Synthesis of Potent Vanin‐1 Inhibitors Labelled With Carbon‐14 and Deuterium

Vanin‐1 is an enzyme highly expressed in the kidneys, liver, and small intestines. Inhibition of this enzyme has been postulated as a novel approach in the treatment of several inflammatory diseases. BI 764122 , BI 1585773 , and BI 1595043 are very potent inhibitors of this enzyme. These three analogs share the same ( S )‐ N ‐(nicotinoyl)pyrrolidin‐3‐yl)‐ N ‐methyl acetamide moiety. The preparation of these analogs labelled with carbon‐14 was accomplished via carbon‐14 carboxylation with carbon dioxide of corresponding aryl halides, followed by amide bond formation with ( S )‐ N ‐(methyl)‐ N‐ (pyrrolidin‐3‐yl)acetamide. For metabolic considerations, the radioactive carbon was also incorporated in a cyclopropyl in [ 14 C ] ‐BI 764122 synthesis. The deuterium labelling of these three compounds was completed using the common moiety ( S )‐ N ‐(methyl‐ d 3 )‐ N ‐(pyrrolidin‐3‐yl)acetamide‐ d 3 , which was prepared in three steps and then coupled to the corresponding aryl acids via amide bond.