US20130309196A1 - Antiviral compounds - Google Patents

Antiviral compounds Download PDF

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Publication number
US20130309196A1
US20130309196A1 US13/831,116 US201313831116A US2013309196A1 US 20130309196 A1 US20130309196 A1 US 20130309196A1 US 201313831116 A US201313831116 A US 201313831116A US 2013309196 A1 US2013309196 A1 US 2013309196A1
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United States
Prior art keywords
imidazol
mmol
tert
compound
naphtho
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Abandoned
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US13/831,116
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English (en)
Inventor
John O. Link
Jeromy J. Cottell
Teresa Alejandra Trejo Martin
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Gilead Pharmasset LLC
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Gilead Sciences Inc
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Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to US13/831,116 priority Critical patent/US20130309196A1/en
Priority to ES17160683T priority patent/ES2738012T3/es
Priority to NZ725365A priority patent/NZ725365A/en
Priority to SI201331447T priority patent/SI3239153T1/sl
Priority to CN201380029171.0A priority patent/CN104487442B/zh
Priority to KR1020147034784A priority patent/KR102078233B1/ko
Priority to CA2873485A priority patent/CA2873485C/en
Priority to MX2014013660A priority patent/MX362060B/es
Priority to CN201811468769.0A priority patent/CN109970749A/zh
Priority to PL17160683T priority patent/PL3239153T3/pl
Priority to JP2015512796A priority patent/JP6209209B2/ja
Priority to EA201790963A priority patent/EA034749B1/ru
Priority to CN201610856469.4A priority patent/CN106432254B/zh
Priority to ES13726936.1T priority patent/ES2628350T3/es
Priority to SI201330651T priority patent/SI2850085T1/sl
Priority to PT137269361T priority patent/PT2850085T/pt
Priority to SG10201703451RA priority patent/SG10201703451RA/en
Priority to EA201492002A priority patent/EA028026B1/ru
Priority to PT17160683T priority patent/PT3239153T/pt
Priority to AU2013262874A priority patent/AU2013262874B2/en
Priority to BR112014028221-8A priority patent/BR112014028221B1/pt
Priority to SG11201407533SA priority patent/SG11201407533SA/en
Priority to PCT/US2013/041201 priority patent/WO2013173488A1/en
Priority to EP17160683.3A priority patent/EP3239153B1/en
Priority to IN2459MUN2014 priority patent/IN2014MN02459A/en
Priority to EP13726936.1A priority patent/EP2850085B1/en
Priority to KR1020207003891A priority patent/KR20200017557A/ko
Priority to PL13726936T priority patent/PL2850085T3/pl
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LINK, JOHN O., COTTELL, JEROMY J., MARTIN, TERESA ALEJANDRA TREJO
Publication of US20130309196A1 publication Critical patent/US20130309196A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BACON, ELIZABETH M.
Assigned to GILEAD PHARMASSET LLC reassignment GILEAD PHARMASSET LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GILEAD SCIENCES, INC.
Priority to US14/316,573 priority patent/US20140316144A1/en
Priority to IL235645A priority patent/IL235645A0/en
Priority to HK15105957.3A priority patent/HK1205126A1/xx
Priority to US14/925,203 priority patent/US9682989B2/en
Priority to US15/590,846 priority patent/US20170342085A1/en
Priority to JP2017124206A priority patent/JP6408656B2/ja
Priority to AU2017248566A priority patent/AU2017248566A1/en
Priority to HK18104656.7A priority patent/HK1245262B/zh
Priority to US16/209,860 priority patent/US10800789B2/en
Priority to AU2019204423A priority patent/AU2019204423A1/en
Abandoned 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
    • A61K31/33—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
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • 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
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • Hepatitis C is recognized as a chronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.
  • HCV hepatitis C virus
  • HCV therapeutic agents that have broad activity against HCV genotypes (e.g. genotypes 1a, 1b, 2a, 3a, 4a).
  • HCV genotypes e.g. genotypes 1a, 1b, 2a, 3a, 4a
  • agents that are less susceptible to viral resistance Resistance mutations to inhibitors have been described for HCV NS5A for genotypes 1a and 1b in Antimicrobial Agents and Chemotherapy, September 2010, Volume 54, p. 3641-3650.
