Zinc-dependent histone deacetylases (HDAC) are a class of 11 different enzymes, involved in regulating the acetylation status of histone and non-histone proteins. HDAC inhibitors were first developed in oncol. based on the observation of frequent epigenetic defects in both solid and hematol. malignancies. These first-generation inhibitors however hit several, if not all, of the 11 Zn-dependent HDACs and suffer from a low therapeutic window that limits the possibility to target specific biol. functions of individual HDAC subtypes. To further explore therapeutic opportunities in the HDAC field, there is a considerable interest in the development of isoform-selective HDAC inhibitors. HDAC6 appears to be a particularly attractive target, since its expression and function alterations have been correlated to a variety of pathologies, such as autoimmune disorders, neurodegenerative diseases and cancer. HDAC6 is primarily a cytoplasmic protein and its main deacetylase activity is on non-histone substrates, such as tubulin, HSP90 and cortactin. Moreover, selective inhibition of HDAC6 does not show cytotoxic effects in normal cells. With the aim of improving potency, HDAC6 vs Class I selectivity and ADME of a series of amides of the p-amino Me benzoic hydroxamic acid (see, for example, compound 1), we designed a library of 3,5-difluoro-benzohydroxamate-derivatives, bearing a 5-membered heterocyclic ring scaffold as a non-classical amide bioisostere (see, for example, compounds 2 and 3). More than 200 compounds were prepared, most of them showing a relevant low nM HDAC6 inhibitory activity, with selectivity of up to 3 orders of magnitude vs Class I and, in some cases, better ADME profiles when compared to other known HDAC6 inhibitors.