Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC

Starting from the binding mode of allosteric EGFR inhibitor JBJ-04-125-02 and the key pharmacophore of the third-generation EGFR inhibitors, we designed and synthesized a novel series of EGFR inhibitors, represented by (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindolin-2-yl)-2-phenylacetamide (6q). Docking study demonstrated that top compound 6q spanned orthosteric and allosteric sites of EGFR, and formed three key H-bonds with the residues Asp855, Lys745, and Met793 located in two sites. Biological evaluation indicated that compound 6q showed potential inhibitory activity against Ba/F3-EGFR