  • the disclosure provides a compound of formula (I):
  • W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, optionally substituted aryl, optionally substituted heterocycle, and cyano;
  • the disclosure also provides isotopically enriched compounds that are compounds of the disclosure that comprise an enriched isotope at one or more positions in the compound.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt or prodrug thereof and at least one pharmaceutically acceptable carrier.
  • the present disclosure also provides a pharmaceutical composition for use in treating hepatitis C(HCV).
  • the composition comprises at least one additional therapeutic agent for treating HCV.
  • the therapeutic agent is selected from ribavirin, an NS3 protease inhibitor, a nucleoside or nucleotide inhibitor of HCV NS5B polymerase, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a non-nucleoside inhibitor of HCV polymerase, or combinations thereof.
  • the composition further comprises a nucleoside or nucleotide inhibitor of HCV NS5B polymerase.
  • the nucleoside or nucleotide inhibitor of HCV NS5B polymerase is selected from ribavirin, viramidine, levovirin, a L-nucleoside, or isatoribine.
  • a pharmaceutical composition comprising a compound as described herein and at least one nucleoside or nucleotide inhibitor of HCV NS5B polymerase, and at least one pharmaceutically acceptable carrier.
  • the composition further comprises an interferon, a pegylated interferon, ribavirin or combinations thereof.
  • the nucleoside or nucleotide inhibitor of HCV NS5B polymerase is sofosbuvir.
  • a pharmaceutical composition comprising a compound as described herein and at least one NS3 protease inhibitor, and at least one pharmaceutically acceptable carrier. In one embodiment, the composition further comprises sofosbuvir.
  • the present disclosure also provides a pharmaceutical composition further comprising an interferon or pegylated interferon.
  • the present disclosure also provides a pharmaceutical composition further comprising a nucleoside analog.
  • the present disclosure also provides for a pharmaceutical composition wherein said nucleoside analogue is selected from ribavirin, viramidine, levovirin, an L-nucleoside, and isatoribine and said interferon is ⁇ -interferon or pegylated ⁇ -interferon.
  • said nucleoside analogue is selected from ribavirin, viramidine, levovirin, an L-nucleoside, and isatoribine and said interferon is ⁇ -interferon or pegylated ⁇ -interferon.
  • the present disclosure also provides for a method of treating hepatitis C, said method comprising administering to a human patient a pharmaceutical composition which comprises a therapeutically effective amount of a compound of the disclosure.
  • the present disclosure also provides a method of inhibiting HCV, comprising administering to a mammal afflicted with a condition associated with HCV activity, an amount of a compound of the disclosure, effective to inhibit HCV.
  • the present disclosure also provides a compound of the disclosure for use in medical therapy (e.g. for use in inhibiting HCV activity or treating a condition associated with HCV activity), as well as the use of a compound of the disclosure for the manufacture of a medicament useful for inhibiting HCV or the treatment of a condition associated with HCV activity in a mammal.
  • medical therapy e.g. for use in inhibiting HCV activity or treating a condition associated with HCV activity
  • a compound of the disclosure for the manufacture of a medicament useful for inhibiting HCV or the treatment of a condition associated with HCV activity in a mammal.
  • the present disclosure also provides synthetic processes and novel intermediates disclosed herein which are useful for preparing compounds of the disclosure. Some of the compounds of the disclosure are useful to prepare other compounds of the disclosure.
  • the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt or prodrug thereof, for use in the prophylactic or therapeutic treatment of hepatitis C or a hepatitis C associated disorder.
  • the disclosure provides a method of inhibiting HCV activity in a sample comprising treating the sample with a compound of the disclosure.
  • the “P” groups (eg P 1a and P 1b ) defined for formula (I) herein have one bond to a —C( ⁇ O)— of formula (I) and one bond to a W 1a group. It is to be understood that a nitrogen of the P group is connected to the —C( ⁇ O)— group of formula (I) and that a carbon of the P group is connected to the W 1a group.
