Design and Synthesis of Novel Dual Inhibitors for JAK3 and TEC Kinases in Autoimmune Disorders

Janus kinase 3 (JAK3) and tyrosine-protein kinase (TEC) play crucial roles in autoimmune diseases. Here, we report the optimization of JAK3/TEC dual covalent inhibitors through a series of rational design strategies. Through the fusion of a fluorine-substituted benzene ring to the piperidine, we achieved compound 8a with improved in vitro activity and selectivity and good drug-like properties. Compound 8a demonstrated excellent therapeutic efficacy in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis orally, with no body weight loss, suggesting a preliminary indication of good safety. These findings support the potential of compound 8a as a promising candidate for the development of new therapies targeting JAK3 and TEC.