Substituted quinazolines as inhibitors of KRAS G12C
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, prodrug or stereoisomer thereof, wherein R 1 , R 2a , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , A, B, W, X, Y, Z 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:
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 —;
Y is CR 6 ;
X is N;
Z is N;
L 1 is a bond;
L 2 is a bond or alkylene;
R′ is R 1 and R″ is R 2c ; or R′ is H and R″ is R 1 ;
R 1 is heterocyclyl, heteroaryl or aryl;
R 2a , R 2b and R 2c are each independently H, halo, —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 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 2 -C 6 alkynyl, hydroxyalkyl, 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, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 6 is H, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —CO 2 NR a R b , alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl or arylalkyloxy;
R a and R b are each independently H or C 1 -C 6 alkyl; or
R a and R b join to form a carbocyclic or heterocyclic ring;
R 8 is H, C 1 -C 6 alkyl or hydroxyalkyl;
R 8′ is H, —OH, cyano or C 1 -C 6 alkyl;
indicates a double bond;
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxy, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxyalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic 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 hydroxyalkyl,
provided that at least one of R 2a , R 2b or R 2c is not H when R 1 is pyridyl, and wherein each alkylene, heterocyclyl, heteroaryl, aryl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkynyl, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, carbocyclic ring, heterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, quanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryloxy, arylaminyl, arylalkylaminyl and arylalkyloxy is optionally substituted with one or more substituents selected from the group consisting of aminyl, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C 1 -C 12 alkyl, C 1 -C 6 alkylaminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, C 1 -C 12 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, cyanoC 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 1 -C 6 alkylhetercycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenylcarbonylaminyl, C 1 -C 6 thioalkyl, aryl, aralkyl, C 3 -C 8 cycloalkyl optionally substituted with cyano, C 3 -C 8 cycloalkylalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 fused cycloalkyl, heterocycyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl.
2. The compound of claim 1 , wherein the compound has the following structure (I′f):
3. The compound of claim 1 , wherein the compound has the following structure (I′j):
4. The compound of claim 1 , wherein L 2 is a bond.
5. The compound of claim 1 , wherein R 1 is optionally substituted aryl.
6. The compound of claim 5 , wherein R 1 is substituted with one or more substituents.
7. The compound of claim 6 , wherein the substituents are selected from the group consisting of halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfonyl, aminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 cycloalkylalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl and heteroaryl.
8. The compound of claim 7 , wherein the substituents are selected from the group consisting of fluoro, chloro, bromo, cyano, hydroxy, hydroxymethyl, methoxy, methoxymethyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl and cyclopropyl.
9. The compound of claim 1 , wherein R 1 is aryl substituted with one or more substituents selected from the group consisting of halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfonyl, aminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 cycloalkylalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl and heteroaryl, and each of R a , R b , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 6 , R 8 , R 8′ , R 9 , R 10 and L 2 are unsubstituted.
10. The compound of claim 5 , wherein R 1 is phenyl.
11. The compound of claim 5 , wherein R 1 has one of the following structures:
12. The compound of claim 1 , wherein R 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl.
13. The compound of claim 12 , wherein R 1 is substituted with one or more substituents.
14. The compound of claim 13 , wherein the substituents are selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 2 -C 6 alkenylcarbonylaminyl.
15. The compound of claim 13 , wherein the substituents are selected from the group consisting of fluoro, chloro, amino and methyl.
16. The compound of claim 1 , wherein R 1 is heteroaryl substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 2 -C 6 alkenylcarbonylaminyl, and each of R a , R b , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 6 , R 8 , R 8′ , R 9 , R 10 and L 2 are unsubstituted.
17. The compound of claim 12 , wherein R 1 is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.
18. The compound of claim 12 , wherein R 1 has one of the following structures:
19. The compound of claim 1 , wherein R 2a is halo.
20. The compound of claim 19 , wherein R 2a is chloro or fluoro.
21. The compound of claim 1 , wherein R 2b is halo.
22. The compound of claim 21 , wherein R 2b is chloro or fluoro.
23. The compound of claim 1 , wherein R 3a , R 3b , R 4a and R 4b are each independently H.
24. The compound of claim 1 , wherein R 6 is heterocyclylaminyl.
25. The compound of claim 1 , wherein R 6 is H.
26. The compound of claim 1 , wherein Q is —C(═O)—.
27. The compound of claim 1 , wherein at least one of R 9 or R 10 is H.
28. The compound of claim 27 , wherein each of R 9 and R 10 are H.
29. The compound of claim 1 , wherein
has one of the following structures:
30. The compound of claim 1 , wherein
has the following structure:
31. The compound of claim 1 , wherein each of R a , R b , R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 6 , R 8 , R 8′ , R 9 , R 10 and L 2 are unsubstituted.
32. The compound of claim 1 , wherein the compound has one of the following structures:
33. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.