Targeting Ubiquitin‐Specific Protease 7 with Novel 5‐Amino‐Pyrazole Inhibitors: Design, Synthesis, and Biological Evaluation

To further extend the structure–activity relationships (SARs) of thepreviously published ubiquitin-specific protease 7 (USP-7) inhibi-tor STIRUR-41, a small library of 5-aminopyrazoles 1a–d and 2a–dis designed and synthesized. The chemical identity of the desiredstructure is confirmed by nuclear magnetic resonance and singlecrystal X-ray diffraction analyses. All novel derivatives are testedas potential USP-7 inhibitors and compounds 1a–d block enzymeactivity in a dose-dependent manner and with lower IC 50 valuescompared to the lead compound STIRUR-41. Notably, 1d, bearinga meta-trifluoromethylphenyl group linked to the carbamate moi-ety, proved to be the most active candidate. Conversely, com-pounds belonging to series 2, which possess greater sterichindrance, exhibit no activity. The most effective compoundsof series 1 are noncytotoxic across a panel of tumor and normalcell lines at 10 μM concentration. For the most active compound1d, a parallel artificial membrane permeability assay is also per-formed, as well as docking and molecular dynamics simulations.