Novel and selective spiroindoline-based inhibitors of sky kinase

We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase. Structure determination using X-ray crystallography clearly demonstrates that the compounds bind in the canonical ATP-binding site yet exhibit high levels of kinome selectivity through the occupation of a unique selectivity subpocket found adjacent to Ala571. Although novel and highly selective, inhibitors in this series exhibit modest oral bioavailability in the rat due to low absorption across the gut wall.