Isothiazolo[4,3-b]pyridines are known to be endowed with potent affinity for cyclin G associated kinase (GAK). In this paper, we expanded the structure–activity relationship study by broadening the structural variety at position 3 of the isothiazolo[4,3-b]pyridine scaffold. The most potent GAK ligands (displaying K_d values of less than 100 nM) within this series carry an alkoxy group at position 3 of the central scaffold. Unfortunately, these ligands display only modest antiviral activity against the hepatitis C virus.