Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR L858R/T790M/C797S ).

Tertiary EGFRc797s mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR(L858R/T790M/C797S) inhibitors. A representative compound, 8r-B, exhibited an ICso of 27.5 nM against the EGFR(L858R/T790M/C797S) mutant, while being a significantly less potent for EGFRwr (IC50 > 1.0 NM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.