Cyclin‐dependent kinase (CDK) 9 is a protein kinase that plays a major regulatory role in the process of transcription, thereby representing an attractive target in cancer therapy. A series of novel, highly potent, selective derivatives (coined compounds 8–15) were designed, synthesized, and evaluated for their inhibitory effect on CDK functions using cancer cell lines. Here, we showed that our compound 8exhibited a potent CDK9 inhibitory activity in ICR mice, with an IC50value of 2.3 nM as well as favorable pharmacokinetic properties. Using an MV4‐11 xenograft mouse model, compound 8showed antitumor efficacy at a dose of 10 mg/kg; compound 8treatment was well tolerated, with no adverse effects on body weight or animal health. Our in vitroand in vivofindings strongly suggest that compound 8holds great promise for the development of highly potent CDK9 inhibitors in anticancer approaches. Structural formula and in‐vitro efficacy (kinase and cell assay) results for compound 8