Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC₅₀ values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors.

间变性淋巴瘤激酶（ALK）是负责各种肿瘤类型发展的受体酪氨酸激酶。在这项研究中，我们合成了一系列新型的2,4-二芳基氨基嘧啶衍生物，它们具有独特的N-（3-吡啶基甲基）脲作为ALK抑制剂。带有3-甲氧基-4-吗啉代苯基取代基的最有前途的类似物5m可显着抑制ALK阳性H3122和Karpas-299细胞的增殖，IC ₅₀值约为10 nM，与阳性对照LDK378相当。化合物5m抑制ALK及其下游蛋白的磷酸化，并且对正常人原代成纤维细胞（BJ细胞）显示出低细胞毒性。装订方式5m由对接模拟提出，其解释了N-（3-吡啶基甲基）脲部分的重要作用。此外，在H3122异种移植小鼠模型中，化合物5m表现出良好的肝微粒体稳定性和显着的功效。有趣的是，化合物5m对其他人肿瘤细胞系也显示出更广泛的抗增殖活性，这与其他ALK抑制剂不同。