Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors.

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.