- INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
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- 5,5-FUSED ARYLENE OR HETEROARYLENE HEPATITIS C VIRUS INHIBITORS
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Provided herein are 5,5-fused heteroarylene hepatitis C virus inhibitor compounds, for example, of Formula I, IA, or IB, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.
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Paragraph 0306; 0308; 0310
(2018/08/20)
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- Peptidomimetics for Targeting Protein-Protein Interactions between DOT1L and MLL Oncofusion Proteins AF9 and ENL
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MLL-fusion proteins, AF9 and ENL, play an essential role in the recruitment of DOT1L and the H3K79 hypermethylation of MLL target genes, which is pivotal for leukemogenesis. Blocking these interactions may represent a novel therapeutic approach for MLL-rearranged leukemia. Based on the 7 mer DOT1L peptide, a class of peptidomimetics was designed. Compound 21 with modified middle residues, achieved significantly improved binding affinities to AF9 and ENL, with KD values of 15 nM and 57 nM, respectively. Importantly, 21 recognizes and binds to the cellular AF9 protein and effectively inhibits the AF9-DOT1L interactions in cells. Modifications of the N- and C-termini of 21 resulted in 28 with 2-fold improved binding affinity to AF9 and much decreased peptidic characteristics. Our study provides a proof-of-concept for development of nonpeptidic compounds to inhibit DOT1L activity by targeting its recruitment and the interactions between DOT1L and MLL-oncofusion proteins AF9 and ENL.
- Du, Lei,Grigsby, Sierrah M.,Yao, Aihong,Chang, Yujie,Johnson, Garrett,Sun, Haiying,Nikolovska-Coleska, Zaneta
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supporting information
p. 895 - 900
(2018/09/06)
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- Impact of lead impurities in zinc dust on the selective reduction of a dibromoimidazole derivative
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A low level of lead in zinc dust was identified as the causative agent responsible for inhibiting selective reduction of a dibromoimidazole derivative via metal agglomeration and lead deposition on the zinc surface.
- Yin, Jianguo,Maguire, Courtney K.,Yasuda, Nobuyoshi,Brunskill, Andrew P. J.,Klapars, Artis
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- Structure–activity relationships of proline modifications around the tetracyclic-indole class of NS5A inhibitors
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We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
- Tong, Ling,Yu, Wensheng,Coburn, Craig A.,Chen, Lei,Selyutin, Oleg,Zeng, Qingbei,Dwyer, Michael P.,Nair, Anilkumar G.,Shankar, Bandarpalle B.,Kim, Seong Heon,Yang, De-Yi,Rosenblum, Stuart B.,Ruck, Rebecca T.,Davies, Ian W.,Hu, Bin,Zhong, Bin,Hao, Jinglai,Ji, Tao,Zan, Shuai,Liu, Rong,Agrawal, Sony,Carr, Donna,Curry, Stephanie,McMonagle, Patricia,Bystol, Karin,Lahser, Frederick,Ingravallo, Paul,Chen, Shiying,Asante-Appiah, Ernest,Kozlowski, Joseph A.
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p. 5354 - 5360
(2016/10/30)
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- Fused tricyclic hepatitis virus inhibitor and application thereof
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The invention belongs to the field of medical chemistry, relates to a fused tricyclic hepatitis virus inhibitor and application thereof, and particularly, provides a compound of the general formula I or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a medicine composition containing the compounds and application of the compounds or the composition in medicine preparation. The compound has the good inhibiting activity on hepatitis C virus, meanwhile has the low toxicity on host cells, and is high in effectiveness, good in safety and likely to become the medicine for treating and/or preventing diseases relevant to HCV infection.
