Cyclin-dependent protein kinases (CDKs) have a central role in the regulation of cell proliferation, apoptosis and gene expression. CDK7, in particular, not only regulates the activation of the cell cycle kinases CDK1, CDK2, CDK4 and CDK6, but is also involved in the regulation of transcription as part of the transcription factor TFIIH-complex. While a common feature of cancer is the over-expression of cyclin, there is compelling evidence that CDK2, CDK4 and CDK6 are not essential for the cell cycle, making CDK7 a highly attractive target for anti-cancer drug development. The two pyrazolo[1,5-a]pyrimidine kinase inhibitors BS181 and BS194 were chosen as starting points for the development of a CDK7 selective drug candidate. BS181 is a selective CDK7 inhibitor (IC50: 21 nM) that shows moderate growth inhibition in the MCF7 breast cancer cell line (GI50: 15 μM) as well as in the HCT116 colorectal carcinoma cell line (GI50: 16 μM). The compound suffers from an insufficient oral bioavailability and a poor pharmacokinetic profile. The biological data of the second lead compound BS194 are significantly different: it is a CDK2 pan-inhibitor (IC50: 3 nM) with excellent growth inhibition in MCF7 (GI50: 0.12 μM) and in HCT116 cancer cells (GI50: 0.12 μM). The compound is highly bioavailable and has a good PK profile. The properties of BS181 and BS194 needed to be 'merged' to create a CDK7 selective compound with good overall properties. The multidimensional optimisation of both compounds was driven by iterative circles of computer-aided drug design (CADD), synthesis and biological assessment. Thus, analogues with highly functionalised northern, southern and eastern side chains as well as a novel series of 2,4-diaminopyrimidine kinase inhibitors were designed and subsequently synthesised.