To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFR^T790M) for use as EGFR^L858R/T790M kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFR^L858R/T790M, with an IC₅₀ value of 4.0 nM and more than 42-fold selectivity for EGFR^WT (IC₅₀ = 170.0 nM). Moreover, compound A12 showed strong anti-proliferative activity against H1975 cells, with IC₅₀ value of 0.086 μΜ. Additionally, the effective inhibition of cell migration and the promotion of apoptosis by A12 verified its mechanism of action, as a selective inhibitor of EGFR^L858R/T790M.

为解决非小细胞肺癌表皮生长因子受体（EGFR）突变引起的耐药问题，我们利用搭配原理，设计合成了一系列含4,5,6,7-四氢噻吩的氨基嘧啶衍生物。 [3,2-c]吡啶侧链（根据 AZD9291 与 EGFR ^T790M的结合模式）用作 EGFR ^L858R/T790M激酶抑制剂。最有前途的化合物A12是一种非共价结合的可逆抑制剂，对 EGFR ^L858R/T790M表现出优异的激酶抑制活性，IC _{50值为 4.0 nM，对 EGFR} ^WT的选择性超过 42 倍（IC ₅₀  = 170.0 nM） . 此外，复合A12对H1975细胞具有很强的抗增殖活性，IC ₅₀值为0.086 μM。此外， A12对细胞迁移的有效抑制和对细胞凋亡的促进验证了其作用机制，作为EGFR ^L858R/T790M的选择性抑制剂。