CDK4/6 pathway is an attractive target for development of anti-cancer drugs. Herein, we reported the design and synthesis of a series of 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives as selective CDK4/6 inhibitors. Applied with the optimizing strategy to the initial scaffold, it is found that compound 13n is able to selectively inhibit CDK4 and CDK6 with IC₅₀ values 0.01 and 0.026 μM, respectively. The compound showed good anti-proliferative activity when tested in a panel of tumor cell lines with CDK4/6 related mechanism of action, the results clearly suggest that compound 13n works much better than Ly2385219 which is a selective CDK4/6 inhibitor. This compound was also found to have favorable pharmacokinetic parameters. Taken together, compound 13n could be selected for further preclinical evaluation.

CDK4 / 6途径是开发抗癌药物的有吸引力的靶标。在这里，我们报道了设计和合成一系列的4,5-二氢-1H-吡唑并[4,3-h]喹唑啉衍生物作为选择性CDK4 / 6抑制剂。将优化策略应用于初始支架，发现化合物13n能够选择性抑制CDK4和CDK6，IC ₅₀值分别为0.01和0.026μM。当在一组具有CDK4 / 6相关作用机制的肿瘤细胞系中进行测试时，该化合物显示出良好的抗增殖活性，结果清楚地表明，化合物13n比选择性CDK4 / 6抑制剂Ly2385219更好。还发现该化合物具有有利的药代动力学参数。综合起来，复合可以选择13n进行进一步的临床前评估。