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WO2011106929A1 - Inhibiteurs de polymérase du virus de l'hépatite c ns5b - Google Patents

Inhibiteurs de polymérase du virus de l'hépatite c ns5b Download PDF

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Publication number
WO2011106929A1
WO2011106929A1 PCT/CN2010/070831 CN2010070831W WO2011106929A1 WO 2011106929 A1 WO2011106929 A1 WO 2011106929A1 CN 2010070831 W CN2010070831 W CN 2010070831W WO 2011106929 A1 WO2011106929 A1 WO 2011106929A1
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Prior art keywords
alkyl
group
independently selected
methyl
mmol
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PCT/CN2010/070831
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English (en)
Inventor
Casey Cameron Mccomas
Nigel J. Liverton
Joerg Habermann
Uwe Koch
Frank Narjes
Peng Li
Xuanjia Peng
Richard Soll
Hao Wu
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.)
Organon Pharma UK Ltd
Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Merck Sharp and Dohme LLC
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Application filed by Merck Sharp and Dohme Ltd, Istituto di Ricerche di Biologia Molecolare P Angeletti SpA, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Priority to PCT/CN2010/070831 priority Critical patent/WO2011106929A1/fr
Priority to PCT/CN2010/080332 priority patent/WO2011106986A1/fr
Priority to TW100106743A priority patent/TW201136919A/zh
Priority to ARP110100621A priority patent/AR080433A1/es
Priority to CA2791426A priority patent/CA2791426A1/fr
Priority to PCT/CN2011/000332 priority patent/WO2011106992A1/fr
Priority to US13/582,240 priority patent/US20120328569A1/en
Priority to EP11750145.2A priority patent/EP2542545A4/fr
Priority to JP2012555284A priority patent/JP2013521237A/ja
Priority to AU2011223394A priority patent/AU2011223394A1/en
Publication of WO2011106929A1 publication Critical patent/WO2011106929A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates to antiviral compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS5B (non-structural protein 5B) polymerase, compositions comprising such compounds, the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, methods for inhibiting the function of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.
  • HCV hepatitis C virus
  • NS5B non-structural protein 5B
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals.
  • Current treatments for HCV infection include immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin.
  • RNA-dependent RNA polymerase RNA-dependent RNA polymerase
  • HCV NS5B polymerase Sven-Erik Behrens et al , Identification and properties of the RNA-dependent RNA polymerase of heptatitis C virus, 15(1) EMBO J. 12-22 (1996). Antagonists of NS5B activity are inhibitors of HCV replication. Steven S. Carroll et al, Inhibition of Hepatitis C Virus RNA Replication by 2'- Modified Nucleoside Analogs, 278(14) J. BIOL. CHEM. 1 1979-84 (2003).
  • novel compounds of formula I and/or pharmaceutically acceptable salts thereof are useful, either as compounds or their pharmaceutically acceptable salts (when appropriate), in the inhibition of HCV (hepatitis C virus) NS5B (non- structural 5B) polymerase, the prevention or treatment of one or more of the symptoms of HCV infection, the inhibition of HCV viral replication and/or HCV viral production, and/or as pharmaceutical composition ingredients.
  • these compounds and their salts may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti-infectives, immunomodulators, antibiotics or vaccines, as well as the present Standard of Care treatment options for HCV
  • each R 1 is independently selected from the group consisting of halogens
  • n 0, 1, 2 or 3;
  • R 2 is C(0)NR A R B ;
  • R A and R B are independently selected from the group consisting of hydrogen, Ci-Ce alkyl and 0(Ci-C 6 alkyl);
  • R 3 is ArA, wherein ArA is an aromatic ring system selected from the group consisting of:
  • ArA is substituted by 0, 1, 2 or 3 substitutents R c ;
  • each R c is independently selected from the group consisting of:
  • each ArB is an independently selected aromatic ring system selected from the group consisting of:
  • each R c c) d-C 6 alkyl, d) 0(d-C 6 alkyl), and f) (CH 2 )o- 3 -ArB is substituted by 0, 1, 2 or 3 substituents R F ;
  • each R D is independently selected from the group consisting of hydrogen and Ci- 6 alkyl
  • each R E is independently selected from the group consisting of hydrogen, Ci- 6 alkyl, OCi_ 6 alkyl and 5- or 6-membered monocyclic rings with 0, 1 , 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, wherein each R E OCi- 6 alkyl and 5- or 6-membered monocyclic rings is substituted by 0, 1, 2, 3 substituents independently selected from the group consisting of Ci-Ce alkyl, 0(Ci-C6 alkyl), halogen and OH;
  • each R F is independently selected from the group consisting of:
  • each ArC is an independently selected aromatic ring system selected from the group consisting of:
  • each R G is independently selected from the group consisting of halogen, CN, Ci-ealkyl, 0(Ci-C 6 alkyl), CF 3 and C(0)OH;
  • R 4 is selected from the group consisting of NR H R : ;
  • R H is selected from the group consisting of:
  • R J is selected from the group consisting of and R X R Y , where R x and R Y are independently selected from the group consisting of hydrogen and Ci-ealkyl;
  • R 1 is selected from the group consisting of:
  • R 1 is substituted by 0, 1, 2, 3 or 4 R ;
  • each R K is independently selected from the group consisting of: a) OR L ,
  • each ArD is an independently selected aromatic ring system selected from the group consisting of: i) 5- or 6-membered monocyclic rings with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from the group consisting of N, O or S, and
  • R L is selected from the group consisting of hydrogen, and phenyl
  • R M is selected from the group consisting of hydrogen, Ci. 6 alkyl and (CH 2 ) 0 -3(phenyl);
  • R N is selected from the group consisting of hydrogen
  • R M and R N are taken together with the N to which they are attached to form a 5- to 7-membered ring substituted by 0, 1, 2 or 3 R p ;
  • each R° is independently selected from the group consisting of halogen, Ci -6 alkyl, OCi -6 alkyl and C(0)0(Ci -6 alkyl);
  • each R p is independently selected from the group consisting of halogen, Ci-ealkyl, OCi-ealkyl, oxo and C(0)0(Ci_ 6 alkyl);
  • R H and R 1 are taken together with the N to which they are attached to form a 5- to 7-membered ring.
