Epidermal　growth　factor　receptor　tyrosine　kinase　inhibitors　(EGFR-TKIs)　have　emerged　as　the　first-line　treatment　for　patients　with　EGFR-mutant　non-small　cell　lung　cancer　(NSCLC).　A　series　of　2H-[1,4]oxazino[2,3-f]quinazolin　derivatives　were　synthesized　and　evaluated　as　irreversible　EGFR-TKIs　for　the　treatment　of　NSCLC.　Most　of　the　synthesized　compounds　demonstrated　strong　inhibitory　activity　against　the　EGFR　kinase　and　the　tested　cancer　cells.　Notably,　compound　4a　exhibited　considerable　inhibitory　effects　against　the　EGFR　kinase　and　the　EGFRL858R/T790M　mutant　NCI-H1975　cancer　cells.　Compound　4a　was　found　to　suppress　cell　proliferation,　colony　formation,　cell　invasion,　and　migration,　while　also　inducing　G0/G1　phase　arrest　of　the　cell　cycle　in　NCI-H1975　cells.　Compound　4a　was　docked　into　the　active　pocket　of　the　EGFR　mutant　to　ascertain　the　probable　binding　conformation.　Overall,　compound　4a　was　identified　as　a　promising　irreversible　EGFR-TKI　for　the　treatment　of　NSCLC.