We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequence of seven synthetic transformations. The solid-state structure of 7-chloro-9-ethyl-1-thia-2,4a-diazacyclopenta[b]naphthalene-3,4-dione was determined by X-ray diffraction. The prepared derivatives of desfluoroisothiazolopyridones exhibited (a) antibacterial activity against Gram-negative and Gram-positive organisms, (b) inhibitory activities against DNA gyrase and topoisomerase IV, and (c) no inhibitory activity against human topoisomerase II.