  • the present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions.
  • the present invention further includes methods of treating or reducing the likelihood or severity of HCV infection, methods for inhibiting the activity of the NS5B polymerase, and methods for inhibiting HCV viral replication and/or viral production.
  • the present invention includes compounds of formula I above, and pharmaceutically acceptable salts thereof.
  • the compounds of formula I are HCV NS5B polymerase inhibitors
  • n is 1. In this embodiment, all other groups are as provided in the general formula above.
  • the compound is a compound of formula la:
  • R is selected from the group consisting of fluorine, bromine and chlorine.
  • R 1 is fluorine.
  • all other groups are as provided in the general formula above and/or in the first or second embodiments.
  • R A is hydrogen.
  • all other groups are as provided in the general formula above and/or in the first through third embodiments.
  • R B is selected from the group consisting of -CH 3 and -OCH 3
  • all other groups are as provided in the general formula above and/or in the first through fourth embodiments.
  • ArA is phenyl.
  • all other groups are as provided in the general formula above and/or in the first through fifth embodiments.
  • each R c is independently selected from the group consisting of a) fluorine, b) OH, c) C ⁇ alkyl, d) Od_ 3 alky
  • each R c is
  • R H is selected from hydrogen, CH 3 and S0 2 CH 3 .
  • R H is S0 2 CH 3 .
  • all other groups are as provided in the general formula above and/or in the first through seventh embodiments.
  • R 1 is selected from the group consisting of Ci-6alkyl and C 2 _6alkenyl.
  • all other groups are as provided in the general formula above and/or in the first through eighth embodiments.
  • R K is selected from the group consisting of a) OR L , b) halogen, c) CN, d) NR M R N , e) OC(0)Ci. 6 alkyl, and f) C(0)OCi. 6 alkyl.
  • all other groups are as provided in the general formula above and/or in the first through ninth embodiments.
  • R L is selected from the group consisting of Ci-ealkyl.
  • all other groups are as provided in the general formula above and/or in the first through tenth embodiments.
  • R M is selected from the group consisting of hydrogen and Ci_ 6 alkyl.
  • all other groups are as provided in the general formula above and/or in the first through eleveth embodiments.
  • Ci_ 6 alkyl is selected from the group consisting of Ci_ 6 alkyl and S0 2 (Ci_ 6 alkyl). In this embodiment, all other groups are as provided in the general formula above and/or in the first through twelfth embodiments.
  • the compound of the invention is selected from the exemplary species depicted in Examples 1 through 154 shown below, and pharmaceutically acceptable salts thereof.
  • composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • a pharmaceutical combination that is (i) a compound of formula I and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of formula I and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS5B activity, or for inhibiting HCV viral replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV antiviral agents are one or more antiviral agents selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • (k) A method of inhibiting HCV viral replication and/ or HCV viral production in a cell-based system, which comprises administering to the subject an effective amount of a compound of formula I in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents,
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV NS5B activity in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • a method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments.
  • the embodiments of compositions and methods provided as (a) through (n) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (n) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS5B activity, or (b) inhibiting HCV viral replication, or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, or (d) use in medicine.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
  • alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
  • Ci_6 alkyl (or “Ci-Ce alkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • C1.4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated.
  • halogenated refers to a group or molecule in which a hydrogen atom has been replaced by a halogen.
  • haloalkyl refers to a halogenated alkyl group.
  • halogen refers to atoms of fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • alkoxy refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.
  • cycloalkyl refers to any cyclic ring of an alkane or alkene having a number of carbon atoms in the specified range.
  • C3-8 cycloalkyl (or “C3-C cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl.
  • cycloalkoxy refers to a "cycloalkyl-O-" group. Cycloalkyl groups may be substituted as indicated.
  • aryl refers to aromatic mono- and poly- carbocyclic ring systems wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
  • aryl includes aromatic mono- and poly-carbocyclic ring systems that include from 0 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S.
  • Suitable aryl groups include phenyl, naphthyl, biphenylenyl, pyridinyl, pyrimidinyl and pyrrolyl, as well as those discussed below.
  • Aryl groups may be substituted as indicated.
  • Aryl ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the aryl ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.
  • carbocycle (and variations thereof such as “carbocyclic”) as used herein, unless otherwise indicated, refers to (i) a C5 to C7 monocyclic, saturated or unsaturated ring, or (ii) a Cg to C 10 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. Carbocycle groups may be substituted as indicated. When the carbocycles contain one or more heteroatoms independently chosen from N, O and S, the carbocycles may also be referred to as
  • heterocycles as defined below.
  • the carbocycle may be attached to the rest of the molecule at any carbon or nitrogen atom that results in a stable compound.
  • the fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle” generally refers to a Cs to Cio bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system.
  • a fused bicyclic carbocycle in which both rings are saturated is a saturated bicyclic ring system.
  • Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • a fused bicyclic carbocycle in which one or both rings are unsaturated is an unsaturated bicyclic ring system.
  • Carbocycle ring systems may include, where appropriate, an indication of the variable to which a particular ring atom is attached. Unless otherwise indicated, substituents to the ring systems can be attached to any ring atom, provided that such attachment results in formation of a stable ring system.
  • heterocycle broadly refers to (i) a stable 5- to 7-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 8- to 10-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g ., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally qua
  • heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
  • Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
  • heteroaryl ring system refers to aryl ring systems, as defined above, that include from 1 to 4 heteroatoms (non-carbon atoms) that are independently chosen from N, O and S.
  • heteroatoms non-carbon atoms
  • substitutions can be those resulting in N-oxide formation.
  • heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo- 1,4-dioxinyl and benzo-l,3-dioxolyl.
  • alkyl, cycloalkyl, and aryl groups are not substituted.
