Discovery of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as novel, potent and selective c-Met kinase inhibitors: Synthesis, SAR study, and biological activity

A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were designed, synthesized and evaluated for their biological activity. Most of these compounds showed potent activities against c-Met kinase and cell growth inhibition. The most promising compound, 7d, has the IC50 values of 2.02 and 88 nM to inhibit c-Met kinase activity and cell growth in the MKN45 cell line, respectively. In addition, 7d is highly selective to c-Met and exhibits over 2500-fold selective inhibition to 16 tyrosine kinases evaluated. [Display omitted] •A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were designed and synthesized.•The target compounds showed potent antitumor activity.•Compound 7d showed nanomolar c-Met kinase and subnanomolar cell growth inhibitory activity.•Compound 7d inhibiting the phosphorylation of c-Met kinase in MKN45 cell line.•Compound 7d was highly selective to c-Met with over 2500-fold selectivity.