  • a Y 5 group is present in the W 1a group.
  • that Y 5 group is defined as —O—CH 2 —, or —CH 2 —O— group
  • those Y 5 groups have a directionality.
  • the Y 5 group is connected to the W 1a group in the same left to right directionality that each is drawn. So for example, when Y 5 is —O—CH 2 —, the directly following structure is intended:
  • the W 1a group has a left-to-right directionality as depicted in I and W 1a as they drawn.
  • the P 1a group is connected to the imidazole group of W 1a
  • the P1b group is connected to the pentacyclic ring system of W 1a .
  • Alkyl is C 1 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 ) 3 ), 1-pentyl (n-pentyl,
  • Alkenyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. Examples include, but are not limited to, ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ).
  • Alkynyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (—C ⁇ CH) and propargyl (—CH 2 C ⁇ CH).
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to, methylene (—CH 2 —) 1,2-ethyl (—CH 2 CH 2 —), 1,3-propyl (—CH 2 CH 2 CH 2 —), 1,4-butyl (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (—CH ⁇ CH—).
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • Typical alkynylene radicals include, but are not limited to, acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH).
  • alkoxy or “alkyloxy,” as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • cycloalkyl refers to a saturated monocyclic, hydrocarbon ring system having three to seven carbon atoms and zero heteroatoms.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.
  • the cycloalkyl groups of the present disclosure are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and —NR x R y wherein the aryl and the heterocyclyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.
  • cycloalkylcarbonyl refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group.
  • cycloalkyloxy refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • cycloalkyloxycarbonyl refers to a cycloalkyloxy group attached to the parent molecular moiety through a carbonyl group.
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Typical substituents include, but are not limited to: halo (e.g.
  • Haloalkyl as used herein includes an alkyl group substituted with one or more halogens (e.g. F, Cl, Br, or I). Representative examples of haloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.
  • halogens e.g. F, Cl, Br, or I.
  • Representative examples of haloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.
  • Heterocycle or “heterocyclyl” as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc . (1960) 82:5566.
  • “heterocycle” includes a “carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
  • the term heterocycle also includes “heteroaryl” which is a heterocycle wherein at least one heterocyclic rings is aromatic.
  • heterocycles include by way of example and not limitation pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring having up to about 25 carbon atoms.
  • a carbocycle typically has about 3 to 7 carbon atoms as a monocycle, about 7 to 12 carbon atoms as a bicycle, and up to about 25 carbon atoms as a polycycle.
  • Monocyclic carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g., arranged as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system.
  • carbocycle includes “cycloalkyl” which is a saturated or unsaturated carbocycle.
  • monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • amino refers to —NH 2 .
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as, for example, electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • d and l or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the disclosure includes all stereoisomers of the compounds described herein.
  • prodrug refers to any compound that when administered to a biological system generates a compound of the disclosure that inhibits HCV activity (“the active inhibitory compound”).
  • the compound may be formed from the prodrug as a result of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzed chemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemical reaction(s).
  • Prodrug moiety refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
  • Enzymes which are capable of an enzymatic activation mechanism with the prodrug compounds of the disclosure include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a prodrug moiety may include an active metabolite or drug itself.
  • prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters —CH 2 OC( ⁇ O)R 99 and acyloxymethyl carbonates —CH 2 C( ⁇ O)OR 99 where R 99 is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
  • acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the disclosure.
  • An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH 2 C( ⁇ O)C(CH 3 ) 3 .
  • An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH 2 C( ⁇ O)OC(CH 3 ) 3 .
  • protecting groups include prodrug moieties and chemical protecting groups.
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion.
  • Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as, for example, the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
  • Chemically protected intermediates may themselves be biologically active or inactive.
  • Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as, for example, passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
  • Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the disclosure. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG.
  • PG will be used to protect functional groups such as, for example, carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency.
  • the order of deprotection to yield free deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
  • protecting groups for —OH groups include “ether- or ester-forming groups”.
  • Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
  • some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
  • the compounds of the disclosure may have chiral centers, e.g., chiral carbon or phosphorus atoms.
