1,3,5-三取代吡唑类ALK5抑制剂的合成与生物评价研究

目的 设计合成1,3,5-三取代吡唑类化合物，并研究其对ALK5所介导的TGFβ信号通路的抑制活性，以期发现新型ALK5抑制剂。方法 先以取代的苯甲醛和4-乙酰苯甲腈为原料，合成取代的查儿酮，再与芳基肼或芳基肼盐酸盐反应生成1,3,5-三取代吡唑啉，然后氧化脱氢得到相应的1,3,5-三取代吡唑类化合物，最后对官能团做适当的变换，得到目标化合物。应用基于细胞的TGF-Smad2 检测评价了化合物的ALK5抑制活性。结果与结论 合成目标化合物29个，其结构均经过了核磁与质谱的确证，其中化合物6c显示有较好的ALK5抑制活性。

Synthesis and biological evaluation of 1,3,5-trisubstituted pyrazoles as inhibitors of ALK5

Aim To design and synthesize a series of novel 1,3,5-trisubstituted pyrazole derivatives with ALK5 inhibition activities. Methods Firstly, substituted chalcones were prepared through the condensation between substituted benzaldehyde and 4-acetylbenzonitril. Then, substituted chalcones were reacted with arylhydrazine or hydrochloric arylhydrazine to give the 1,3,5-trisubstituted pyrazolins, which were oxidized to corresponding 1,3,5-tri-substitutedpyrazoles subsequently. After further functional groups transformation, the target compounds were obtained. The synthesized compounds were evaluated for their ALK5 inhibitory activity in TGF-Smad2 assay. Results and conclusion Twenty-nine novel compounds were synthesized and characterized using 1H-NMR and MS. Compound 6c showed relatively potent ALK5 inhibitory activity.