Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFR inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR inhibitors by using a macrocyclization strategy. Representative compound potently inhibited EGFR and EGFR mutants with IC values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR and Ba/F3-EGFR cells with IC values of 0.036 and 0.052 μM, respectively, which is 10-20-fold more potent than brigatinib. also potently inhibited the EGFR-mutated PC-9-OR NSCLC cell proliferation with an IC value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFR-mediated resistance in NSCLC patients.