Design, Synthesis and Biological Evaluation of Novel 9H Purine Derivatives as Potent CDK9 Inhibitors

ABSTRACT Cyclin‐dependent kinase 9 (CDK9) is considered as an important target in the research of antitumor drugs. Taking the CDK2/9 inhibitor CYC065 as the positive control and an in‐house library compound ( 64 ) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure–activity relationships (SAR). In general, SAR of 9H purine CDK9 inhibitors is systematically described in this paper, resulting in the discovery of two compounds ( B2 and B5 ) with further research value. After conducting selectivity testing against CDK2/9 kinase, compound B5 demonstrated approximately five‐fold greater selectivity towards CDK9‐cyclinT1 over CDK2‐cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors.