2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
申请人:Araxes Pharma LLC
公开号:US10414757B2
公开(公告)日:2019-09-17
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 R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, G1, G2, L1, L2, m1, m2, n, X and E are as defined herein and, wherein at least one of R3a, R3b, R4a or R4b is not H. 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.
本研究提供了具有抑制 G12C 突变 KRAS 蛋白活性的化合物。这些化合物具有以下结构 (I):
或其药学上可接受的盐、立体异构体或原药,其中 R1、R2a、R2b、R2c、R3a、R3b、R4a、R4b、R5a、R5b、R6、A、G1、G2、L1、L2、m1、m2、n、X 和 E 如本文所定义,其中 R3a、R3b、R4a 或 R4b 中至少有一个不是 H。还提供了与制备和使用此类化合物相关的方法、包含此类化合物的药物组合物以及调节G12C突变型KRAS蛋白活性以治疗疾病(如癌症)的方法。