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Currently the discovery and development of potent <i>β</i>-glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives <b>1–27</b> were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds <b>1–27</b> were then evaluated for their <i>β</i>-glucuronidase inhibitory activity, and among them, compound <b>24</b> (IC₅₀ = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and <i>β</i>-glucuronidase, in silico study was performed. Conclusively, this study has identified a potent <i>β</i>-glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products.