Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). There have been three generation drugs developed to treat of NSCLC. The third-generation EGFR tyrosine kinase inhibitors (TKIs) Rociletinib and Osimertinib (AZD9291) achieved remarkable clinical efficacy. However, due to the inhibitory activity against the wild-type EGFR, the side effect of associated skin rash and gastrointestinal toxicity appeared. Thus, there is still an urgent need to develop novel inhibitors with potent inhibitory activity and high selectivity for T790M-containing EGFR over EGFR^WT. Herein, guided by the molecular dynamic simulation results, a series of potent and selective Osimertinib derivatives were designed, synthesized and evaluated. The promising compounds 7f, 7g, 7k, 7m and 7n demonstrated excellent kinase inhibitory activity and high selectivity for EGFR^T790M/L858R mutant. The selectivity of 7m to EGFR^T790M/L858R was the highest in the current known compounds near to 2500-fold. In addition, the compound 7m showed considerable activity against NCI–H1975 and HCC827 cells, arrested NCI–H1975 cell cycle at the G2/M stage and significantly induced apoptosis in NCI–H1975 cell. These encouraged results indicated that 7m will be used as a candidate targeting EGFR^T790M/L858R for further pharmacodynamic and pharmacokinetic studies, and all these studies provide important clues for the discovery of potent EGFR^T790M/L858R inhibitors with high selectivity.

表皮生长因子受体（EGFR）是非小细胞肺癌（NSCLC）药物研究最有吸引力的靶点。已经开发了三代药物来治疗NSCLC。第三代EGFR酪氨酸激酶抑制剂（TKI）罗西替尼和奥希替尼（AZD9291）取得了显着的临床疗效。然而，由于对野生型EGFR的抑制活性，出现了相关的皮疹和胃肠道毒性的副作用。因此，仍然迫切需要开发对含有 T790M 的 EGFR 比 EGFR ^WT具有强抑制活性和高选择性的新型抑制剂。在此，以分子动力学模拟结果为指导，设计、合成和评估了一系列有效且选择性的奥希替尼衍生物。有前途的化合物7f、7g、7k、7m和7n对EGFR ^T790M/L858R突变体表现出优异的激酶抑制活性和高选择性。7m对EGFR ^T790M/L858R的选择性是目前已知化合物中最高的，接近2500倍。此外，化合物7m对 NCI-H1975 和 HCC827 细胞显示出相当大的活​​性，使 NCI-H1975 细胞周期停滞在 G2/M 阶段，并显着诱导 NCI-H1975 细胞凋亡。这些令人鼓舞的结果表明，7m将用作靶向 EGFR ^{T790M/L858R的候选药物}为进一步的药效学和药代动力学研究，所有这些研究为发现具有高选择性的强效EGFR ^{T790M/L858R抑制剂提供了重要线索。}