Design, synthesis and biological evaluation of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds as EGFR-TKIs

Based on EGFR-TKI Osimertinib as lead compound, a series of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds were designed and synthesized by macrocyclization. Their structures were identified by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. The pharmacological activities of the target compounds were tested and the preliminary structure-activity relationship was discussed. Among them, 17-membered ring compound H1 displayed the best inhibitory activities against EGFR^L858R/T790M and EGFR^{d746-750/T790M} with IC₅₀ value of 2.92 nM and 0.34 nM, respectively. Exhilaratingly, 17-membered ring compound H7 possessed the most potent antiproliferative activity against BaF3-EGFR^del19/T790M cell lines (IC₅₀ = 0.035 µm), which rivaled that of Osimertinib (IC₅₀ = 0.033 µm).

EGFR-TKIs; Macrocyclic derivatives; Macrocyclization; Pharmacological activity test; Synthesis.