Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

A series of pyrazole diaminopyrimidines with dual KDR/Aurora B kinase inhibitory activity has been identified. The SAR, physiochemical properties and antitumor activity of this series (e.g., (+)-38) are discussed.Figure optionsDownload as PowerPoint slide