  • the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, -CF 3 , -NH 2 , -N(Ci-C6 alkyl) 2 , -NO2, oxo, - CN, -N 3 , -OH, -0(Ci-C 6 alkyl), C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 6 alkyl) S(0)o-2-, aryl-S(O) 0.2 -, (C 0 -C 6 alkyl)S(0)o-2(Co-C 6 alkyl)-, (C 0 -C 6 alkyl)C(0)NH-, H 2 N-C(NH)-
  • the term “compound” is intended to encompass chemical agents described by generic formula I in all forms, including hydrates and solvates of such chemical agents.
  • the term “compound” is intended to encompass prodrugs of the chemical agents described by generic formula I.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of formula I.
  • different isotopic forms of hydrogen (H) include protium ( ⁇ ) and deuterium ( 2 H or D).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • heteroaryl ring described as containing from “0 to 3 heteroatoms” means the ring can contain 0, 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.
  • any variable for example, R 1 or R 3
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g. , therapeutic or prophylactic administration to a subject).
  • certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
  • a reference to a compound of formula I is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
  • the compounds of the present inventions are useful in the inhibition of HCV replication (e.g., HCV NS5B activity), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection.
  • HCV replication e.g., HCV NS5B activity
  • the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5B, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt that possesses the effectiveness of the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
  • Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential provision of the compound or salt and other agents.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the term "effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the effective amount is a "therapeutically effective amount” for the alleviation of one or more symptoms of the disease or condition being treated.
  • the effective amount is a "prophylactically effective amount” for reduction of the severity or likelihood of one or more symptoms of the disease or condition.
  • the effective amount is a "therapeutically effective amount” for inhibition of HCV viral replication and/or HCV viral production.
  • the term also includes herein the amount of active compound sufficient to inhibit HCV NS5B activity and thereby elicit the response being sought (i.e., an "inhibition effective amount").
  • active compound i.e., active ingredient
  • references to the amount of active ingredient are to the free acid or free base form of the compound.
  • the compounds of the present invention optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by one or more
  • Liquid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like.
  • Solid preparations suitable for oral administration e.g., powders, pills, capsules and tablets
  • solid excipients as starches, sugars, kaolin, lubricants, binders,
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).
  • the compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, HCV viral genotype, viral resistance, and the host undergoing therapy.
  • the present invention also relates to a method of inhibiting HCV NS5B activity, inhibiting HCV viral replication and/or HCV viral production, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an
  • Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, R7025 (an enhanced interferon (Roche)), interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ (peginterferon-a), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
  • Interferon- ⁇ includes, but is not limited to, recombinant interferon-a2a (such as ROFERON interferon available from Hoffmann- LaRoche, Nutley, NX), pegylated interferon-a2a (PEGASYS), interferon-a2b (such as INTRON-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon-a2b
  • interferon-a2a such as ROFERON interferon available from Hoffmann- LaRoche, Nutley, NX
  • PGASYS pegylated interferon-a2a
  • interferon-a2b such as INTRON-A interferon available from Schering Corp., Kenilworth, NJ
  • the compounds of the invention may also be administered in combination with the antiviral agent NS5B polymerase inhibitor R7128 (Roche)
  • the compounds of the present invention also may be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in Rogers E. Harry-O'Kuru et al., A Short, Flexible Route toward 2 '-C-Branched Ribonucleosides, 62 J. ORG. CHEM. 1754-59 (1997); Michael S. Wolfe & Rogers E. Harry-O'Kuru, A Concise Synthesis of2'-C- Methylribonucleosides, 36(42) TETRAHEDRON LETTERS 7611-14 (1995); U.S. Patent
  • Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine, 2'-C-methyl- guanosine, and 9-(2-C-methyl-P-D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3 ', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3-propanediol esters of the 5'-phosphate derivatives.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
  • HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication.
  • Exemplary substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116, WO 02/48172, WO 2008/057208 and WO 2008/057209, in British Patent No. GB 2 337 262, and in U. S. Patent Nos. 6,323, 180 and 7,470,664.
  • the compounds of the present invention may also be combined for the treatment of HCV infection with nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publications WO 02/51425, WO 01/79246, WO 02/32920, WO 02/48165 and WO 2005/003147 (including R1656, (2'i?)-2'-deoxy-2'-fluoro-2'-C- methylcytidine, shown as compounds on page 77); WO 01/68663; WO 99/43691;
  • WO 02/18404 and WO 2006/021341 and U.S. Patent Application Publication US 2005/0038240, including 4'-azido nucleosides such as R1626, 4'-azidocytidine; U.S. Patent Application Publications US 2002/0019363, US 2003/0236216, US 2004/0006007, US 2004/0063658 and US 2004/0110717; U.S. Patent Nos.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase.
  • HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publications
  • HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2' -F-2' -beta- methyl cytidine (see also WO 2005/003147).
  • additional nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl-p-D-arabinofuranosyl)-7H-pyrrolo[2,3-tf]pyrimidine; 4- amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-methylamino-7-(2-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i/
  • the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in U.S. Patent Applciation Publications US 2006/0100262 and US 2009/0048239; International Patent Application Publications WO 01/77091, WO 01/47883, WO 02/04425, WO 02/06246, WO 02/20497, WO 2005/016927 (in particular JTK003), WO 2004/041201, WO 2006/066079, WO 2006/066080, WO 2008/075103, WO 2009/010783 and WO 2009/010785; the content of each is incorporated herein by reference in its entirety.
  • additional non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS5B inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5, 6,7,8- tetrahydroindolo[2, l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2-morpholin- 4-ylethyl)-5,6,7,8-tetrahydroindolo[2, l-a][2,5]benzodiazocine-l l-carboxylic acid; 14- cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2, l-a]
  • [2, 5 ]benzodiazocine-l 1-carboxylic acid 6-allyl-14-cyclohexyl-3-methoxy-5, 6,7,8- tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclopentyl-6-[2- (dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine- 11-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2, l- ][2,5]benzodiazocine- 11-carboxylic acid; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][l,4]diazocino[l
  • HCV NS5B polymerase inhibitors are used in combination with non-nucleoside HCV NS5A inhibitors and pharmaceutically acceptable salts thereof.
