Over expression of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein a series of novel 6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepine derivatives were designed, synthesised and evaluated for their c-Met kinase inhibition. Compounds 17e, 17f, 18a, and 18b were further examined for their anti-proliferative activities against four typical cancer cell lines (PC-3, Panc-1, HepG2, and Caki-1). The promising compound 17f was identified as a multi-target receptor tyrosine kinase inhibitor, which also displayed favourable pharmacokinetic properties in rats, had an acceptable safety profile in preclinical studies, and significant anti-tumour activity in the Caki-1 tumour xenograft model.

已知c-Met酪氨酸激酶的过表达促进肿瘤发生和转移，并引起治疗抗性。本文设计，合成并评价了一系列新颖的6,11-二氢-5 H-苯并[e]嘧啶[5,4- b ] [1,4]二氮杂卓衍生物，并对其c-Met激酶抑制作用进行了评估。进一步检查了化合物17e，17f，18a和18b对四种典型癌细胞系（PC-3，Panc-1，HepG2和Caki-1）的抗增殖活性。有前途的化合物17f 被鉴定为多靶受体酪氨酸激酶抑制剂，在大鼠中也显示出良好的药代动力学特性，在临床前研究中具有可接受的安全性，并且在Caki-1肿瘤异种移植模型中具有显着的抗肿瘤活性。