WO2011109037A1 - Combination pharmaceutical agents as inhibitors of hcv replication - Google Patents

Combination pharmaceutical agents as inhibitors of hcv replication Download PDF

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Publication number
WO2011109037A1
WO2011109037A1 PCT/US2010/044591 US2010044591W WO2011109037A1 WO 2011109037 A1 WO2011109037 A1 WO 2011109037A1 US 2010044591 W US2010044591 W US 2010044591W WO 2011109037 A1 WO2011109037 A1 WO 2011109037A1
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WO
WIPO (PCT)
Prior art keywords
hcv
optionally substituted
compound
additional agent
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2010/044591
Other languages
English (en)
French (fr)
Inventor
Yat Sun Or
Christopher M. Owens
Bradley B. Brasher
Yao-Ling Qiu
Lijuan Jiang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Enanta Pharmaceuticals Inc
Original Assignee
Enanta Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enanta Pharmaceuticals Inc filed Critical Enanta Pharmaceuticals Inc
Priority to JP2012556049A priority Critical patent/JP2013521279A/ja
Priority to EP10847147.5A priority patent/EP2542074A4/en
Priority to KR1020127025741A priority patent/KR20120124495A/ko
Priority to BR112012022311A priority patent/BR112012022311A2/pt
Priority to CA2791630A priority patent/CA2791630A1/en
Priority to AU2010347272A priority patent/AU2010347272A1/en
Priority to MX2012010252A priority patent/MX2012010252A/es
Priority to EA201201235A priority patent/EA201201235A1/ru
Priority to CN2010800662365A priority patent/CN102858157A/zh
Publication of WO2011109037A1 publication Critical patent/WO2011109037A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/204—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/208—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • HCV is a major human pathogen, infecting an estimated 170 million persons worldwide-roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. (Lauer, G. M.; Walker, B. D. N. Eng. J. Med. (2001), 345, 41-52).
  • HCV therapy employs a combination of pegylated alpha-interferon and ribavirin, leading to sustained efficacy in 50% of patients and a treatment that is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N. Engl. J. Med.
  • the additional anti-HCV agent compounds can be one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
  • the additional agent can, for example, suppress HCV viral replication by direct or indirect mechanisms.
  • agents include, but are not limited to, host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleo-tides and the like); antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering RNA; anti-sense R A; vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV; agents that interact
  • contemplated herein is combination therapy to treat such co-infections by co- administering a compound that inhibits the function of HCV NS5A protein, and an additional agent selected from at least an HIV inhibitor, an HAV inhibitor and an HBV inhibitor, or a combination of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor; and optionally additionally administering an additional anti-HCV agent.
  • the invention encompasses a pharmaceutical composition comprising a pharmaceutically excipient or carrier, a compound that inhibits the function of HCV NS5A protein, an additional anti-HCV agent and an additional agent selected from at least an HIV inhibitor, an HAV inhibitor and an HBV inhibitor, or a combination of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • a still further embodiment of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a Hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove, with a pharmaceutically acceptable carrier.
  • an RNA-containing virus particularly a Hepatitis C virus (HCV)
  • HCV Hepatitis C virus
  • hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • a “therapeutically effective amount” of a compound or agent described herein and/or a combination of a compound that inhibits function of the HCV NS5A protein and an additional anti-viral agent or combination of anti-viral agents is meant to describe an amount of the compound, or anti-viral agent, either alone or in combination with one another, which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • An effective amount of the compound of Formula (I) may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg.
  • compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 90, Compound 93, Compound 95 and pharmaceutically acceptable salts of these compounds in an amount effective to inhibit the function of the HCV NS5A protein and an effective amount of an additional agent having anti-viral activity selected from the group consisting of boceprivir, R7128, GSK 625433 and interferon-a.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 90, Compound
  • the method comprises administering a compound selected from the group consisting of Compound 90, Compound 93, Compound 95 and pharmaceutically acceptable salts of these compounds in an amount effective to inhibit the function of the HCV NS5A protein and administering an effective amount of an additional agent having anti-viral activity selected from the group consisting of a cyclosporine analog, ITMN-191, boceprivir, telaprivir (VX-950), R7128, GSK 625433, and interferon a.
  • the method comprises administering a compound selected from the group consisting of

