Design, synthesis and biological evaluation of 2-phenylaminopyrimidine derivatives as EGFR inhibitors

In the treatment of non-small cell lung Cancer (NSCLC), acquired drug resistance is a major factor that affects the efficacy of third-generation epidermal growth factor receptor (EGFR) inhibitors like Osimertinib. To overcome the L858R/T790M/C797S mutation, taking the Brigatinib as the positive control, two classes of 20 target compounds were designed and synthesized with 2-phenylaminopyrimidine as the core structure on the basis of summarizing the structure-activity relationship (SAR), following the basic principles of drug design. Representative compound I-10 potently inhibited EGFR^{L858R/T790M/C797S} with an IC₅₀ value of 33.26 nM and suppressed Ba/F₃-EGFR^{L858R/T790M/C797S} cells with an IC₅₀ value of 106.4 nM, which is 5-fold more potent than Brigatinib. Besides, the compound exhibited an inhibition rate of less than 50 % against wild-type cell (NCI-H838), which reflected its toxicity or selectivity. Furthermore, this work serves as a foundation for future studies on EGFR inhibitors.