  • the HCV NS5B inhibitory activity of the present compounds may be tested using assays known in the art.
  • the HCV NS5B polymerase inhibitors described herein have activities in a genotype lb replicon assay as described in the Examples.
  • the assay is performed by incubating a replicon harboring cell-line in the presence of inhibitor for a set period of time and measuring the effect of the inhibitor on HCV replicon replication either directly by quantifying replicon RNA level, or indirectly by measuring enzymatic activity of a co-encoded reporter enzyme such as luciferase or ⁇ -lactamase. By performing a series of such measurements at different inhibitor concentrations, the effective inhibitory concentration of the inhibitor (EC50 or EC90) is determined.
  • the present invention also includes processes for making compounds of formula I.
  • the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice.
  • This scheme describes the preparation of compounds with the general structure of G and H.
  • compound A obtained according to procedure in WO 2004/041201 A2
  • coupling with a substituted or unsubstituted phenylboronic acid catalyzed by a transition metal, in this case Pd(dppf)Cl2 furnishes compounds of the general structure B.
  • Pd(dppf)Cl2 a transition metal
  • This type of transition- metal-mediated cross-coupling is common and there are numerous conditions that one skilled in the art can use to execute such a transformation.
  • Compounds of type C are next generated by reduction of the nitro group in compound B, which can be accomplished by exposure to common reducing conditions, in this case treatment by Fe in NH 4 CI solution under reflux.
  • the amino group in compounds C is then sulfonylated with a sulphonyl chloride to give compounds of type D.
  • the sulfonamide D can be coupled with an alkylating agent (an alkyl halide for example) in the presence of a suitable base, such as potassium carbonate, to provide compounds E.
  • a suitable base such as potassium carbonate
  • the ester functionality in compounds E is readily hydrolyzed by aqueous base to afford compounds F.
  • the carboxylic acid of compound F was condensed with methanamine or
  • Compound C can be coupled with an alkylating agent (an alkyl halide for example) in the presence of a suitable base, such as potassium carbonate, to provide compounds I where Z represents an alkylated aniline.
  • C may be condensed with substituted carboxylic acid in the presence of coupling reagents, such as EDCI and HOBT, to afford compounds I where Z represents a substituted amide.
  • Compounds J may be obtained from compounds I by further N-alkylation or N-acylation reaction.
  • Compounds of general structure I or J are hydrolyzed by aqueous hydroxide to provide compounds F.
  • the carboxylic acid of compound F may be condensed with an amine as shown in Scheme 1 to provide target compounds of general structure G and H.
  • Compound A may be reduced by a catalyst in the presence of a hydrogen source (for example, Pd in the presence of formic acid) to afford compound K. Further reduction of K provides aniline L. The amino group of compound L is reacted with sulfonyl chloride to afford compound M, which can be further N-alkylated with a wide variety of alkylating agents in the presence of a suitable base, such as potassium carbonate, to provide compound ⁇ . Halogenation of compound ⁇ , in this case bromination with FeCl 3 and Br2 in anhydrous CCU gives compound O. Compounds of general structure O are hydrolyzed by aqueous hydroxide to provide compounds P.
  • a hydrogen source for example, Pd in the presence of formic acid
  • the carboxylic acid of compound P may be condensed with an amine as shown in Scheme 1 to provide compounds of general structure Q.
  • Transition metal mediated coupling of compounds Q with a boronic acid (alternatively alkyl tin, silicon, or other types of coupling partners may be used) provides the target compounds of general structure G.
  • Compounds E that possess a hydroxyl group may be obtained from compounds D by reacting with 2-bromo ethanol.
  • the hydroxyl group E can be converted to a leaving group (by reaction with MsCl for example) to afford compound R.
  • Compound R may be treated with nucleophilic reagents such as an amine in the presence of a suitable base, such as triethylamine, to afford compound S.
  • Compounds T can then be obtained from compound S by further N-alkylation or N-acylation.
  • Compounds of structure T are readily converted to the target structures G following the general procedure described in Scheme 1.
  • Compound F' can be converted to compound G' by treated with fuming HNO 3 .
  • Compound H' is generated by reduction of the nitro group in compound G', and the amino group in compound H' is then sulfonylated with MsCl to furnish compound I'.
  • the sulfonamide I' can be coupled with Mel in the presence of potassium carbonate to provide compound J' .
  • the ester functionality in compound J' is readily hydro lyzed by aqueous base to afford compound K'.
  • the carboxylic acid of compound K' was condensed with methanamine using common amide forming reagents such as EDCI and HOBT to give compound L'.
  • Transition metal mediated coupling of compound L' with a meta-heterocycle-substituted phenyl boronic ester provides the target compounds of general structure M'.
  • Coupling compound L' with a substituted or unsubstituted 3-formylphenylboronic acid catalyzed by a transition metal, in this case Pd(dppf)Cl 2 furnishes compounds of the general structure N ⁇
  • Compounds of type N' were cyclized with ortho-amino anilines or ortho-amino thiophenols to provide the target compounds of general structure O' or P'.
  • LiHMDS Lithium bis(trimethylsilyl) amide
  • Example 1 2- 4-fluorophenvn-A r -methyl-6-[methyl(methylsulfonYnaminol-5-phenyl-l- benzofuran-3-carboxamide
  • Step 1 ethyl 2-(4-fluorophenyl)-6-nitro-5-phenyl-l-benzofuran-3-carboxylate
  • Phenylboronic acid 100 mg, 0.8 mmol
  • K 3 P0 4 -3H 2 0 119 mg, 0.8 mmol
  • ethyl 2-(4-fluorophenyl)-6-nitro-5- ⁇ [(trifluoromethyl)sulfonyl] oxy ⁇ -l-benzofuran-3-carboxylate obtained according to procedure in WO 2004/041201 A2, 200 mg, 0.4 mmol
  • dioxane 2 mL
  • DMF 2 mL
  • Pd(dppf)Cl 2 5 mg, 0.08 mmol
  • Step 3 ethyl 2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-5 ⁇ henyl-l-benzofuran-3- carboxylate
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl-l-bem
  • Step 5 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5 ⁇ henyl-l-benzofuran- carboxylic acid
  • Step 4 The product of Step 4 (78 mg, 0.17 mmol) was dissolved in THF (2 mL) and H 2 0 (2 mL) Then, Li OH (71 mg, 1.7 mmol) was added to the solution, and the mixture was stirred at RT overnight. After acidification with HC1 (1 N) and extraction with EtOAc, the combined organic phases were washed with brine, dried over Na 2 S0 4 , filtered and evaporated to give the product of 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-5-phenyl- 1 -benzofuran-3- carboxylic acid (50 mg, yield: 67%). It was used for the next step without further purification. Step 6: 2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino
  • Steps 1-5 were performed in accordance with Example 1, Steps 1-5.
