Investigation of various heterocyclic core isosteres of imidazopyrazines ass="boldFont">1 & ass="boldFont">2 yielded purine derivatives ass="boldFont">3 & ass="boldFont">8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of ass="boldFont">20 as a leading compound. Compound ass="boldFont">20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.