From a screening campaign involving a library of novel 3-substituted or 3,6-disubstituted pyrazolo[1,5-a]pyrimidines a new lead compound was discovered. Library compounds were prepared via a microwave-assisted synthesis that allowed modular construction of a wide range of substrates. The method involved a one-pot 3-step conversion of acetonitriles to give the target compounds in excellent isolated yields (62% ave). The method was exceptionally straightforward and gave products after only 1 hour total reaction time: (1) DMF-dimethylacetal (120 °C, 20 min), (2) NH2NH2.HBr (120 °C, 20 min), and (3) 2-aryl-substituted malondialdehdyes, or 1,1,3,3-tetramethoxypropane (120 °C, 20 min). Compounds were screened against MCF7 breast cancer cancer and A2780 ovarian cell lines in vitro. Significantly, 3-(benzothiazol-2-yl)pyrazolo[1,5-a]pyrimidine was as active as more synthetically challenging 3,6-disubstituted derivatives and had a uniquely selective binding profile against a panel of 403 protein kinases (Kinomescan™ selectivity score = 0.005, Kd = 0.55 ± 0.055 μM and 0.410 ± 0.20 μM for JAK1 JH2 pseudokinase and VPS34, respectively). Details of the synthesis and optimization will be presented.

Optimization of a novel pyrazolo[1,5-a]pyrimidine exhibiting selective activity against VPS34 and JAK1-JH2

ACS Spring 2022

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