Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
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, isotopic form, stereoisomer or prodrug thereof, wherein A, B, X, R1, R2a, R2b, R2c, L, L1 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 (Ie):
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
indicates an aromatic ring;
B is CR 2c ;
W is C bonded to L 2 ;
Y is —CR;
R is H, aminocarbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 1 -C 6 alkylaminyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or C 3 -C 8 heterocyclyl;
X and Z are each independently N;
R 1 is bicyclic aryl, indazolyl, indolyl, benzotriazolyl, benzothiadiazolyl optionally oxidized, quinolinyl or quinazolinyl;
R 2a , R 2b and R 2c are, at each occurrence, 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 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
L is absent or a linker selected from the group consisting of —O—, —NR a —, —NR a C(═O)—, —NR a S(═O) 2 — and —S(═O) 2 —, wherein R a is H or C 1 -C 6 alkyl;
L 2 is a bond or —NH—;
L 3 is a bond or alkylene;
m 1 and m 2 are each independently 1, 2 or 3;
G 1 is CH;
G 2 is N;
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 —;
when is a double bond then R 5 and R 6 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
when is a triple bond then R 5 is absent and R 6 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R 7 is H, —OH, —CN or C 1 -C 6 alkyl; and
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonylalkyl,
wherein R 1 is optionally substituted with amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylcarbonyloxy, or combinations thereof.
2. The compound of claim 1 , having the following structure (Ig):
wherein:
R 2a , R 2b and R 2c are 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 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl.
3. The compound of claim 1 , having the following structure (Io):
wherein:
R 2a , R 2b and R 2c are 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 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl.
4. The compound of claim 1 , having the following structure (Iw):
wherein:
R 2a , R 2b and R 2c are 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 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl.
5. The compound of claim 1 , wherein R 1 has one of the following structures:
6. The compound of claim 1 , wherein:
R 2a is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2b and R 2c are each H;
R 2b is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2a and R 2c are each H; or
R 2c is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2b and R 2b are each H.
7. The compound of claim 1 , wherein each R 3a , R 3b , R 4a and R 4b is H.
8. The compound of claim 1 , wherein at least one occurrence of R 3a , R 3b , R 4a or R 4b is C 1 -C 6 alkyl.
9. The compound of claim 1 , wherein Q is —C(═O)—.
10. The compound of claim 1 , wherein each of R 5 and R 6 are H.
11. The compound of claim 1 , wherein
has one of the following structures:
12. The compound of claim 1 , wherein L is absent.
13. The compound of claim 1 , having one of the following structures:
14. A (R-) or (S-) atropisomer according to claim 1 .
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
16. The compound of claim 1 , wherein:
m 1 and m 2 are both 1;
m 1 and m 2 are both 2; or
m 1 is 3 and m 2 is 1.