Design and Synthesis of New JAK1 Inhibitors based on SulfonamideTriazine Conjugates.

AIMS Design of sulfonamide-triazine derivatives as JAK1 inhibitors. BACKGROUND JAK1 is a kinase involved in different autoimmune diseases. JAK1 inhibitors have shown promising results in treating autoimmune diseases. OBJECTIVES To design new JAK1 inhibitors based on sulfonamides-triazine conjugates capable of binding interactions comparable to observed interactions anchoring potent crystallographic JAK1 inhibitors. METHODS The crystallographic structures of 4 diverse nanomolar inhibitors complexed within JAK1 were used to guide the synthesis of new diaminotriazine-sulfonamide-based JAK1 inhibitors. RESULTS Nineteen compounds have been prepared some of which exhibited low micromolar IC50 values against JAK1. CONCLUSIONS Crystallographic complexes of diverse JAK1 inhibitors were successfully used to guide the synthesis of novel sulfonamide-triazine-based low micromolar JAK1 inhibitors.