Pyrroformyl-containing 2,4-diaminopyrimidine derivatives as a new optimization strategy of ALK inhibitors combating mutations.

Aiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC50 value of 0.034 μM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC50 values of 1.9 nM and 3.1 nM against ALKWT and ALKL1196M, respectively, surpassing the reference ceritinib (IC50 = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment.