In this study, we design, synthesize and evaluated a number of novel quinazoline derivatives by exchanging the positions of the C5 and C6 substituents and varying the C4-amino functionality of gefitinib, and report that compound V1801 having a trifluoromethyl group at the C5'-position and a bromine at the C2'-position of the aniline moiety substituted at the C4 position of quinazoline core overcomes gefitinib resistance via up-regulation of Noxa, suggesting a novel strategy to fight against NSCLC with EGFR T790M mutation. The gene discussed is PMAIP1; the disease is non-small cell lung carcinoma.