Phenyl vinyl sulfone (PVS, 1) and phenyl vinylsulfonate (PVSN, 2) were previously reported as promising active site-directed covalent ligands for PTPs. They were shown to be cell-permeable, owing to their relatively simple structures and lack of charged functional groups. An azide-tagged variant of PVSN was also reported as the starting point for activity-based profiling. We envisioned that a more elaborate scaffold structure, larger than a phenyl ring, might improve the potency of PVSN while retaining the potentially favorable features of the vinyl sulfonate moiety. Thus, we synthesized a series of aryl vinylsulfonates and assessed their ability to covalently label and inhibit tyrosine phosphatases using two complementary assays (Figure ). In the first assay, the residual activities of several tyrosine phosphatase catalytic domains were measured using the colorigenic substrate p-nitrophenyl phosphate (pNPP) after treatment with each covalent inhibitor. In the second assay, we assessed the extent of labeling of the same PTPs by each vinyl sulfonate using intact protein mass spectrometry.