Versatile synthetic methods that allow late-stage introduction of substituents are of great interest to the medicinal chemist. We now wish to report a flexible synthetic route to 3,5,8-trisubstituted [1,2,4]triazolo[4,3-a]pyrazines in four to five steps in good to excellent overall yields starting from commercially available 2,3-dichloropyrazine. Addition of hydrazine followed by hydrazone formation and oxidative cyclization establishes the core scaffold with a wide range of R1 substituents. Substitution of the remaining chloride followed by lithiation of the core and addition of an electrophile serve to install the R2 and R3 groups. Further coupling reactions enable the introduction of a variety of substituents at R2 and R3. To illustrate the usefulness of this methodology, we report the re-scaffolding of a previously reported p38a MAPK inhibitor [1] to afford a new compound with p38a IC50 = 260 nM.Reference 1. Wurz, R. P.; Pettus, L. H.; Henkle, B.; Sherman, L.; Plant, M; Miner, K; McBride, H. J.; Wong, L. M.; Saris, C. J.; Lee, M. R.; Chmait, S.; Mohr, C.; Hsieh, F.; Tasker, A. S. Bioorg. Med. Chem. Lett. 2010  , 20, 1680.

Versatile synthesis of trisubstituted triazolopyrazines with applications to medicinal chemistry

245th National Meeting (2013)

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