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).

以EGFR-TKI奥希替尼为先导化合物，通过大环化方法设计合成了一系列新型的以苯胺嘧啶为支架的大环衍生物。它们的结构通过¹ H NMR、¹³ C NMR、¹⁹ F NMR和HRMS鉴定。测试了目标化合物的药理活性，并讨论了初步的构效关系。其中，17元环化合物H1对EGFR ^L858R/T790M和EGFR ^{d746-750/T790M}的抑制活性最好，IC ₅₀值分别为2.92 nM和0.34 nM。令人兴奋的是，17 元环化合物H7^{对 BaF3-EGFR del19/T790M}细胞系具有最强的抗增殖活性(IC ₅₀  = 0.035 µm)，与奥希替尼 (IC ₅₀  = 0.033 µm) 相媲美。