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- Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors
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A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
- Dwyer, Michael P.,Keertikar, Kerry M.,Chen, Lei,Tong, Ling,Selyutin, Oleg,Nair, Anilkumar G.,Yu, Wensheng,Zhou, Guowei,Lavey, Brian J.,Yang, De-Yi,Wong, Michael,Kim, Seong Heon,Coburn, Craig A.,Rosenblum, Stuart B.,Zeng, Qingbei,Jiang, Yueheng,Shankar, Bandarpalle B.,Rizvi, Razia,Nomeir, Amin A.,Liu, Rong,Agrawal, Sony,Xia, Ellen,Kong, Rong,Zhai, Ying,Ingravallo, Paul,Asante-Appiah, Ernest,Kozlowski, Joseph A.
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p. 4106 - 4111
(2016/08/01)
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- 9,9,10,10-TETRAFLUORO-9,10-DIHYDROPHENANTHRENE HEPATITIS C VIRUS INHIBITOR AND APPLICATION THEREOF
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The present invention belongs to the field of chemical pharmaceuticals, and specifically relates to compounds represented by formula I having a 9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene structure and being able to inhibit hepatitis C virus activity, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of said compounds, a pharmaceutical composition containing said compounds, and an application of said compounds or composition in the preparation of a drug. The compounds of the present invention have a good HCV inhibitory effect.
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Paragraph 0122-0124
(2016/10/31)
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- PROCESS FOR PREPARING TETRACYCLIC HETEROCYCLE COMPOUNDS
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The present invention is directed to a process for preparing Tetracyclic Heterocycle Compounds of formula (I): which are useful as HCV NS5A inhibitors. The present invention is also directed to compounds that are useful as synthetic intermediates for making the compounds of formula (I).
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- Enantioselective synthesis of an HCV NS5a antagonist
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A concise, enantioselective synthesis of the HCV NS5a inhibitor MK-8742 (1) is reported. The features of the synthesis include a highly enantioselective transfer hydrogenation of an NH imine and a dynamic diastereoselective transformation. The synthesis of this complex target requires simple starting materials and nine linear steps for completion.
- Mangion, Ian K.,Chen, Cheng-Yi,Li, Hongmei,Maligres, Peter,Chen, Yonggang,Christensen, Melodie,Cohen, Ryan,Jeon, Ingyu,Klapars, Artis,Krska, Shane,Nguyen, Hoa,Reamer, Robert A.,Sherry, Benjamin D.,Zavialov, Ilia
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p. 2310 - 2313
(2014/05/20)
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- Discovery of MK-8742: An HCV NS5A inhibitor with broad genotype activity
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The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin- 2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection. Effective treatment of chronic hepatitis C with direct-acting antivirals will require combination therapy with multiple agents that target different steps in the viral replication cycle and impose a high barrier to resistance. MK-8742 is a potent inhibitor of hepatitis C virus non-structural protein 5A (HCV NS5A) that is being developed as a component of an once-daily, all-oral, interferon-free regimen for the treatment of chronic HCV infection. Copyright
- Coburn, Craig A.,Meinke, Peter T.,Chang, Wei,Fandozzi, Christine M.,Graham, Donald J.,Hu, Bin,Huang, Qian,Kargman, Stacia,Kozlowski, Joseph,Liu, Rong,McCauley, John A.,Nomeir, Amin A.,Soll, Richard M.,Vacca, Joseph P.,Wang, Dahai,Wu, Hao,Zhong, Bin,Olsen, David B.,Ludmerer, Steven W.
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p. 1930 - 1940
(2014/01/06)
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- FUSED TRICYCLIC COMPOUNDS AND USE THEREOF FOR TREATING VIRAL DISEASES
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Fused tricyclic compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed, wherein X1, X2, X3, X4, Y1, Y2, M1, M2, Ra, Rb, R1, R2 and R6 are as defined in the description. Compositions comprising at least one fused tricyclic compound and methods of using the fused tricyclic compounds for treating or preventing HCV infection in a patient are also disclosed.
