A new series of sulfonate derivatives 1a-zk were synthesized and evaluated as inhibitors of nucleotide pyrophosphatases. Most of the compounds exhibited good to moderate inhibition towards NPP1, NPP2, and NPP3 isozymes. Compound 1m was a potent and selective inhibitor of NPP1 with an IC<sub>50</sub> value of 0.387 ± 0.007 µM. However, the most potent inhibitor of NPP3 was found as 1x with an IC<sub>50</sub> value of 0.214 ± 0.012 µM. In addition, compound 1e was the most active inhibitor of NPP2 with an IC<sub>50</sub> value of 0.659 ± 0.007 µM. Docking studies of the most potent compounds were carried out, and the computational results supported the in vitro results.