Design, synthesis, and biological evaluation of novel aminopyrimidine derivatives as EGFR inhibitors

Abstract

The treatment of non-small cell lung cancer (NSCLC) is significantly challenged by the development of acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors, such as Osimertinib, which limits their therapeutic efficacy. Using the EGFR ^{L858R/T790M/C797S} inhibitor Brigatinib as a reference compound, we designed and synthesized 24 target compounds with aminopyrimidine as the core structure. Among these, the representative compound IIB-5 demonstrated potent inhibition of EGFR^{L858R/T790M/C797S}, achieving an IC₅₀ value of 18.81 nM. It also exhibited strong inhibition against Ba/F3-EGFR^{L858R/T790M/C797S} cells with an IC₅₀ of 97.12 nM, showing a five-fold potency increase over Brigatinib. Compound IIB-5 provides a valuable reference for further research on EGFR inhibitors.