- P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: Discovery of MK-2748 and MK-6325
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With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
- Rudd, Michael T.,Butcher, John W.,Nguyen, Kevin T.,McIntyre, Charles J.,Romano, Joseph J.,Gilbert, Kevin F.,Bush, Kimberly J.,Liverton, Nigel J.,Holloway, M. Katharine,Harper, Steven,Ferrara, Marco,Difilippo, Marcello,Summa, Vincenzo,Swestock, John,Fritzen, Jeff,Carroll, Steven S.,Burlein, Christine,Dimuzio, Jillian M.,Gates, Adam,Graham, Donald J.,Huang, Qian,McClain, Stephanie,McHale, Carolyn,Stahlhut, Mark W.,Black, Stuart,Chase, Robert,Soriano, Aileen,Fandozzi, Christine M.,Taylor, Anne,Trainor, Nicole,Olsen, David B.,Coleman, Paul J.,Ludmerer, Steven W.,McCauley, John A.
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- Organophotoredox-Catalyzed Decarboxylative N-Alkylation of Sulfonamides
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We developed an organophotoredox-catalyzed reaction for N-alkylation of sulfonamides with aliphatic carboxylic acid-derived redox active esters as alkylating reagents. Under mild and transition metal-free conditions, a series of functionalized N-alkylated sulfonamides were prepared. This protocol also enabled the functionalization of pharmaceutical drugs bearing a sulfonamide or carboxylic acid moiety. This radical-mediated process allowed the assembly of three components including sulfonamides, redox active esters, and alkenes to yield complex sulfonamides in a one-pot manner.
- Nakagawa, Masanari,Nagao, Kazunori,Ikeda, Zenichi,Reynolds, Matthew,Ibá?ez, Ignacio,Wang, Junsi,Tokunaga, Norihito,Sasaki, Yusuke,Ohmiya, Hirohisa
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p. 3930 - 3933
(2021/08/03)
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- Zn- And Cu-catalyzed coupling of tertiary alkyl bromides and oxalates to forge challenging C?O, C?S, and C?N bonds
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We describe here the facile construction of sterically hindered tertiary alkyl ethers and thioethers via the Zn(OTf)2catalyzed coupling of alcohols/phenols with unactivated tertiary alkyl bromides and the Cu(OTf)2-catalyzed thiolation of unactivated tertiary alkyl oxalates with thiols. The present protocol represents one of the most effective unactivated tertiary C(sp3)? heteroatom bond-forming conditions via readily accessible Lewis acid catalysis that is surprisingly less developed.
- Gong, Yuxin,Zhu, Zhaodong,Qian, Qun,Tong, Weiqi,Gong, Hegui
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supporting information
p. 1005 - 1010
(2021/02/01)
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- ANTIVIRAL PYRIDOPYRAZINEDIONE COMPOUNDS
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The invention provides compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by herpesviruses.
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Paragraph 0596-0597
(2020/04/09)
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- Hepatitis C virus inhibitors
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Hepatitis C virus inhibitors 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 22
(2017/01/23)
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- Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl α-Amino-β-fluoro-β-vinylcyclopropanecarboxylate as Key Intermediate
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Synthesis of fluorocyclopropyl building blocks, which constitute the core of various therapeutic agents against the hepatitis C virus, is described. The relevant methyl α-amino-β-fluoro-β-vinylcyclopropanecarboxylate has been used as a key intermediate for the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a HCV NS3/4A protease inhibitor.
- Milanole, Ga?lle,Andriessen, Floris,Lemonnier, Gérald,Sebban, Muriel,Coadou, Ga?l,Couve-Bonnaire, Samuel,Bonfanti, Jean-Fran?ois,Jubault, Philippe,Pannecoucke, Xavier
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supporting information
p. 2968 - 2971
(2015/06/30)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors 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
(2013/05/21)
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- HCV NS3 PROTEASE INHIBITORS
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The present invention relates to macro-cyclic compounds of formula I that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections
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Page/Page column 35
(2012/04/10)
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- Preparation of cyclopropyl sulfonylamides
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A novel process for the preparation of cyclopropyl sulfonamide of the formula I is described. Cyclopropyl sulfonamide is a versatile building block for many biologically active compounds.
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Page/Page column 2-3
(2009/05/28)
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- NOVEL MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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The embodiments provide compounds of the general Formula I, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
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Page/Page column 213
(2009/01/20)
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- PYRIDAZINONE COMPOUNDS
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The invention is directed to pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 167
(2008/12/07)
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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 26-27
(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 25
(2008/12/04)
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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 51
(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 24
(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 25
(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 23
(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 49
(2008/12/05)
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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 26
(2008/06/13)
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- HEPATITIS C INHIBITOR PEPTIDE ANALOGS
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The compounds of formula I wherein R1, R2, R3 , R4 and R5 are defined herein, are useful as inhibitors of the hepatitis C virus NS3 protease The invention further relates to azalactone compounds of the formula (II) which can be reacted with an amide anion to produce the HCV NS3 protease inhibitors of formula (I)
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Page/Page column 42
(2010/11/25)
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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 26; 39
(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 28; 29
(2010/11/26)
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- HEPATITIS C INHIBITOR DIPEPTIDE ANALOGS
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The present invention relates to compounds of formula (I): wherein R1, R2, R4, n and m are as defined herein and R3 is selected from: (i) -C(O)OR31 wherein R31 is (C1-6)alkyl or aryl, wherein the (C1-6)alkyl is optionally substituted with one to three halogen substituents; (ii) -C(O)NR32R33, wherein R32 and R33 are each independently selected form H, (C1-6)alkyl, and Het; (iii) -SOvR34, wherein v is 1 or 2 and R34 is selected from: (C1-6)alkyl, aryl, Het, and NR32R33 wherein R32 and R33 are as defined above; and (iv) -CO(O)-R35, wherein R35 is selected from (C1-8)alkyl, (C3-7)cycloalkyl-(C1-4)alkyl, aryl, aryl-(C1-6)alkyl, Het and Het-(C1-6)alkyl, each of which are optionally substituted with one or more substituents each independently selected from halo, (C1-6)alkyl, (C3-7)cycloalkyl, aryl, Het, hydroxyl, -O-(C1-6)alkyl, -S-(C1-6)alkyl, -SO-(C1-6)alkyl, -SO2-(C1-6)alkyl, -O-aryl, -S-aryl, -SO-aryl and -SO2-aryl, wherein the aryl portion of the -O-aryl, -S-aryl, -SO-aryl and -SO2-aryl are each optionally substituted with one to five halo substituents. The present invention further relates to pharmaceutical compositions containing the compounds of formula (I) and methods for using these analogs in the treatment of HCV infection.
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Page/Page column 79-80
(2008/06/13)
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- Hepatitis C inhibitor peptide analogs
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Compounds of formula (I): wherein R1, R2, R3, R4, R5, Y, n and m are as defined herein. The compounds are useful as inhibitors of HCV NS3 protease.
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Page/Page column 35
(2010/02/15)
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- A facile synthesis of 1-substituted cyclopropylsulfonamides
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A practical, convenient, and high-yielding three-step synthesis of cyclopropanesulfonamide and 1-substituted cyclopropanesulfonamides, starting from 3-chloropropanesulfonyl chloride, is described. Georg Thieme Verlag Stuttgart.
- Li, Jianqing,Smith, Daniel,Wong, Henry S.,Campbell, Jeffrey A.,Meanwell, Nicholas A.,Scola, Paul M.
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p. 725 - 728
(2007/10/03)
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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 25
(2008/06/13)
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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 77-78
(2010/02/11)
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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 33
(2010/02/06)
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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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- 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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