  • Step 6 2-(4-fluorophenyl)-N-methoxy-6-[meth l(methylsulfonvUamino]-5- ⁇
  • Examples 8- 12 were prepared according to the general procedures of Example 7.
  • Example 13 6-[icYclohexYlmethvnimethylsulfonyl aininol-2-(4-fluorophenYn-jV-inethyl-5-
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 6 6-[(cyclohexylmethyl)(methylsulfonyl)amino]-2-(4-fluoropheny
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 5 2-(4-fluorophenyl)-5-phenyl-6-[(l ⁇ henylethyl)amino]-l-benzofuran-3-carboxylic acid
  • Example 69 (20 mg, yield: 48.6%) was prepared according to the general procedure in Example 1, Step 6.
  • Example 70 2-f4-fluorQphenyl)-A-methyl-6-( ⁇ 2-[methyl(phenyl)aminolethyl ⁇ amino)-5- phenyl-l-benzofuran-3-carboxamide
  • Example 70 was prepared according to the general procedures of Example 69.
  • Steps 1-4 were performed in accordance with Example 69, Steps 1-4.
  • Step 5 ethyl 2-(4-fluorophenyl)-6-[methyl(l ⁇ henylethyl)amino]
  • Step 6 2-(4 ⁇ uoropheriyl)-6-[methyl(l ⁇ heriylethyl)amino]-5 ⁇ heny
  • the carboxylic acid (75 mg, yield: 90 %) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
  • Step 7 2-(4-fluorophenyl)-N-methyl-6-[methyl(l-phenylethyl)ammo]-5- ⁇
  • Example 72 ethyl [2-(4-fluorophenv0-3-(methylcarbamov0-5-phenyl-l-benzofuran-6-
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 4 ethyl 6-[(ethoxycarbonyl)amino]-2-(4-fluorophenyl)-5-phen l-l-benzofuran-3- carboxylate
  • DCM 3 mL
  • Step 5 ethyl 6-[ (ethoxycarbonyl) ⁇ 2-[methyl(phenyl)ammo]ethyl ⁇ amino]-2-(4-fluorophenyl)-5-
  • Step 4 The product of Step 4 (474 mg, 1.06 mmol), 2-(methyl(phenyl)amino)ethyl methanesulfonate (243 mg, 1.06 mmol) and Cs 2 C0 3 (7.8 g, 24 mmol) in dry DMF (100 mL) was stirred at 140°C for 4 hours. After the mixture was concentrated, the residue was diluted with DCM, washed with water, dried over Na 2 S0 4 and concentrated. The residue was purified by prep-TLC to give the desired amino carbamate (335 mg, yield: 54.6%). MS (M+H) + : 581. Step 6: 6-[(ethoxycarbonyl) ⁇ 2-[methyl(phenyl)amino]ethyl ⁇ amino]-2-(4-fl orophenyl)-5-
  • Step 5 The product of Step 5 (25 mg, yield: 90%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used directly in the next step without further purification.
  • Step 7 ethyl [2-(4-fluorophenyl)-3-(methylcarbamoyl)-5-phenyl-l-benzofuran-6-yl] ⁇ 2- [methyHphenyl)ammo]ethyl ⁇ carbamate
  • Example 72 (15 mg, yield: 48.7%) was prepared according to the general procedure in Example 1, Step 6.
  • Steps 1-2 were performed in accordance with Example 1, Steps 1-2.
  • Step 3 ethyl 2-(4-fluorophenyl)-6-[ (N-methyl-N-phenylglycyl)amino]-5-phenyl-l-benzofuran-3- carboxylate
  • the amide (75 mg, yield: 50%) was prepared from the product of Step 2 according to the general procedure in Example 1, Step 6.
  • Step 4 2-(4-fluorophenyl)-6-[ (N-methyl-N-phenylglvcyl)amino]-5-phenyl-l-benzofuran-3- carboxylic acid
  • the carboxylic acid (50 mg, yield: 75%) was prepared in an analogous manner to Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
  • Step 5 2-(4-fluorophenyl)-N-methyl-6-[ (N-methyl-N-phenylglycyl)amino]-5-phenyl-l-
  • Steps 1-3 were performed in accordance with Example 73, Steps 1-3.
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[methyl( -methyl-N ⁇ henylglycyl)amino]-5-phenyl-l- benzofuran-3-carboxylate
  • the alkylated amide (90 mg, yield: 90%) was prepared in an analogous manner to the compound prepared in Example 1, Step 4.
  • the carboxylic acid (85 mg, yield: 95%o) was prepared in an analogous manner to
  • Example 13 using the general procedure in Example 13, Step 4. The carboxylic acid was used in the next step without further purification.
  • Step 6 2-(4-fluorophenyl)-N-methyl-6-[methyl(N-methyl-N ⁇ henylglvcyl)amin ⁇
  • Examples 75 and 76 were prepared according to the general procedures of
  • Example 77 2- 4-fluorophenyl)-A-methyl-6-[(4 t y,5 J RV4-methyl-2-oxo-5-phenyl-l,3- oxazolidin-3-yl1-5-phenyl-l-benzofuran-3-carboxamide
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 6 2-(4-fluorophenyl)-6-[(4S, 5R)-4-methyl-2-oxo-5-phenyl-l , 3-oxazolidin-3-yl]-5-phenyl-l-
  • Step 7 2-(4-fluorophenyl)-N-methyl-6-[(4S, 5R)-4-methyl-2-oxo-5 -phenyl- 1, 3-oxazolidin-3-yl]- 5-phenyl-l-benzofuran-3-carboxamide
  • Step 1 ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate
  • Step 4 ethyl 5-(2-fluorophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)ammo]-l- benzofuran-3-carboxylate
  • Steps 1-5 were performed in accordance with Example 78, Steps 1-5.
