A Greener and Scalable Approach for the Synthesis of MRT67307 and Its AntiInflammatory Activity

Activation of I-kappa-B kinase (IKK) epsilon (IKKε, or IKBKE) and TNK-binding kinase 1 (TBK1) is a potential cellular mechanism that regulates several biological processes. Activation of IKKε/TBK1 axes leads to the phosphorylation of interferon regulatory factor 3 (IRF3) and the subsequent production of interferon-stimulated genes (ISGs). MRT67307 is a potent reversible dual inhibitor of IKKε/TBK1 and has been reported in some studies to understand the relevant disease mechanisms. However, there is no straightforward high-yielding, and greener process reported in the literature for the synthesis of the MRT compound. We are, therefore, reporting herewith a scalable high-yielding, greener process with an overall yield of 11% (calculated without involving several preparative purifications) for the synthesis of MRT compound. The new method is expected to facilitate the availability of MRT compound in larger quantities to carry out required in vitro and in vivo studies in detail and its suitability for relevant disease models. This new synthetic scheme reported in this manuscript may also be helpful in the creation of new synthetic compound libraries starting with the parent chemotype and intermediate compounds.