A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1<i>H</i>‑[1,2,3]­triazolo[4,5‑<i>c</i>]­pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (<i>S</i>)-(2-fluoro-3-(trifluoromethyl)­phenyl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>29</b>) and (<i>S</i>)-(3-fluoro-2-(trifluoromethyl)­pyridin-4-yl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>35</b>), were found to have robust P2X7 receptor occupancy at low doses in rat with ED₅₀ values of 0.06 and 0.07 mg/kg, respectively. Compound <b>35</b> had notable solubility compared to <b>29</b> and showed good tolerability in preclinical species. Compound <b>35</b> was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders