Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors.

BTK is a tyrosine kinase playing an important role in B cell and myeloid cell functions through B cell receptor (BCR) signaling and Fc receptor (FcR) signaling. Selective inhibition of BTK has the potential to provide therapeutical benefits to patients suffering from autoimmune diseases. Here we report the design, optimization, and characterization of novel potent and highly selective covalent BTK inhibitors. Starting from a piperazinone hit derived from a selective reversible inhibitor, we solved the whole blood cellular potency issue by introducing an electrophilic warhead to reach Cys481. This design led to a covalent irreversible BTK inhibitor series with excellent kinase selectivity as well as excellent CD69 cellular potency. Optimization of metabolic stability led to representative compound like 42, which demonstrated strong cellular potency based on BTK target occupancy and the inhibition of B-cell proliferation as readouts of proximal and distal functional activity.