  • Example 90 was prepared using conditions analogous to the coupling reaction described in Example 7, Step 6 (40 mg, yield: 51%).
  • Steps 1-4 ethyl 5-(3-cyanophenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l- benzofuran-3-carboxylate
  • Steps 1-4 were performed in an analogous manner to Example 1, Steps 1-4.
  • the ester (450 mg, 0.92 mmol) was dissolved in dioxane (5 mL). Then LiOH (96 mg, 4 mmol) was added to the solution, and the mixture was stirred at RT overnight. After acidifmg with HCl (I N) and extracting with EtOAc, the combined organic phases were washed with brine, dried over Na 2 SC1 ⁇ 4, filtered and evaporated to give the cyano carboxylic acid (300 mg, yield: 50%) and dicarboxylic acid (100 mg, yield: 30%). The crude mixture was used for the next step without further purification.
  • Step 6 2-(4-fluorophenyl)-N-methoxy-5-[ 3-(methoxycarbamoyl)phenyl]-6-
  • Example 99 was prepared using condition analogous to the coupling reaction described in Example 7, Step 6 (55 mg, yield: 73%).
  • Example 100 2-f4-fluorophenvn-A f -methyl-5-[3-(methYlcarbamoYnphenyll-6-
  • Steps 1-5 5-(3-carboxyphenyl)-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)a
  • Steps 1-5 were performed according to the general procedures in Example 99, Steps 1-5.
  • Step 6 2-(4-fluorophenyl)-N-methyl-5-[ 3-(methylcarbamoyl)phenyl]-6- [methyl(methylsulforiyl)amino]-l-benzofuran-3-carboxamide
  • Example 100 was prepared according to the general procedure in Example 1, Step 6.
  • Step 1 5-f 3-(aminomethyl)phenyl]-2-(4-fluorophenyl)-N-methyl-6- [methyl(methylsulfonyl)amino]-l-benzofuran-3-carboxamide
  • Example 102 2- 4-fluorophenvn-A r -methyl-6-[methvirmethylsulfonvnamino1-5- 3- i[(methylsulfonvnaminolmethyl ⁇ phenvn-l-benzofuran-3-carboxamide
  • Steps 1-2 were performed according to the general procedures in Example 1, Steps 1-2.
  • Example 102 was prepared in an analogous manner to the sulfonamide synthesis described in Example 1, Step 3 (20 mg, yield: 60%).
  • Example 103 was prepared according to the general procedures of Example 102.
  • Example 104 2- 4-fluorophenvn-A r -methyl-6-[methvirmethylsulfonvnamino1-5- 4-
  • Step 1 5-f 4-(aminomethyl)phenyl]-2-(4-fluorophenyl)-N-methyl-6-
  • Step 2 2-(4-fluorophenyl)-N-methyl-6-[methy methylsulfonyl)amino]-5-(4- ⁇ [(methylsulfonyl)amino]methyl ⁇ phenyl)-l-benzofuran-3-carboxamide
  • Example 104 was prepared in an analogous manner to the sulfonamide prepared in Example 1, Step 3 (20 mg, yield: 60%).
  • Examples 105-107 were prepared according to the general procedures of
  • Example 108 2-(4-fluorophenvn-A-meth ⁇ l-6-[niethylfinethylsulfonvnaininol-5-[4- (trifluoromethvQphenyll-l-benzofuran-3-carboxamide
  • Step 1 ethyl 2-(4-fluorophenyl)-6-nitro-l-benzofuran-3-carboxylate
  • Step 2 ethyl 6-amino-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l-benzofuran-3-carboxylate
  • Step 5 ethyl 5-bromo-2-(4-fluorophenyl)-6-[methyl(methylsulfonyl)amino]-l- ⁇
  • the ester (210 mg, yield: 80%) was hydrolysed in an analogous manner to the general procedure of Example 78, Step 5.
  • the carboxylic acid was used in the next step without further purification.
  • Step 7 5-bromo-2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)a
  • Step 8 2-(4-fluoropheriyl)-N-methyl-6-[methyl(methylsulfonyl)amino]-5-[4-
  • Steps 1-4 were performed in an analogous manner to Example 1, Steps 1-4.
  • Step 5 ethyl 2-(4-fluorophenyl)-6-[(methylmlfonyl) ⁇ 2-[(methylsulfony
  • Step 6 ethyl 6- ⁇ [2-(benzylamino)ethyl](methylsnlfonyl)ammo ⁇ -2-(4-fluorophenyl)-5-phenyl-l-
  • Benzylamine (0.5 mL, 0.27 mmol) was added to a solution of mesylate (50 mg, 0.09 mmol) in Ets (1 mL) and MeCN (1 mL). The reaction mixture was stirred overnight at 60°C. After dilution with 3 ⁇ 40 and extraction with EtOAc, the mixture was washed with brine, dried over Na 2 SC>4 and filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by prep-TLC to give the benzylic amine (30 mg, yield: 58%).
  • Step 7 6-if2-(benzylamino)ethyllfmethylsulfonyl)amino ⁇ -2-(4-flnorophenyl)-5-phenyl-l-
  • the ester (30 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL) and 3 ⁇ 40 (1 mL). Then LiOH (21 mg, 0.5 mmol) was added to the solution, and the mixture was refluxed for 2 hours. After being acidified with HC1 (1 N) and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na 2 SC>4, filtered and evaporated to give the carboxylic acid (22 mg, yield: 79%). The acid was used in the next step without further purification.
