Synthesis and SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors

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. [Display omitted] •Novel 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives were designed targeting CDK4/6.•Introducing a 2-aminopyridine side chain at the C-8 position could inhibit CDK4/6 with exquisite selectivity over CDK2.•Both compounds 13m and 13n displayed potent antiproliferative activities against MCF-7 cell.•The CDK4/6 inhibitor 13n exhibited reasonable pharmacokinetic profiles.•Molecular docking in the active site of CDK6.