Discovery and antitumor activity of Benzo[d]imidazol-containing 2,4-diarylaminopyrimidine analogues as ALK inhibitors with mutation-combating effects.

To address drug resistance caused by ALK kinase mutations, a series of novel 2,4-diarylaminopyrimidine (DAAP) analogues were designed by incorporating 1H-benzo[d]imidazol motif onto the maternal framework. All compounds were efficiently synthesized and antiproliferative activities against Karpas299, H2228 and A549 cell lines were evaluated by MTT assay. Delightly, the most promising derivative H-11 was detected with IC values of 0.016 μM and 0.099 μM against ALK- positive Karpas299 and H2228 cells. Meanwhile, H-11 displayed encouraging enzymatic inhibitory potency with IC values of 2.7 nM, 3.8 nM and 5.7 nM toward ALK, ALK and ALK, respectively. Ultimately, the binding modes of optimal H-11 with ALK wild-type and mutants were ideally established which further confirmed the structural basis in accordance with the SARs analysis.