- Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile
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Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.
- Walton, Mary C.,Yang, Yun-Fang,Hong, Xin,Houk,Overman, Larry E.
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- Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis
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Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.
- Scanio, Marc J. C.,Searle, Xenia B.,Liu, Bo,Koenig, John R.,Altenbach, Robert,Gfesser, Gregory A.,Bogdan, Andrew,Greszler, Stephen,Zhao, Gang,Singh, Ashvani,Fan, Yihong,Swensen, Andrew M.,Vortherms, Timothy,Manelli, Arlene,Balut, Corina,Jia, Ying,Gao, Wenqing,Yong, Hong,Schrimpf, Michael,Tse, Chris,Kym, Philip,Wang, Xueqing
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- General Asymmetric Synthesis of Densely Functionalized Pyrrolidines via Endo-Selective [3+2] Cycloaddition of β-Quaternary-Substituted Nitroalkenes and Azomethine Ylides
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A scalable endo-selective synthesis of 2,3,4,5-tetrasubstituted pyrrolidines via cycloaddition of nitroalkenes and azomethine ylides is reported using a P,N-type ferrocenyl ligand and [Cu(OTf)]2·C6H6. The robust method is tolerant of a wide range of functionalities, including rarely reported quaternary nitroalkene substitution and heteroaromatic and hindered ortho-substituted arenes on the azomethine ylide. Subsequent transformations highlight the utility of the method in the synthesis of densely functionalized small molecules suitable for fragment-based drug discovery and the cystic fibrosis C2-corrector clinical candidate ABBV-3221.
- Buchman, Marek,Greszler, Stephen N.,Liu, Bo,Searle, Xenia B.,Voight, Eric A.,Zhao, Gang
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- Design, synthesis and biological evaluation of novel 2-(5-aryl-1H-imidazol-1-yl) derivatives as potential inhibitors of the HIV-1 Vpu and host BST-2 protein interaction
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Novel ethyl 2-(5-aryl-1H-imidazol-1-yl)-acetates 17 and propionates 18, together with their acetic acid 19 and acetohydrazide 20 derivatives, were designed and synthesized using TosMIC chemistry. Biological evaluation of these newly synthesized scaffolds in the HIV-1 Vpu- Host BST-2 ELISA assay identified seven hits (17a, 17b, 17c, 17g, 18a, 20f and 20g) with greater than 50% inhibitory activity. These hits were validated in the HIV-1 Vpu- Host BST-2 AlphaScreen and six of the seven compounds were found to have comparable percentage inhibitory activities to those of the ELISA assay. Compounds 17b and 20g, with consistent percentage inhibitory activities across the two assays, had IC50 values of 11.6 ± 1.1 μM and 17.6 ± 0.9 μM in a dose response AlphaScreen assay. In a cell-based HIV-1 antiviral assay, compound 17b exhibited an EC50 = 6.3 ± 0.7 μM at non-toxic concentrations (CC50 = 184.5 ± 0.8 μM), whereas compound 20g displayed antiviral activity roughly equivalent to its toxicity (CC50 = 159.5 ± 0.9 μM). This data suggests that compound 17b, active in both cell-based and biochemical assays, provides a good starting point for the design of possible lead compounds for prevention of HIV-1 Vpu and host BST-2 protein binding in new anti-HIV therapeutics.
- Bode, Moira L.,Coyanis, E. Mabel,Mosebi, Salerwe,Njengele, Zikhona,Rashamuse, Thompho J.,Sayed, Yasien
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- SUBSTITUTED PYRROLIDINES AND THEIR USE
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The invention discloses compounds of Formula (I) wherein R1, R2, R3, R3A, R4, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.
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Paragraph 0394
(2019/10/30)
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- Preparation of homoallylic amines via a three-component coupling process
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A three-component synthesis of homoallylic amines is described. The allylboronic species were generated in situ by homologation of vinyl boroxines with trimethylsilyldiazomethane, then followed by trapping of the allylboron intermediate with imines. Twenty-seven compounds were successfully prepared in moderate to high yields. Imines bearing various functional groups were tolerated, including aliphatic, aromatic and heteroaromatic substituents. Further elaboration of some of the homoallylic amines to form azeditines is also reported.
- Battilocchio, Claudio,Labes, Ricardo,Ley, Steven V.,Ou, Xiaoxu
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supporting information
p. 6652 - 6654
(2018/09/29)
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- Substituted Pyrrolidines and Methods of Use
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The invention discloses compounds of Formula (I) wherein R1, R2, R2A, R3, R3A, R4, R4A, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.
