- Click Variations on the Synthesis of 2-Nitrophenyl-4-aryl-1,2,3-triazoles without Isolation of 2-Nitrophenyl Azides
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We report a series of efficient procedures to prepare 2-nitrophenyl-4-aryl-1,2,3-triazoles avoiding the isolation of potentially hazardous 2-nitrophenyl azides. An organocatalyzed azide-enolate variant allows efficient access to the target compounds while
- Cisnetti, Federico,Roux, Amélie
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p. 610 - 614
(2020/03/27)
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- Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876
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Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.
- McComas, Casey C.,Palani, Anandan,Chang, Wei,Holloway, M. Katharine,Lesburg, Charles A.,Li, Peng,Liverton, Nigel,Meinke, Peter T.,Olsen, David B.,Peng, Xuanjia,Soll, Richard M.,Ummat, Ajay,Wu, Jie,Wu, Jin,Zorn, Nicolas,Ludmerer, Steven W.
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p. 1436 - 1448
(2017/09/19)
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- BICYCLIC HETEROCYCLES AS BET PROTEIN INHIBITORS
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The present invention relates to bicyclic heterocycles which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.
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Paragraph 0534; 0535; 0622; 0623
(2015/06/03)
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- INHIBITORS OF HEPATITIS C VIRUS NS5B POLYMERASE
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Compounds of formula (I) that are used as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and /or viral production in a cell-based system. Wherein Z, R30, R40, R50 and R60 of compounds of formula (I) are herein defined as in the description.
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Page/Page column 119
(2011/10/03)
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- 2-ALKOXY-3,4,5-TRIHYDROXYALKYLAMIDE-BENZOTHIAZEPINES PREPARATION THEREOF, COMPOSITIONS CONTAINING THEM AND USE THEREOF
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The present invention relates to 2-alkoxy-3,4,5-trihydroxyalkylamide benzothiazepine compounds, to pharmaceutical compositions comprising such compounds, to methods of treatment comprising administering such compounds, to processes for the preparation of
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Page/Page column 29
(2009/04/24)
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- Tricyclic delta-opioid modulators
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The invention is directed to delta opioid receptor modulators. More specifically, the invention relates to tricyclic δ-opioid modulators. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using com
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Page/Page column 32-33
(2008/06/13)
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- The neighboring group effect of fluorine in the tritium labeling of organic substrates with [Cp*(PMe3)IrMe(CH2Cl 2)]+ [BArf]-, a cationic iridium(III) complex
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The cationic Ir(III) complex, [Cp*(PMe3)IrMe(CH 2Cl2)][BArf] (1, Cp* = η5-C5Me5, BArf = MeB(C 6F5)3), has been shown to be a useful reagent in the tritium and deuterium labeling of organic substrates. During a recent reaction of 1 with a fluorinated molecule, we observed an unusually high incorporation of tritium ortho to the aromatic fluorines. To probe whether this was an isolated incident or a more general phenomenon, we have investigated the application of 1 towards the tritiation of simple fluorinated organic substrates. Our results indicate that aromatic fluorine indeed does exhibit a neighboring group effect in terms of directing ortho H/T exchange. The directing influence appears to be at least as strong as the hydroxyl moiety reported in previous works. Copyright
- Skaddan, Marc B.,Bergman, Robert G.
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p. 623 - 634
(2007/10/03)
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- Structure-activity relationship of a series of phenylureas linked to 4- phenylimidazole. Novel potent inhibitors of acyl-CoA:cholesterol O- acyltransferase with antiatherosclerotic activity. 2
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In our continuing search to find systemically bioavailable ACAT (acyl- CoA:cholesterol O-acyl-transferase) inhibitors with more potent antiatherosclerotic effect than N-[2-(dimethylamino)-6-[3-(5-methyl-4- phenyl-1H-imidazol-1-yl)propoxy]phenyl]-N'-pentyl
- Kimura,Watanabe,Matsui,Hayashi,Tanaka,Ohtsuka,Saeki,Kogushi,Kabayashi,Akasaka,Yamagishi,Saitou,Yamatsu
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p. 1641 - 1653
(2007/10/02)
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