Recently, the importance of targeted covalent inhibitors in addressing potency, selectivity and drug resistance has become of great interest, especially in the area of non-small cell lung cancer (NSCLC). Although several covalent EGFR TKIs that are advancing in NSCLC clinical development are active against mutations which are refractory to the reversible TKI drugs Tarceva and Iressa, limited chemical diversity has been explored; all of the irreversible and reversible clinical compounds share the same quinazoline scaffold. We describe the design of a novel pyrimidine-based irreversible inhibitor of EGFR (CNX17) which is active against both the WT EGFR as well as the resistance mutation L858R/T790M in biochemical assays. The inhibitor is also a potent inhibitor of EGFR signaling, including the L858R/T790M resistance mutation in cells (H1975 cell line, EC50 441 nM). Importantly, it also potently inhibits proliferation in both HCC827 (EGFR Δ746-750 EC50 < 5 nM) and H1975 (EC50 134 nM). This novel chemical scaffold may be an important addition to the armamentarium in overcoming drug resistance to current EGFR therapies. Recently, the importance of targeted covalent inhibitors in addressing potency, selectivity and drug resistance has become of great interest, especially in the area of non-small cell lung cancer (NSCLC).