Fused-tricyclic inhibitors of KRAS 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, stereoisomer or prodrug thereof, wherein A is a heterocyclic or heteroaryl ring, and R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , A, G 1 , G 2 , L 1 , L 2 , m 1 , m 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′a):
or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:
A is a carbocyclic, heterocyclic or heteroaryl ring;
G 1 and G 2 are each independently N or CH;
L 1 is a bond or NR 5 ;
L 2 is a bond or alkylene;
R 1 is aryl or heteroaryl;
R 2a , R 2b and R 2c are each independently H, amino, halo, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, 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;
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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a and R 3b join to form a carbocyclic or heterocyclic ring; or R 3a is 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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a and R 4b join to form a carbocyclic or heterocyclic ring; or R 4a is 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 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 5 is, at each occurrence, independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or heterocycloalkyl;
m 1 and m 2 are each independently 1, 2 or 3;
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 8′ )—, NR 8 C(═O)—, —S(═O) 2 — or NR 8 S(═O) 2 ;
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8 cycloalkyl or heterocycloalkyl;
R 8′ is H, —OH, —CN or C 1 -C 6 alkyl;
when is a double bond then R 9 and R 10 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R 9 and R 10 join to form a carbocyclic, heterocyclic or heteroaryl ring; 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.
2. The compound of claim 1 , wherein the compound has one of the following structures (I′b), (I′c), (I'd) or (I′e):
3. The compound of claim 1 , wherein A is a 5, 6 or 7-membered heterocyclic or heteroaryl ring.
4. The compound of claim 1 , wherein A has one of the following structures:
wherein:
R 6 is, at each occurrence, independently H, halo, amino, cyano, arayl, heteroaryl, C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, heterocycloalkyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, arylalkyl or heteroarylalkyl;
X is O or CH 2 ; and
n is 0, 1 or 2.
5. The compound of claim 1 , wherein R 1 is aryl.
6. The compound of claim 5 , wherein R 1 is phenyl or naphthyl.
7. The compound of claim 5 , wherein R 1 is substituted with halo, amino hydroxyl, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, boronic acid, —OC(═O)R, phosphate, phosphoalkoxy or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.
8. The compound of claim 7 , wherein R 1 is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.
9. The compound of claim 1 , wherein R 1 is heteroaryl.
10. The compound of claim 9 , wherein R 1 is indazolyl, indolyl, benzimidazolyl, benzotriazolyl or quinolinyl.
11. The compound of claim 9 , wherein R 1 is substituted with hydroxyl, halo or C 1 -C 6 alkyl, or combinations thereof.
12. The compound of claim 1 , wherein R 1 has one of the following structures:
13. The compound of claim 1 , wherein R 2c is H.
14. The compound of claim 1 , wherein R 2a and R 2b are each independently halo, haloalkyl, alkyl or alkoxy.
15. The compound of claim 1 , wherein Q is C(═O)—.
16. The compound of claim 1 , wherein R 9 and R 10 are each H.
17. The compound of claim 1 , wherein the moiety
has one of the following structures:
18. The compound of claim 1 , wherein the moiety has the following structure:
19. The compound of claim 1 , wherein L 1 is a bond.
20. The compound of claim 1 , wherein L 2 is a bond.
21. The compound of claim 1 , wherein R 3a , R 3b , R 4a and R 4b are each H.
22. The compound of claim 1 , wherein the compound has one of the following structures:
23. A substantially purified atropisomer of a compound according to claim 1 .
24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
25. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 24 to a subject in need thereof.
26. A method for regulating activity of a KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C mutant protein with the compound of claim 1 .
27. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of claim 1 .
28. A method for preparing a labeled KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS, HRAS or NRAS G12C mutant with a compound of claim 1 , to result in the labeled KRAS, HRAS or NRAS G12C protein.