Discovery of 5,7-Dihydro-6<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors

Abstract

A series of exceptionally selective CDK2 inhibitors are described. Starting from an HTS hit, we successfully scaffold hopped to a 5,7-dihydro-6<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-6-one core structure, which imparted a promising initial selectivity within the CDK family. Extensive further SAR identified additional factors that drove selectivity to above 200× for CDKs 1/4/6/7/9. General kinome selectivity was also greatly improved. Finally, use of <i>in vivo</i> metabolite identification allowed us to pinpoint sulfonamide dealkylation as the primary metabolite, which was ameliorated through the deuterium effect.