Identification of Imidazo[1,2-<i>b</i>]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors

Abstract

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-<i>N</i>1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-<i>b</i>]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor <b>6</b>, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.