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- TETRACYCLIC HETEROCYCLE COMPOUNDS FOR TREATING HEPATITIS C VIRAL INFECTION
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Tetracyclic heterocycle compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, wherein A, A', G, R1, R15, U, V, V', W, W, X, X', Y and Y' are as defined in the invention. The pharmaceutical compositions comprising these compounds and the use of the compounds for treating hepatitis C virus (HCV) infection are also provided.
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Page/Page column 74-75
(2012/04/17)
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- TETRACYCLIC INDOLE DERIVATIVES FOR TREATING HEPATITIS C VIRUS INFECTION
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Tetracyclic indole derivatives of formula (I), pharmaceutically acceptable salts and the pharmaceutical compositions thereof are provided, wherein A, A', G, R1, R15, U, V, V, W, W, X, X', Y, Y' are as defined in the invention. Use of these derivatives for treating hepatitis C virus (HCV) infection is also provided.
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Page/Page column 93-94
(2012/04/17)
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- TETRACYCLIC INDOLE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Tetracyclic Indole Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, A', G, R1, R15, U, V, V', X, X', Y and Y' are as defined herein. The present invention also relates to compositions comprisingat least one Tetracyclic Indole Derivative, and methods of using the Tetracyclic Indole Derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 81-82
(2012/04/17)
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- FUSED TETRACYCLE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Fused Tetracycle Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, A', B, G, R1, U, V, W, W', X, X', Y and Y' are as defined herein. The present invention also relates to compositions comprising at least one Fused Tetracycle Derivative, and methods of using the Fused Tetracycle Derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 81
(2012/05/04)
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- FUSED TETRACYCLIC HETEROCYCLE COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention discloses novel Fused Tetracyclic Heterocycle Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, A', G, R1, R15, U, V, V', W, W', X, X', Y and Y' are as defined herein. The present invention also discloses compositions comprising at least one Fused Tetracyclic Heterocycle Compound, and methods of using the Fused Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
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- ANTI-VIRAL COMPOUNDS
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Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
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Page/Page column 151-152
(2012/06/30)
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- TETRACYCLIC XANTHENE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Tetracyclic Xanthene Derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, Y1, Y2, Z, Ra, Rb, R1a, R1b and R2 are as defined herein. The present invention also relates to compositions comprising at least one Tetracyclic Xanthene Derivative, and methods of using the Tetracyclic Xanthene Derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 37
(2012/10/07)
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- TETRACYCLIC XANTHENE DERIVATIVES AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention discloses tetracyclic xanthene derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, Y1, Y2, Z, Ra, Rb, R1a, R1b, and R2 are as defined herein. The present invention also discloses compositions comprising at least one tetracyclic xanthene derivative, and methods of using the tetracyclic xanthene derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 56
(2012/10/07)
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- BENZIMIDAZOLE-IMIDAZOLE DERIVATIVES
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Inhibitors of HCV replication of formula (I) including stereochemically isomeric forms, and salts, solvates thereof, wherein R and R' are, each independently,-CR1R2R3, aryl, heteroaryl or heteroC4-6cycloalkyl, whereby aryl and heteroaryl may optionally be substituted with 1 or 2 substituents selected from halo and methyl. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.
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- ANTIVIRAL COMPOUNDS COMPOSED OF THREE LINKED ARYL MOIETIES TO TREAT DISEASES SUCH AS HEPATITIS C
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The present invention relates to novel Linked Tricyclic Aryl Compounds, compositions comprising at least one Linked Tricyclic Compound, and methods of using Linked Tricyclic Aryl Compounds for treating or preventing HCV infection in a patient. in one aspect, the present invention provides Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein: Non-limiting examples of the Compounds of Formula (II) include compound 56
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Page/Page column 85
(2010/12/26)
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- INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
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Page/Page column 119
(2010/11/04)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to (4-4' -diimidazolyl) biphenyls 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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- Hepatitis C Virus Inhibitors
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The present disclosure relates to 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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- Hepatitis C Virus Inhibitors
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The present disclosure relates to 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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- Hepatitis C Virus Inhibitors
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The present disclosure relates to 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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