Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors

Isothiazolo[4,3- b ]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5- b ]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5- b ]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5- b ]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders. A novel route to various substituted isothiazolo[4,5- b ]pyridines was established. The compounds completely lacked GAK affinity, which was explained by in silico analysis.