC(═O)R, wherein R is C 1 -C 6 alkyl optionally substituted with amino.
7. The compound of claim 1 , wherein R 1 is substituted with one or more substituent selected from hydroxyl, methyl, trifluoromethyl and fluoro.
8. The compound of claim 7 , wherein R 1 is substituted with fluoro or trifluoromethyl.
9. The compound of claim 1 , wherein R 1 has one of the following structures:
10. The compound of claim 1 , wherein Q is —C(═O)—.
11. The compound of claim 1 , wherein each of R 9 and R 10 are H.
12. The compound of claim 1 , wherein E has one of the following structures:
13. The compound of claim 1 , wherein each R 3a , R 3b , R 4a and R 4b are H.
14. The compound of claim 1 , wherein at least one R 3a , R 3b , R 4a and R 4b is C 1 -C 6 alkyl.
15. The compound of claim 1 , wherein R 2a and R 2b are each independently H, halo, oxo or C 1 -C 6 alkyl.
16. The compound of claim 1 , wherein m 1 and m 2 are each 2.
17. The compound of claim 1 , wherein G 1 and G 2 are N.
18. The compound of claim 1 , wherein the compound has one of the following structures:
19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
20. 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 19 to a subject in need thereof.
21. The method of claim 20 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
22. The method of claim 20 , further comprising administering an additional therapeutic agent for treatment of cancer to the subject.