| 摘要 |
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):;;or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R, R1, R2a, R2b, R2c, A, B, 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. |
| 主权项 |
1. A compound having the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:
A is N or C;B is oxo, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, amino, alkylamino, arylamino, —CO2H, —CONH2, aminylcarbonyl, aminylcarbonylalkyl, heteroarylamino, halo, haloalkyl, alkoxy, haloalkoxy, aryl or —X-L2-Ra;X is —NRb— or —O—;L1 is alkylene, cycloalkylene, heterocyclylene or absent;L2 is alkylene or absent;R is H, cyano, amino, halo, haloalkyl, hydroxyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, —CO2H, —CONH2, aminylcarbonyl, C1-C6 alkyl, C1-C6 alkylaminyl or C1-C6 alkoxy;Ra is cycloalkyl, heterocyclyl, heteroaryl, —(C═O)OH, —(C═O)NH2 or —(C═O)NHOH;Rb is, at each occurrence, independently H or C1-C6 alkyl;is aryl or heteroaryl;R2a, R2b and R2c are each independently H, amino, cyano, halo, hydroxyl, C1-C6 alkyl, C1-C6 alkylaminyl, —NRb(C═O)Rb, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C2-C6 alkynyl, C2-C6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl; is a single or double bond such that all valences are satisfied; andE is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein. |