  • the compounds of the disclosure thus include all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the disclosure include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the non-racemic or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the disclosure.
  • racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material or through enantioselective reactions.
  • the compounds of the disclosure can also exist as tautomeric isomers in certain cases. Although only one tautomer may be depicted, all such forms are contemplated within the scope of the disclosure.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the disclosure.
  • physiologically or pharmaceutically acceptable salts of the compounds of the disclosure include salts derived from an appropriate base, such as, for example, an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • an appropriate base such as, for example, an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as, for example, acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as, for example, methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as, for example, hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as, for example, acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as, for example, methanesulfonic, ethanesulfonic, benzenesul
  • Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as, for example, Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of active ingredients of the compounds of the disclosure will typically be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present disclosure.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this disclosure.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds of the disclosure in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as, for example, glycine, serine, threonine, alanine, isoleucine, or leucine.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid
  • a neutral group such as, for example, glycine, serine, threonine, alanine, isoleucine, or leucine.
  • Another aspect of the disclosure relates to methods of inhibiting the activity of HCV comprising the step of treating a sample suspected of containing HCV with a compound or composition of the disclosure.
  • the treating step of the disclosure comprises adding the compound of the disclosure to the sample or it comprises adding a precursor of the composition to the sample.
  • the addition step comprises any method of administration as described above.
  • the activity of HCV after application of the compound can be observed by any method including direct and indirect methods of detecting HCV activity. Quantitative, qualitative, and semiquantitative methods of determining HCV activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as, for example, observation of the physiological properties of a living organism are also applicable.
  • HCV Many organisms contain HCV.
  • the compounds of this disclosure are useful in the treatment or prophylaxis of conditions associated with HCV activation in animals or in man.
  • the compounds of this disclosure are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice.
  • Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as, for example, those set forth in the Handbook of Pharmaceutical Excipients (1986).
  • Excipients include ascorbic acid and other antioxidants, chelating agents such as, for example, EDTA, carbohydrates such as, for example, dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the compound will be administered in a dose from 0.01 milligrams to 2 grams. In one embodiment, the dose will be from about 10 milligrams to 450 milligrams. It is contemplated that the compound may be administered once, twice or three times a day.
  • the formulations both for veterinary and for human use, of the disclosure comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as, for example, capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as, for example, a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as, for example, 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as, for example, propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • a polyhydric alcohol i.e. an alcohol having two or more hydroxyl groups
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this disclosure may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as, for example, di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as, for example, white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present disclosure comprise one or more compounds of the disclosure together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as, for example, calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as, for example, maize starch, or alginic acid; binding agents, such as, for example, cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid or talc.
  • inert diluents such as, for example, calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as, for example, maize starch
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as, for example, peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the disclosure contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as, for example, a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate
  • the aqueous suspension may also contain one or more preservatives such as, for example, ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as, for example, sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as, for example, liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as, for example, beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as, for example, those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as, for example, ascorbic acid.
  • Dispersible powders and granules of the disclosure suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as, for example, olive oil or arachis oil, a mineral oil, such as, for example, liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as, for example, gum acacia and gum tragacanth, naturally occurring phosphatides, such as, for example, soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the disclosure may be in the form of a sterile injectable preparation, such as, for example, a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as, for example, a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as, for example, a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as, for example, oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as, for example, gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as, for example, 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as, for example, compounds heretofore used in the treatment or prophylaxis of conditions associated with HCV activity.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this disclosure may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • compositions comprising one or more compounds of the disclosure formulated for sustained or controlled release.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
  • One or more compounds of the disclosure are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this disclosure is that they are orally bioavailable and can be dosed orally.
  • non-limiting examples of suitable combinations include combinations of one or more compounds of formula (I) and (A1-A4) with one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs or therapeutic agents for treating HCV.
  • one or more compounds of the present as described herein may be combined with one or more compounds selected from the group consisting of
  • compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, prodrug, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a compound of formula (I) as described herein and sofosbuvir and/or GS-5885 and optionally an interferon or ribavirin.
