Discovery Of A Novel Series Of Potent And Selective Alkynylthiazole-Derived Pi3k Gamma Inhibitors

Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that control a wide variety of cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3K gamma plays a critical role in mediating leukocyte chemotaxis as well as mast cell degranulation, making it a potentially interesting target for autoimmune and inflammatory diseases. We previously disclosed a novel series of PI3K gamma inhibitors derived from a benzothiazole core. The truncation of the benzothiazole core led to the discovery of a structurally diverse alkynyl thiazole series which displayed high PI3K gamma potency and subtype selectivity. Further medicinal chemistry optimization of the alkynyl thiazole series led to identification of compounds such as 14 and 32, highly potent, subtype selective, and CNS penetrant PI3K gamma inhibitors. Compound 14 showed robust inhibition of PI3K gamma mediated neutrophil migration in vivo.