The high distribution of CB<sub>2</sub> receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: selective CB<sub>2</sub> agonists are able to modulate inflammation without triggering psychotropic effects. In this work, we report a new series of selective CB<sub>2</sub> agonists based on a benzo[d]thiazol-2(3H)-one scaffold. This drug design project led to the discovery of compound 9, as a very potent CB<sub>2</sub> agonist (K<sub>i</sub> = 13.5 nM) with a good selectivity versus CB<sub>1</sub>. This compound showed no cytotoxicity, acceptable ADME-Tox parameters and demonstrates the ability to counteract colon inflammatory process in vivo.