  • a pharmaceutical composition comprising a compound of formula (I) as described herein and a nucleoside or nucleotide inhibitor of HCV NS5B polymerase and optionally an interferon or ribavirin.
  • additional therapeutic agents will be administered in a manner that is known in the art and the dosage may be selected by someone of skill in the art.
  • additional therapeutic agents may be administered in a dose from about 0.01 milligrams to about 2 grams per day.
  • the disclosure includes compounds produced by a process comprising contacting a compound of this disclosure with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabelled (e.g., C 14 or H 3 ) compound of the disclosure, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as, for example, rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • an animal such as, for example, rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from the urine, blood or other biological samples typically isolating its conversion products from the urine, blood or other biological samples.
  • the metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis.
  • the disclosure also relates to methods of making the compositions of the disclosure.
  • the compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis.
  • reaction conditions such as, for example, temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • the temperatures will be ⁇ 100° C. to 200° C.
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as, for example, azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable.
  • treated when used in connection with a chemical synthetic operation, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • treating compound one with compound two is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • treating indicates the reasonable and usual manner in which organic chemicals are allowed to react.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as, for example, activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as, for example, antibodies, binding proteins, selective chelators such as, for example, crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as, for example, formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3) 283-302).
  • Racemic mixtures of chiral compounds of the disclosure can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as, for example, brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as, for example, carboxylic acid and sulfonic acid.
  • enantiomerically pure chiral bases such as, for example, brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like
  • asymmetric compounds bearing acidic functionality such as, for example, carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as, for example, menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched substrate.
  • a method of determining optical purity involves making chiral esters, such as, for example, a menthyl ester, e.g., ( ⁇ ) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • chiral esters such as, for example, a menthyl ester, e.g., ( ⁇ ) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as, for example, optical rotation and circular dichroism.
  • a number of exemplary methods for the preparation of compounds of the disclosure are provided herein, for example, in the Examples below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. Certain compounds of the disclosure can be used as intermediates for the preparation of other compounds of the disclosure.
  • the fragment E-V— can also be written as R9-.
  • PG represents a protecting group common for the given functional group that it is attached. The installation and removal of the protecting group can be accomplished using standard techniques, such as, for example, those described in Wuts, P. G. M., Greene, T. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, Inc.: Hoboken, N.J., 2007.
  • Scheme 1 shows a general synthesis of an E-V—C( ⁇ O)—P—W—P—C( ⁇ O)—V-E molecule of the invention wherein, for illustrative purposes, E is methoxycarbonylamino.
  • E is methoxycarbonylamino.
  • the treatment of either 1a or 1c with one or two equivalents respectively of methyl chloroformate under basic conditions (e.g. sodium hydroxide) provides the molecule 1b or 1d.
  • Scheme 2 shows a general synthesis of an E-V—C( ⁇ O)—P—W—P—C( ⁇ O)—V-E molecule of the invention wherein, for illustrative purposes, P is pyrrolidine.
  • Coupling of amine 2a with acid 2b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 2c.
  • amine 2d is coupled with two equivalents of 2b under similar conditions to provide 2e.
  • Scheme 6 shows a general synthesis of an R 1 —V—C( ⁇ O)—P—R 2 intermediate wherein, for illustrative purposes, P is pyrrolidine, R 1 is a generic group that is depicted as either -E or a amino protecting group, and R 2 is a generic group that is depicted as —W—P—C( ⁇ O)—V-E, —W—P—C( ⁇ O)—V—NH—PG, —W—P—NH-PG, or —W—NH—PG.
  • Coupling of amine 6a (or 6d, 6h, 6k) with acid 6b or 6e is accomplished using a peptide coupling reagent (e.g. HATU) to afford 6c (or 6f, 6g, 6i, 6j, 6l, 6m) respectively.
  • a peptide coupling reagent e.g. HATU
  • Scheme 7 shows a general synthesis of an E-V—C( ⁇ O)—R′ intermediate wherein, for illustrative purposes, E is methoxycarbonylamino and R 1 is a generic group that is depicted as either —P—W—P—C( ⁇ O)—V—NH—PG, —P—W—P—PG, —P—W—PG, —P—PG, or —O—PG.
