Synthesis and biological study of 2-amino-4-aryl-5-chloropyrimidine analogues as inhibitors of VEGFR-2 and cyclin dependent kinase 1 (CDK1)

The series of 2-amino-4-aryl-5-chloropyrimidines was discovered to be potent for both VEGFR-2 and CDK1. Described here are the chemistry for analogue synthesis, SAR study, and its kinase selectivity prolifing. The full rat PK data and in vivo efficacy study are also included.

Graphical abstractThe novel series of 2-amino-4-aryl-5-chloropyrimidines was identified to be potent for both VEGFR-2 and CDK1. SAR at the 2- and 4-positions of the 5-chloropyrimidien core was studied, resulting in many potent analogues with (2-aminoethyl)phenylamino at the 2-position and cumylamino, indol-3-yl, or indol-6-yl at the 4-position. Several derivatives showed good bioavailability in rat PK study.Figure optionsDownload full-size imageDownload as PowerPoint slide