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Paragraph 2066; 2076; 2114
(2018/04/20)
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- Substituted Pyrrolidines and Methods of Use
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The invention discloses compounds of Formula (I) wherein R1, R2, R2A, R3, R3A, R4, and R5 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.
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Paragraph 1532; 1541
(2018/04/20)
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- Macrocyclic compounds for suppressing replication of hepatitis C virus
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A compound as represented by Formula (I) is provided, wherein groups are defined in the description. The compound is used as HCV protease inhibitor for treating HCV infection.
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Page/Page column 38; 39
(2016/05/24)
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- MACROCYCLIC COMPOUNDS FOR SUPPRESSING REPLICATION OF HEPATITIS C VIRUS
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A compound as represented by Formula (I) is provided, wherein groups are defined in the description. The compound is used as HCV protease inhibitor for treating HCV infection.
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Page/Page column
(2015/02/19)
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- METHOD OF PRODUCING OPTICALLY ACTIVE 1-AMINO-2-VINYLCYCLOPROPANE CARBOXYLIC ACID ESTER
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An optically active 1-amino-2-vinylcyclopropanecarboxylic acid ester with high optical purity can be obtained by a method of producing an optically active 1-amino-2-vinylcyclopropanecarboxylic acid ester by reacting a 1-amino-2-vinylcyclopropanecarboxylic acid ester with an optically active tartaric acid or an optically active camphorsulfonic acid in a solvent, isolating one diastereomeric salt from the obtained diastereomeric salt mixture and treating the isolated diastereomeric salt with an inorganic acid or a base.
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Paragraph 0128
(2014/01/23)
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- QUATERNARY AMMONIUM SALT
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A quaternary ammonium salt represented by formula (5) (wherein R1 represents an alkyl group having 1 to 4 carbon atoms, R2 represents an alkyl group having 1 to 10 carbon atoms, R3 represents an alkyl group having 1 to 10 carbon atoms that is optionally substituted with one or more phenyl groups; or a phenyl group that optionally has one or more groups selected from the group consisting of alkyl groups having 1 to 10 carbon atoms and a trifluoromethyl group, R4 represents an alkyl group having 1 to 4 carbon atoms, R5 represents an alkyl group having 1 to 10 carbon atoms, C* represents an asymmetric carbon atom, and X- represents a halide ion) can be used as a catalyst having good stability under basic conditions.
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Paragraph 0111
(2014/01/08)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE 1-AMINO-2-VINYLCYCLOPROPANECARBOXYLIC ACID ESTER
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1-Amino-2-vinylcyclopropanecarboxylic acid ester, which is useful as a synthetic intermediate of pharmaceuticals, can be produced by a process of producing 1-amino-2-vinylcyclopropanecarboxylic acid ester represented by formula (4): including a step of hydrolysis of an optically active 1-N-(arylmethylene)amino-2-vinylcyclopropanecarboxylic acid ester represented by formula (3): which is obtained by reacting an N-(arylmethylene)glycine ester represented by formula (1): with a compound represented by formula (2): in the presence of a base and an optically active quaternary ammonium salt.
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Page/Page column 12-13
(2012/06/01)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 20-21
(2008/06/13)
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- Inhibitors of Hepatitis C Virus
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Macrocyclic peptides are disclosed having the general formula: wherein R3, R3′, R4, R6, R′, X, Q and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 19
(2008/12/04)
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- Bis-sulfonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3 + 2] cycloaddition of azomethine ylides
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Enantioenriched 3-pyrrolines have been synthesized by highly enantioselective Fesulphos-Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl ethylene, followed by reductive sulfonyl elimination. High levels of reactivity, exoselectivity, and enantioselectivity have been accomplished for a variety of substituted azomethine ylides. This cycloaddition-desulfonylation strategy has been applied as a key step in the enantioselective synthesis of a biologically active C-azanucleoside. Copyright
- Lopez-Perez, Ana,Adrio, Javier,Carretero, Juan C.