  • R 1 is a generic group that is depicted as either —P—W—P—C( ⁇ O)—V—NH—PG, —P—W—P—PG, —P—W—PG, —P—PG, or —O—PG.
  • Treatment of 7a (or 7c, 7e, 7g, 7i) with methyl chloroformate under basic conditions (e.g. sodium hydroxide) provides the molecule 7b (or 7d, 7f, 7h, 7j).
  • Scheme 9 shows a general synthesis of an R 1 —P—R 2 intermediate wherein, for illustrative purposes, R 1 is —C( ⁇ O)—V-E or a protecting group and R 2 is a substituted benzamidazole.
  • the formation of the benzimidazole is accomplished by coupling the acid 9b or 9e with an arylamine 9a, using a peptide coupling reagent such as HATU, to afford 9c or 9d. Cyclization of the amide in the presence an acid (such as acetic acid) affords the benzimidazole containing molecule 9d or 9g.
  • Scheme 20 shows a general synthesis of an R 1 —P—W—P—R 2 intermediate of the invention wherein, for illustrative purposes, R 1 and R 2 are independent protecting groups and W is a two aromatic ring unit constructed via a transition metal mediated cyclization.
  • Alkylation of phenol 20b with an alkyl bromide, such as 20a, provides the ether 20c.
  • Cyclization of the aromatic rings in the presence of a palladium catalyst provides the compound 20d.
  • Treatment of 20d with CuBr 2 provides the ⁇ -haloketone 20e, which provides 20f upon addition of an acid under basic conditions (e.g. Et 3 N).
  • Reaction of 20f with an amine or amine salt e.g.
  • ammonium acetate affords the imidazole containing molecule 20g.
  • Oxidation of 20g, 20i, or 20l can be accomplished by heating in the presence of MnO 2 to provide 20h, 20j, or 20m, respectively.
  • Conversion of 20g or 20h with a palladium catalyst, such as Pd 2 dba 3 and X-Phos, and a boron source such as bis(pinacolato)diboron provides the boronic ester 20i or 20j.
  • the boronic ester is coupled with an appropriate coupling partner (e.g. 20k) using a palladium catalyst, such as Pd(PPh 3 ) 4 or PdCl 2 (dppf), to afford 20l or 20m.
  • a palladium catalyst such as Pd(PPh 3 ) 4 or PdCl 2 (dppf
  • transition metal mediated cross-coupling reaction For each transition metal mediated cross-coupling reaction, the roles of the nucleophile and electrophile can be reversed to provide the same coupling product.
  • Other transition metal mediated cross couplings that enable the construction of W, but employ alternative coupling partners and reagents, include, but are not limited to, the Negishi, Kumada, Stille, and Ullman couplings.
  • this general scheme can be applied through the appropriate choice of the starting reagents.
  • Scheme 21 shows a general synthesis of an R 1 —P—W—P—R 2 intermediate of the invention wherein, for illustrative purposes, R 1 and R 2 are independent protecting groups and W is a two aromatic ring unit constructed via a transition metal mediated cyclization.
  • an activated vinyl reagent e.g. potassium vinyltrifluoroborate
  • a palladium catalyst e.g. palladium acetate and S-Phos
  • Conversion to the corresponding ⁇ -halo ketone can be accomplished by bromination with N-bromosuccinimide, followed by oxidation with MnO 2 .
  • Displacement of the ⁇ -halo ketone proceeds by the addition of an acid under basic conditions (e.g. Et 3 N).
  • Bromination of 21d proceeds upon treatment with pyridinium tribromide, and is followed by the addition of a second acid under basic conditions to provide the diester 21e.
  • Reaction of 21e with an amine or amine salt affords the imidazole containing molecule 21f.
  • Oxidation of 21f can be accomplished in the presence of MnO 2 to provide 21g.
  • Scheme 22 shows a general synthesis of an E-V—C( ⁇ O)—P—W—P—R intermediate of the invention wherein, for illustrative purposes, R is a protecting group and W is a two aromatic ring unit.
  • Displacement of the ