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 - 95 . (canceled)
96 . A compound having the following structure (I′b):
or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
X is N;
Y is CR 6 ;
Z is CR 6 ;
(i) R′ is R 1 and R″ is R 2c , or
(ii) R′ is H and R″ is R 1 ;
R 1 is heteroaryl or aryl;
R 2a , R 2b and R 2c are each independently H, halo, hydroxyl, 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 1 -C 6 alkynyl, hydroxylalkyl, 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 alkynyl, hydroxylalkyl, 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 alkynyl, hydroxylalkyl, 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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 6 is, at each occurrence, independently H, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —CO 2 NR a R b , alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, 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;
wherein 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;
L 1 is a bond;
L 2 is a bond;
is a double bond; and
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 or hydroxylalkyl;
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, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxylalkyl or R 9 and R 10 join to form a carboyclic or heterocyclic ring;
when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl; and
provided that least one of R 2a , R 2b or R 2c is not H when R 1 is pyridyl.
97 . The compound of claim 96 , wherein R 1 is aryl.
98 . The compound of claim 97 , wherein R 1 is phenyl.
99 . The compound of claim 97 , wherein R 1 is substituted with one or more substituents selected from halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalky, 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 hydroxylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfone, 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 and C 3 -C 8 cycloalkyl, C 3 -C 8 fusedcycloalkyl and heteroaryl.
100 . The compound of claim 97 , wherein R 1 is substituted with one or more substituents selected from fluoro, chloro, bromo, cyano, hydroxyl, hydroxylmethyl, methoxy, methoxymethyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl and cyclopropyl.
101 . The compound of claim 96 , wherein R 1 has one of the following structures:
102 . The compound of claim 96 , wherein R 1 is heteroaryl.
103 . The compound of claim 102 , wherein R 1 is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.
104 . The compound of claim 103 , wherein R 1 is substituted with one or more substituents selected from fluoro, chloro, amino and methyl.
105 . The compound of claim 96 , wherein R 1 has one of the following structures:
106 . The compound of claim 96 wherein R 2a and R 2b , when present, are each independently is H or halo.
107 . The compound of claim 96 , wherein Q is —C(═O)—.
108 . The compound of claim 96 , wherein
109 . The compound of claim 96 , wherein R 3a , R 3b , R 4a and R 4b are H.
110 . The compound of claim 107 , wherein R′ is H and R″ is R 1 .
111 . The compound of claim 110 , wherein R 2a and R 2b are each independently H or halo.
112 . The compound of claim 111 , wherein R′ is aryl.
113 . The compound of claim 111 , wherein R′ is phenyl.
114 . The compound of claim 111 , wherein R′ is heteroaryl.