The study identifies a novel class of EGFR kinase inhibitors that are highly selective against the EGFR T790M mutation, which is a common mechanism of drug resistance in non-small cell lung cancer (NSCLC). These inhibitors, derived from a covalent pyrimidine scaffold, are 30-100 fold more potent against EGFR T790M compared to quinazoline-based inhibitors and are less potent against wild-type EGFR. In vitro and in vivo studies demonstrate that these inhibitors effectively inhibit EGFR signaling and induce tumor regression in models with EGFR T790M. Crystal structure analysis reveals that the anilinopyrimidine core of the inhibitors forms a bidentate hydrogen bonding interaction with Met 793 and covalently binds to Cys 797, explaining their high selectivity and potency. These findings suggest that this class of inhibitors may be more effective and better tolerated than current EGFR inhibitors, potentially offering a new therapeutic option for patients with EGFR mutant NSCLC.The study identifies a novel class of EGFR kinase inhibitors that are highly selective against the EGFR T790M mutation, which is a common mechanism of drug resistance in non-small cell lung cancer (NSCLC). These inhibitors, derived from a covalent pyrimidine scaffold, are 30-100 fold more potent against EGFR T790M compared to quinazoline-based inhibitors and are less potent against wild-type EGFR. In vitro and in vivo studies demonstrate that these inhibitors effectively inhibit EGFR signaling and induce tumor regression in models with EGFR T790M. Crystal structure analysis reveals that the anilinopyrimidine core of the inhibitors forms a bidentate hydrogen bonding interaction with Met 793 and covalently binds to Cys 797, explaining their high selectivity and potency. These findings suggest that this class of inhibitors may be more effective and better tolerated than current EGFR inhibitors, potentially offering a new therapeutic option for patients with EGFR mutant NSCLC.