A series of novel 2,4-diarylaminopyrimidine derivatives of AZD9291 were discovered as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. The majority of these compounds exhibited moderate to excellent EGFR T790 M/L858R inhibitory activities and comparable anti-proliferative activities against double mutant over-expressed NCI-H1975 cells to that of AZD9291. The most promising compounds 8a displayed an IC₅₀ of 4.1 nM against EGFR L858R/T790M mutants. 8a also showed excellent cytotoxic effect against NCI-H1975 cells with an IC₅₀ of 59 nM and 100-fold selectivity over wide-type EGFR over-expressed A431 cells. Compound 8a significantly inhibited tumor growth in NCI-H1975 xenograft models at a non-toxic dose. Docking study performed for 8a with ATP binding site of EGFR-TK showed the similar binding mode to that of AZD9291. All these results suggested that compound 8a was a potential mutant-selective EGFR inhibitor.

发现了AZD9291的一系列新型2,4-二芳基氨基嘧啶衍生物，作为L858R / T790M突变型选择性表皮生长因子受体（EGFR）抑制剂。这些化合物中的大多数显示出中等至优异的EGFR T790 M / L858R抑制活性，并且对双突变过表达的NCI-H1975细胞的抗增殖活性与AZD9291相当。最有前途的化合物8a对EGFR L858R / T790M突变体的IC ₅₀为4.1 nM。8a还显示出对NCI-H1975细胞的优异细胞毒性作用，IC ₅₀为59 nM，选择性比宽表达EGFR过表达的A431细胞高100倍。化合物8a在NCI-H1975异种移植模型中以无毒剂量显着抑制了肿瘤的生长。对具有EGFR-TK ATP结合位点的8a进行的对接研究显示出与AZD9291相似的结合模式。所有这些结果表明化合物8a是潜在的突变体选择性EGFR抑制剂。