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Their binding affinities for recombinant human CA\u2005I, II, VA, VI, VII, XII, and XIII catalytic domains were determined by fluorescent thermal shift assay, isothermal titration calorimetry, and a stopped\u2010flow CO<jats:sub>2<\/jats:sub> hydration assay. Variation of the substituents at the 2\u2010, 3\u2010, and 4\u2010positions yielded compounds with a broad range of binding affinities and isoform selectivities. Several 2,4\u2010substituted\u20103,5,6\u2010trifluorobenzenesulfonamides were effective CA\u2005XIII inhibitors with high selectivity over off\u2010target CA\u2005I and CA\u2005II. 3,4\u2010Disubstituted\u20102,5,6\u2010trifluorobenzenesulfonamides bound CAs with higher affinity than 2,4\u2010disubstituted\u20103,5,6\u2010trifluorobenzenesulfonamides. Many such fluorinated benzenesulfonamides were found to be nanomolar inhibitors of CA\u2005II, CA\u2005VII, tumor\u2010associated CA\u2005IX and CA\u2005XII, and CA\u2005XIII. 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