  • Step 8 6- ⁇ [2-(benzylamino)ethyl](methylsulfonyl)amino ⁇ -2-(4-fluorophe
  • Examples 124-132 were prepared according to the general procedures of
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amm ⁇
  • Steps 1-3 were performed in accordance with Example 1, Steps 1-3.
  • Step 4 ethyl 2-(4-fluorophenyl)-6-[ ⁇ 2-[methyl(phenyl)amino]ethyll(methylsulfonyl)amino
  • Step 4 was performed in an an analogouos manner to Example 133, Step 4.
  • the crude product was purified by prep-TLC to give pure ethyl 2-(4-fluorophenyl)-6-[ ⁇ 2-
  • Step 5 2-(4-fluorophenyl)-6-[ ⁇ 2-[methyl(phenyl)amino]ethyl ⁇ (methylsulfonyl) amino5-phenyl-
  • Step 5 was performed in an analogous manner to Example 133, Step 5.
  • the crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-6-[ ⁇ 2-[methyl(phenyl)amino] ethyl ⁇ (methyl sulfonyl) amino5-phenyl-l-benzofuran-3-carboxylic acid (50 mg, yield: 87%).
  • Step 6 was performed in an analogous manner to Example 133, Step 6.
  • the crude product was purified by prep-TLC to give pure 2-(4-fluorophenyl)-N-methyl-6-[ ⁇ 2- [methyl(phenyl)amino]ethyl ⁇ (methylsulfonyl)amino]-5-phenyl- 1 -benzofuran-3-carboxamide (13 mg, yield: 42%).
  • Step 2 Methyl 2-(5-bromo-2- tert-butyldimethylsilyl acetate
  • imidazole 0.56 g, 8.23 mmol
  • TBSC1 0.93 g, 6.17 mmol
  • the reaction mixture was washed with H 2 0, brine and concentrated in vacuo, the residue was purified by column chromatography to furnish the pure product of methyl 2-(5- bromo-2-(tert-butyldimethylsilyloxy)phenyl)acetate (1.4 g, yield: 95%).
  • Step 3 Methyl 2-(5-bromo-2-(tert-butyldimethylsilyloxy)phenyl)-3-(4-fluorophenyl)-3- oxopropanoate
  • Step 7 Methyl 6-amin -5-bromo-2-(4-fluorophenyl)-l-benzofuran-3-carboxylate
  • Step 8 Methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)-l-benzofuran-3-carboxylate
  • Step 9 Methyl 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylate
  • Step 10 5-bromo-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-l-benzofuran-3- carboxylic acid
  • Step 12 5-(3-(benzo[d]thiazol-2-yl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(N-
  • Examples 136-142 were prepared according to the general procedures
  • Steps 1-11 were performed in an analogous manner to Example 135, Steps 1-11.
  • Step 12 2-(4-fluorophenyl)-5-(3-formylphenyl)-N-methyl-6-[methyl(methyl)
  • the aryl aldehyde (45 mg, yield: 73%) was prepared in an analogous manner to Example 136, Step 12.
  • Step 13 2-(4-fluorophenyl)-N-methyl-5-[ 3-( 5-methyl-l.3-benzothiazol-2-yl)phenyl]-6-
  • Examples 144-149 were prepared according to the general procedures of
  • Steps 1-12 were performed in an analogous manner to Example 143, Steps 1-12.
  • Step 13 5-[3-(5-fluoro-lH-benzimidazol-2-yl)phenyl]-2-(4-fluorophenyl)-N-m
  • Examples 151-154 were prepared according to the general procedures of Example 150.
  • Stable neomycin phosphotransferase encoding replicons-harboring cell lines were used, so all cell lines were maintained under G418 selection prior to the assay. Potency was deteremined using a cell ELISA assay with an antibody to the replicons encoded NS3/4a protease. See Caterina Trozzi et al , In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor, 77(6) J. Virol. 3669 (2003). To initiate an assay, replicon cells were plated in the presence of a dilution series of test compound in the absence of G418.
  • the assays were performed in a 96-well plate formate for manual operation, or a 384-well plate format for automated assay. Replicon cells and compound were incubated for 96 hours. At the end of the assay, cells were washed free of media and compound, and the cells were then lysed. RNA was quantified indirectly through detection of replicon-encoded NS3/4A protein levels, through an ELISA-based assay with an antibody specific for NS3/4A. EC50 determinations were calculated as a percentage of a DMSO control by fitting the data to a four-parameter fit function.

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Abstract

La présente invention concerne des composés de formule I qui sont utilisés en tant qu'inhibiteurs de polymérase du virus de l'hépatite C (VHC) NS5B, la synthèse de ces composés, et l'utilisation de ces composés pour inhiber l'activité polymérase VHC NS5B, pour traiter ou prévenir l'infection par le VHC et pour inhiber la réplication virale du VHC et/ou la production virale dans un système à base de cellules.
PCT/CN2010/070831 2010-03-02 2010-03-02 Inhibiteurs de polymérase du virus de l'hépatite c ns5b Ceased WO2011106929A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
PCT/CN2010/070831 WO2011106929A1 (fr) 2010-03-02 2010-03-02 Inhibiteurs de polymérase du virus de l'hépatite c ns5b
PCT/CN2010/080332 WO2011106986A1 (fr) 2010-03-02 2010-12-27 Inhibiteurs de polymérase du virus de l'hépatite c ns5b
TW100106743A TW201136919A (en) 2010-03-02 2011-03-01 Inhibitors of hepatitis C virus NS5B polymerase
ARP110100621A AR080433A1 (es) 2010-03-02 2011-03-01 Derivados de benzofurancarboxamidas utiles para tratar o prevenir infecciones por vhc y composiciones farmaceuticas que los contienen.
