Spleentyrosine kinase (Syk) is an attractive drug target in autoimmune,inflammatory, and oncology disease indications. The most advancedSyk inhibitor, R406, 1(or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications,but its clinical progress has been hampered by dose-limiting adverseeffects that have been attributed, at least in part, to the off-targetactivities of 1. It is expected that a more selectiveSyk inhibitor would provide a greater therapeutic window. Herein wereport the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identificationof GS-9973, 68, a highly selective and orally efficaciousSyk inhibitor which is currently undergoing clinical evaluation forautoimmune and oncology indications. [ABSTRACT FROM AUTHOR]