Discovery of a novel series of selective macrocyclic PKCTheta inhibitors

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.