Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR^L858R/T790M inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC₅₀ value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC₅₀ value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR^L858R/T790M-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.

肺癌是癌症死亡的主要原因。已证明表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）在EGFR突变阳性的非小细胞肺癌（NSCLC）患者中有效。在这项工作中，设计，合成和评估了一系列新的含有环丙基部分的2,4-二芳基嘧啶衍生物，作为新型选择性EGFR ^{L858R / T790M}抑制剂。最有前途的化合物8l表现出优异的针对EGFR双重突变的激酶抑制活性，IC ₅₀值为0.26 nM。此外，8l具有IC ₅₀对H1975细胞的强活性值为0.008μM，对四种非致瘤细胞系几乎没有毒性。此外，8l在鼠EGFR ^{L858R / T790M}驱动的H1975异种移植模型中显示出有效的抗肿瘤功效。这些结果表明8l可能是有希望的进一步研究的候选药物。