Discovery of novel 1,2,4-triazolo-1,2,4-triazines with thiomethylpyridine hinge binders as potent c-Met kinase inhibitors.

Mesenchymal-epithelial transition factor (c-Met)/HGF overactivation is involved in diverse human cancers.  Herein, we report the synthesis and biological evaluation of thiomethylpyridine-linked triazolotriazines as c-Met kinase inhibitors. Compounds and were more potent than crizotinib on HepG2 cells with IC values of 0.74 and 0.71 μM in the MTT assay, respectively. Interestingly, all of the target compounds displayed IC values in the range of 3.9-11.1 nM in the c-Met kinase inhibition assay which were lower than the value for crizotinib (11.1 nM). Target compound can be considered as a leading drug candidate due to its lower IC values than crizotinib in both HGF-induced proliferation and c-Met kinase inhibition assays.