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supporting information; experimental part
p. 10084 - 10085
(2009/02/04)
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- MACROCYCLIC PEPTIDES AS HEPATITIS C VIRUS INHIBITORS
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Macrocyclic peptides having the general formula (I): are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 38
(2008/12/05)
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- Inhibitors of Hepatitis C Virus
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Macrocyclic peptides are disclosed having the general formula: wherein R3, R3′, R4, R6, R′, X, Q and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 18-19
(2008/12/04)
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- Inhibitors of Hepatitis C Virus
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Macrocyclic peptides are disclosed having the general formula: wherein R3, R′3, R4, R6, R′, X, Q and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 19
(2008/12/04)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 31-32
(2008/12/05)
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- MACROCYCLIC PEPTIDES AS HEPATITIS C VIRUS INHIBITORS
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Macrocyclic peptides having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 36-37
(2008/12/05)
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- PROCESS FOR PRODUCTION OF MONO-SUBSTITUTED ALKYLATED COMPOUND USING ALDIMINE OR DERIVATIVE THEREOF
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Disclosed is a process for producing an asymmetric mono-substituted alkylated compound of an α-amino acid which is represented by a specific formula by using an aldimine-type Schiff base. In the process, the alkylation of an aldimine-type Schiff base in a medium in the presence of an optically active quaternary ammonium salt phase transfer catalyst and an inorganic base is started, and subsequently the reaction is quenched at any time preceding the completion of the stoichimetrical reaction, thereby yielding a mono-substituted alkylated product having a high optical purity.
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Page/Page column 87
(2008/06/13)
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- Hepatitis C virus inhibitors
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The present disclosure relates to tripeptide compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 19
(2008/06/13)
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- Hepatitis C virus inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 34
(2010/11/26)
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- Hepatitis C virus inhibitors
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Macrocyclic peptides are disclosed having the general formula: wherein R′, R3, R3′, R4, R6, X, Q, and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 23-24
(2010/11/26)
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- Aziridines as templates: A general strategy for the stereospecific synthesis of 2-azetidinones
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Various routes to a variety of azridine-2-carboxylates have been described and the stereochemistry of these compounds has been determined by spectroscopic methods. Further, greater diversity of β-lactams via ring expansion of these azridines-2-carboxylates were obtained by a general, efficient and direct stereospecific approach.
- Sharma,Kanwar, Seema,Rajpoot, Shivani
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- Hepatitis C virus inhibitors
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The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which inhibit the function of the NS3 protease (also referred to herein as “serine protease”) encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS3 protease.
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Page/Page column 35-36
(2008/06/13)
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- Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid vinyl-ACCA derivatives: Key intermediates for the preparation of inhibitors of the hepatitis C virus NS3 protease
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(1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is a key building block in the synthesis of potent inhibitors of the hepatitis C virus NS3 protease such as BILN 2061, which was recently shown to dramatically reduce viral load after administration to patients infected with HCV genotype 1. We have developed a scalable process that delivers derivatives of this unusual amino acid in >99% ee. The strategy was based on the dialkylation of a glycine Schiff base using trans-1,4-dibromo-2-butene as an electrophile to produce racemic vinyl-ACCA, which was subsequently resolved using a readily available, inexpensive esterase enzyme (Alcalase 2.4L). Factors that affect diastereoselection in the initial dialkylation steps were examined and the conditions optimized to deliver the desired diastereomer selectively. Product inhibition, which was encountered during the enzymatic resolution step, initially resulted in prolonged cycle times. Enrichment of racemic vinyl-ACCA through a chemical resolution via diastereomeric salt formation or the use of forcing conditions in the enzymatic reaction both led to improvements in throughput and the development of a viable process. The chemistry described herein was scaled up to produce multikilogram quantities of this building block.
- Beaulieu, Pierre L.,Gillard, James,Bailey, Murray D.,Boucher, Colette,Duceppe, Jean-Simon,Simoneau, Bruno,Wang, Xiao-Jun,Zhang, Li,Grozinger, Karl,Houpis, Ioannis,Farina, Vittorio,Heimroth, Heidi,Krueger, Thomas,Schnaubelt, Juergen
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p. 5869 - 5879
(2007/10/03)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula (I) wherein A, R2, R3, R', B and Y are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 59-60
(2010/02/11)
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- Hepatitis C virus inhibitors
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Hepatitis C virus inhibitors are disclosed having the general formula: wherein R1, R2, R3, R′, B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 26
(2010/02/12)
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- Substituted cycloalkyl P1' hepatitis C virus inhibitors
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The present invention relates to tripeptide compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel tripeptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
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Page/Page column 21
(2010/02/06)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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- HETEROCYCLICSULFONAMIDE HEPATITIS C VIRUS INHIBITORS
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The present invention relates to tripeptide compounds, compositionscontaining such compounds and methods for using such compounds for the treatment of heptitis C virus (HCV) infection. In particular, the present invention provides novel tripeptide analogs, pharmaceutical compositionscontaining such analogs and methods for using these analogs in the treatment of HCV infection.
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- Hepatitis C virus inhibitors
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The present invention relates to tripeptide compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel tripeptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
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