Design and Synthesis of New JAK1 Inhibitors based on Sulfonamide- Triazine Conjugates

Abstract

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.