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
PCT/US2010/044591 2010-03-04 2010-08-05 Combination pharmaceutical agents as inhibitors of hcv replication Ceased WO2011109037A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2012556049A JP2013521279A (ja) 2010-03-04 2010-08-05 Ｈｃｖ複製の阻害剤としての医薬併用剤
EP10847147.5A EP2542074A4 (en) 2010-03-04 2010-08-05 PHARMACEUTICAL COMBINATION ACTIVE AGENTS AS HCV REPLICATION INHIBITORS
KR1020127025741A KR20120124495A (ko) 2010-03-04 2010-08-05 Ｈｃｖ 복제의 억제제로서의 조합 제약 작용제
BR112012022311A BR112012022311A2 (pt) 2010-03-04 2010-08-05 agentes farmacêuticos de combinação como inibidores da replicação de hcv.
CA2791630A CA2791630A1 (en) 2010-03-04 2010-08-05 Combination pharmaceutical agents as inhibitors of hcv replication
AU2010347272A AU2010347272A1 (en) 2010-03-04 2010-08-05 Combination pharmaceutical agents as inhibitors of HCV replication
MX2012010252A MX2012010252A (es) 2010-03-04 2010-08-05 Agentes farmaceuticos en combinacion como inhibidores de la replicacion del virus de hepatitis c (hcv).
EA201201235A EA201201235A1 (ru) 2010-03-04 2010-08-05 Комбинации фармацевтических агентов в качестве ингибиторов репликации hcv
CN2010800662365A CN102858157A (zh) 2010-03-04 2010-08-05 作为hcv复制的抑制剂的组合药物活性剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31057910P 2010-03-04 2010-03-04
US61/310,579 2010-03-04

Publications (1)

Publication Number Publication Date
WO2011109037A1 true WO2011109037A1 (en) 2011-09-09

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PCT/US2010/044591 Ceased WO2011109037A1 (en) 2010-03-04 2010-08-05 Combination pharmaceutical agents as inhibitors of hcv replication

Country Status (11)

Country Link
US (1) US9060971B2 (enExample)
EP (1) EP2542074A4 (enExample)
JP (1) JP2013521279A (enExample)
KR (1) KR20120124495A (enExample)
CN (1) CN102858157A (enExample)
AU (1) AU2010347272A1 (enExample)
BR (1) BR112012022311A2 (enExample)
CA (1) CA2791630A1 (enExample)
EA (1) EA201201235A1 (enExample)
MX (1) MX2012010252A (enExample)
WO (1) WO2011109037A1 (enExample)

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US8552047B2 (en) 2011-02-07 2013-10-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2575866A4 (en) * 2010-05-24 2013-10-16 Presidio Pharmaceuticals Inc HCV NS5A INHIBITORS
EP2593565A4 (en) * 2010-07-16 2013-12-04 Bristol Myers Squibb Co METHODS FOR IDENTIFYING COMBINATIONS OF NS5A TARGETING COMPOUNDS THAT SYNERGISTICALLY WORK TO INHIBIT THE REPLICATION OF HEPATITIS C VIRUS
JP2014504296A (ja) * 2010-12-16 2014-02-20 アッヴィ・インコーポレイテッド 抗ウイルス性化合物
US8765731B2 (en) 2009-07-16 2014-07-01 Vertex Pharmaceuticals Incorporated Benzimidazole analogues for the treatment or prevention of flavivirus infections
US8779156B2 (en) 2010-03-24 2014-07-15 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
JP2015503537A (ja) * 2011-12-28 2015-02-02 ヤンセン・アールアンドデイ・アイルランド Ｈｃｖ阻害剤としてのキナゾリノン誘導体
JPWO2013011932A1 (ja) * 2011-07-15 2015-02-23 塩野義製薬株式会社 Ａｍｐｋ活性化作用を有するアザベンズイミダゾール誘導体
JP2015506987A (ja) * 2012-02-13 2015-03-05 プレシディオ ファーマシューティカルズ インコーポレイテッド Ｈｃｖのｎｓ５ａ阻害剤を含む固形、その組成物、およびそれらの使用
US9072696B2 (en) 2012-09-29 2015-07-07 Novartis Ag Cyclic peptides and use as medicines
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

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US20110152246A1 (en) * 2009-12-18 2011-06-23 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
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US8933110B2 (en) 2010-01-25 2015-01-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
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US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
CN103687489A (zh) 2011-05-18 2014-03-26 埃南塔制药公司 制备5-氮杂螺[2.4]庚烷-6-甲酸及其衍生物的方法
WO2013030750A1 (en) 2011-09-01 2013-03-07 Lupin Limited Antiviral compounds
TW201329096A (zh) 2011-09-12 2013-07-16 Idenix Pharmaceuticals Inc 經取代羰氧基甲基磷酸醯胺化合物及用於治療病毒感染之藥學組成物
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US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
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AU2013266393B2 (en) 2012-05-22 2017-09-28 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
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