Synthesis and evaluation of novel amino pyrimidine derivatives containing sulfonamide and their application as EGFR inhibitors

Twenty pyrimidine derivatives with aminophenylsulfonamide moiety were synthesized and evaluated as inhibitors against EGFR-mutation cancers. The anti-proliferation assay showed that most of the synthesized compounds had excellent inhibitory activity against H1975-EGFR^L858R/T790M and PC9-EGFR^Del19 tumor cells. Among them, the optimal compound 12e, exhibited 0.6 nM and 4 nM of the IC₅₀ values against H1975 cells and PC9 cells, respectively. In PC9 and H1975 xenograft nude mice, TGI of 12e is 98.5 %and 97.7 % when oral administration at dosage of 20 mg/kg. Molecular docking study showed 12e gave preferable affinity upon EGFR then Osimertinib. As for the anti-tumor mechanism, 12e inhibits phosphorylation and downstream signaling by binding to EGFR, then inhibits the proliferation of tumor cell lines, promotes Apoptosis, and prohibits the migration and invasion of the tumor cell lines.