The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in tumor angiogenesis, and inhibition of the VEGF pathway is considered an efficacious method for treating cancer. Herein, we describe synthetic studies of imidazo[1,2-b]pyridazine derivatives as VEGF receptor 2 (VEGFR2) kinase inhibitors. The imidazo[1,2-b]pyridazine scaffold was designed and synthesized as a hinge binder according to the previously reported crystal structure of pyrrolo[3,2-d]pyrimidine 1 with VEGFR2. Structure–activity relationship studies revealed that meta-substituted 6-phenoxy-imidazo[1,2-b]pyridazine derivatives had potent affinity for VEGFR2. In particular, N-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-3-(trifluoromethyl)benzamide (6b) exhibited strong inhibitory activity against VEGFR2 with an IC₅₀ value of 7.1 nM, and it inhibited platelet-derived growth factor receptor β kinase with an IC₅₀ value of 15 nM.

血管内皮生长因子（VEGF）信号转导通路已牵涉到肿瘤血管生成，并且抑制VEGF通路被认为是治疗癌症的有效方法。在这里，我们描述了咪唑并[1,2- b ]哒嗪衍生物作为VEGF受体2（VEGFR2）激酶抑制剂的合成研究。根据先前报道的吡咯并[3,2- d ]嘧啶1与VEGFR2的晶体结构，设计并合成了咪唑并[1,2- b ]哒嗪骨架，作为铰链结合剂。结构-活性关系研究表明，间位取代的6-苯氧基-咪唑并[1,2- b ]哒嗪衍生物对VEGFR2具有强亲和力。特别是N-[3-（咪唑并[1,2 - b ]哒嗪-6-基氧基）苯基] -3-（三氟甲基）苯甲酰胺（6b）对VEGFR2的抑制作用强，IC ₅₀值为7.1 nM，并且抑制血小板衍生的生长因子受体β激酶，IC ₅₀值为15 nM。