Patent ID: 11878985
Assignee: ARAXES PHARMA LLC
Field: Organic fine chemistry (Chemistry)
Classification: CPC C  A | IPC A  C

Claim 0:
1. A method for covalently binding the cysteine 12 residue of a KRAS G12C protein in a human subject with a KRAS G12C-mutated cancer, wherein the method comprises administering to the human subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following structure (I):, , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,, wherein:
A is CR1 or CR2b;
B is CR1 or CR2C;
R1 is heterocyclyl, heteroaryl or aryl, wherein the heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, cyanoC1-C6alkyl, cyanoC3-C8cycloalkyl, hydroxyl, C1-C6alkyl, C1-C6alkylcycloalkyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylaminyl, C1-C6alkylcarbonylaminyl, C1-C6hydroxylalkyl, C1-C6haloalkyl, C1-C6alkoxyalkyl, aminylsulfone, aminylcarbonyl, aminylcarbonylC1-C6alkyl, aminylcarbonylC3-C8cycloalkyl, C1-C6alkylaminylcarbonyl, C3-C8cycloalkylaminylcarbonyl, C3-C8cycloalkylalkyl and C3-C8cycloalkyl, C3-C8fused cycloalkyl and heteroaryl;
R2a is H, halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heteroaryl or aryl;
R2b, when present, is H, halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heteroaryl or aryl;
R2c, when present, is H, halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heteroaryl or aryl;
W is CR6;
X is N;
Y is CR6;
each R6 is independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —CO2NRaRb, wherein Ra and Rb are each independently H or C1-C6 alkyl or Ra and Rb join to form a carbocyclic or heterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C1-C6 alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C1-C6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl, arylalkyloxy or a bond to L;
Z is N;
L1 is a bond or NR7;
R7 is H or C1-C6 alkyl;
G1 is CH or N;
each R3a is independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C2-C6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
each R3b is independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C2-C6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
each R4a is independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C2-C6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
each R4b is independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C2-C6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
G2 is CH or N;
L2 is a bond or alkylene;
m1 is 1, 2 or 3;
m2 is 1, 2 or 3;
E is:, , wherein:
 represents a double or triple bond;
Q is —C(═O)—, —C(═NR8′)—, —NR8C(═O)—, —S(═O)2— or —NR8S(═O)2—;
R8 is H, C1-C6alkyl or hydroxylalkyl;
R8′ is H, —OH, —CN or C1-C6alkyl;
when  is a double bond then R9 and R10 are each independently H, cyano, carboxyl, C1-C6alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxylalkyl or R9 and R10 join to form a carbocyclic or heterocyclic ring;
when  is a triple bond then R9 is absent and R10 is H, C1-C6alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
with the proviso that:
(1) (a) W is CR6, where R6 is a bond to L1; or
(b) Y is CR6, where R6 is a bond to L1; and

(2) if R1 is pyridinyl, then at least one of R2a, R2b or R2c is not H.