Inhibition of the epidermal growth factor receptor (EGFR) has been proved to be one of the most promising strategies for the treatment of non-small cell lung cancers. A series of 2-aryl-4-amino substituted quinazoline derivatives were designed and synthesized with the purpose to overcome L858R/T790M/C797S (CTL) triple mutant drug resistance and the biological activity for inhibition of CTL kinases and EGFR wild type (WT) were evaluated. Three compounds ( 20 , 24 and 27 ) showed excellent inhibitory activities against EGFR kinases triple mutant CTL (IC₅₀ < 1 µM) and high selectivity (IC₅₀: WT/CTL >10000). Cell line evaluation showed that the most potent compound 27 was significantly potent against H1975-EGFR L858R/T790M (IC₅₀ = 3.3 µM) and H1975-EGFR L858R/T790M/C797S (IC₅₀ = 1.2 µM). Compound 27 also exhibited good microsomes stabilities in human, rat and mouse liver species, but low bioavailability. This work would be very useful for discovering new quinazoline derivatives as tyrosine kinase inhibitors targeting triple mutant L858R/T790M/C797S.