CA2791426A CA2791426A1 (fr) 2010-03-02 2011-03-02 Inhibiteurs de polymerase du virus de l'hepatite c ns5b
PCT/CN2011/000332 WO2011106992A1 (fr) 2010-03-02 2011-03-02 Inhibiteurs de polymérase du virus de l'hépatite c ns5b
US13/582,240 US20120328569A1 (en) 2010-03-02 2011-03-02 Inhibitors of hepatitis c virus ns5b polymerase
EP11750145.2A EP2542545A4 (fr) 2010-03-02 2011-03-02 Inhibiteurs de polymérase du virus de l'hépatite c ns5b
JP2012555284A JP2013521237A (ja) 2010-03-02 2011-03-02 Ｃ型肝炎ウィルスｎｓ５ｂポリメラーゼの阻害薬
AU2011223394A AU2011223394A1 (en) 2010-03-02 2011-03-02 Inhibitors of hepatitis C virus NS5B polymerase

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Cited By (15)

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US8324212B2 (en) 2010-02-25 2012-12-04 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8354410B2 (en) 2010-03-11 2013-01-15 Bristol-Meyers Squibb Company Compounds for the treatment of hepatitis C
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
WO2013034048A1 (fr) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Composés benzofuranes substitués et leurs procédés d'utilisation pour le traitement de maladies virales
US8445497B2 (en) 2010-06-30 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2013118097A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction dibenzooxahétérocycle
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
WO2014110066A1 (fr) * 2013-01-10 2014-07-17 Bristol-Myers Squibb Company Composés benzofurane et azabenzofurane macrocycliques pour le traitement de l'hépatite c
US8927593B2 (en) 2011-08-19 2015-01-06 Glaxo Group Limited Benzofuran compounds for the treatment of hepatitis C virus infections
WO2015143256A1 (fr) * 2014-03-21 2015-09-24 Bristol-Myers Squibb Company Composés cyanoamino (aza)benzofurane pour le traitement de l'hépatite c
WO2015179392A1 (fr) * 2014-05-21 2015-11-26 Bristol-Myers Squibb Company Composés 2-(aryl- ou hétéroaryl-)phényl(aza)benzofurane pour le traitement de l'hépatite c
US9303020B2 (en) 2012-02-08 2016-04-05 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2016133972A1 (fr) * 2015-02-19 2016-08-25 Bristol-Myers Squibb Company Composés de benzofurane substitués pour le traitement de l'hépatite c
US10464914B2 (en) 2015-03-23 2019-11-05 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
US12274700B1 (en) 2020-10-30 2025-04-15 Accencio LLC Methods of treating symptoms of coronavirus infection with RNA polymerase inhibitors

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CN1731993A (zh) * 2002-11-01 2006-02-08 维洛药品公司 苯并呋喃化合物、组合物以及治疗和预防丙型肝炎病毒感染及相关疾病的方法

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CN1731993A (zh) * 2002-11-01 2006-02-08 维洛药品公司 苯并呋喃化合物、组合物以及治疗和预防丙型肝炎病毒感染及相关疾病的方法

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324212B2 (en) 2010-02-25 2012-12-04 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8354410B2 (en) 2010-03-11 2013-01-15 Bristol-Meyers Squibb Company Compounds for the treatment of hepatitis C
US8445497B2 (en) 2010-06-30 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9309260B2 (en) 2010-10-26 2016-04-12 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9085587B2 (en) 2010-10-26 2015-07-21 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US8927593B2 (en) 2011-08-19 2015-01-06 Glaxo Group Limited Benzofuran compounds for the treatment of hepatitis C virus infections
US9682999B2 (en) 2011-08-19 2017-06-20 Glaxo Group Limited Benzofuran compounds for the treatment of hepatitis C virus infections
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
US9573939B2 (en) 2011-09-08 2017-02-21 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
WO2013034048A1 (fr) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Composés benzofuranes substitués et leurs procédés d'utilisation pour le traitement de maladies virales
EP2753611A4 (fr) * 2011-09-08 2015-03-11 Merck Sharp & Dohme Composés benzofuranes substitués et leurs procédés d'utilisation pour le traitement de maladies virales
US9303020B2 (en) 2012-02-08 2016-04-05 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2013118102A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction hétérotricycle
US9073942B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a heterotricycle moiety
US9073943B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a dibenzooxaheterocycle moiety
WO2013118097A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction dibenzooxahétérocycle
US9434738B2 (en) 2013-01-10 2016-09-06 Bristol-Myers Squibb Company Macrocyclic benzofuran and azabenzofuran compounds for the treatment of hepatitis C
WO2014110066A1 (fr) * 2013-01-10 2014-07-17 Bristol-Myers Squibb Company Composés benzofurane et azabenzofurane macrocycliques pour le traitement de l'hépatite c
CN104884459A (zh) * 2013-01-10 2015-09-02 百时美施贵宝公司 用于治疗丙型肝炎的大环苯并呋喃和氮杂苯并呋喃化合物
WO2015143256A1 (fr) * 2014-03-21 2015-09-24 Bristol-Myers Squibb Company Composés cyanoamino (aza)benzofurane pour le traitement de l'hépatite c
US20170174667A1 (en) * 2014-03-21 2017-06-22 Bristol-Myers Squibb Company Cyanoamino (aza)benzofuran compounds for the treatment of hepatitis c
US9920036B2 (en) 2014-03-21 2018-03-20 Bristol-Myers Squibb Company Cyanoamino (aza)benzofuran compounds for the treatment of hepatitis C
WO2015179392A1 (fr) * 2014-05-21 2015-11-26 Bristol-Myers Squibb Company Composés 2-(aryl- ou hétéroaryl-)phényl(aza)benzofurane pour le traitement de l'hépatite c
WO2016133972A1 (fr) * 2015-02-19 2016-08-25 Bristol-Myers Squibb Company Composés de benzofurane substitués pour le traitement de l'hépatite c
US10570108B2 (en) 2015-02-19 2020-02-25 Bristol-Myers Squibb Company Substituted benzofuran compounds for the treatment of hepatitis C
US10464914B2 (en) 2015-03-23 2019-11-05 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
US10947210B2 (en) 2015-03-23 2021-03-16 Cocrystal Pharma, Inc. Inhibitors of Hepatitis C virus polymerase
US12274700B1 (en) 2020-10-30 2025-04-15 Accencio LLC Methods of treating symptoms of coronavirus infection with RNA polymerase inhibitors

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