Novel 4-(2-pyrimidinylamino)benzamide derivatives as potent hedgehog signaling pathway inhibitors

A series of novel hedgehog signaling pathway inhibitors have been designed and synthesized based on our previously reported scaffold of 4-(2-pyrimidinylamino)benzamide. The Hh signaling pathway inhibitory activities were evaluated by Gli-luciferase reporter method and most compounds showed more potent inhibitory activities than vismodegib. Three compounds were picked out to evaluated in vivo for their PK properties, and compound 23b bearing a 2-pyridyl A-ring and (morpholin-4-yl)methylene at 3-position of D-ring demonstrated satisfactory PK properties. This study suggested the 4-(2-pyrimidinylamino)benzamides were a series of potent Hh signaling pathway inhibitors, deserving to further structural optimization.