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Scheme 2.Fig. 3. Three representative compounds.meta-substituent on a phenyl inthis position could gain potencyby filling the S2 pocket moreefficiently. In order tosynthesize more stablecompounds we decided tointroduce a urea functionality atthe R3 position, instead of thepreviously used carbamategroup. Different R6 aryls incombination with an unsubstitutedP2 (glycine analogue)were introduced in thedevelopment of a structureactivity relationship around thisposition. Also, we decided toinvestigate the effect oninhibitory potency by using areversed acyl sulfonamidegroup as a P1 substituent(Figure 2). The synthesis isoutlined in Scheme 1 and startswith a two step generation ofthe pyrazinone building block[3] followed by introduction ofthe urea group via a palladiumcatalyzed, Buchwald-type,N-arylation reaction. Afterhydrolysis of the benzylester thearomatic P1 group was introduced.The weak nucleophile (aniline) makes this coupling reaction slow and low yielding.A change from HATU as the coupling reagent to activation of the acid with phosphorusoxychloride in pyridine increased the yield and shortened the reaction time considerably(Scheme 1). The reversed sulfonamide was prepared as outlined in Scheme 2. This protocolenables introduction of a wide range of acid chlorides and hence a variation of suitablearomatic P1 substituents. The phtaloyl protecting group withstands the reaction conditionsand is easily removed in the last step.Evaluation of three representative compounds (C-E, Figure 3) shows a promise in theabove mentioned design. Introduction of a urea function in position R6 (compound C)produced more stable inhibitors with potencies comparable to compounds A and B. Ameta-bromo phenyl group in position R3 gave compound D with much improved inhibitorypotency.The aromatic reversed acyl sulfonamide substituent in P1 was very well tolerated asshown by compound E being more potent than compound C. Further work on this type ofcompounds is in progress.AcknowledgmentsWe gratefully acknowledge financial support from Medivir AB. The Swedish Academy ofPharmaceutical Sciences and Anna-Maria Lundins Foundation for supporting the participation in ACSFall 2010 and the 31 st EPS 2010.References1. Shepard, C.W., et al. Lancet Infect. Dis. 5, 558-567 (2005).2. Webster, D.P., et al. Lancet Infect. Dis. 9, 108-117 (2009).3. Gising, J., et al. Org. Biomol. Chem. 7, 2809-2815 (2009).4. Örtqvist, P., et al. Bioorg. Med. Chem. 18, 6512-6525 (2010).233