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Selective histone deacetylase 6 (HDAC6) inhibitors are safe and well‐tolerated with less off‐target effect. However, most available HDAC6 inhibitors contain hydroxamate as a zinc‐binding group (ZBG), and their unfavorable pharmacokinetic properties along with potential genotoxicity limited wide application in diverse diseases. Therefore, we designed and synthesized a series of selective HDAC6 inhibitors utilizing thiol as the ZBG and discussed their structure‐activity relationship based on molecular docking. In particular, compound 21, obtained by constantly step‐by‐step simplification and evolution based on Ricolinostat, a specific HDAC6 inhibitor in Phase II, unexpectedly showed high selectivity (29‐fold) and moderate potency (73 nM). Utilizing pyrimidine as a linker in thiol‐based HDAC6 inhibitors produces an utterly novel structure, which might display different pharmacokinetic properties and genotoxicity.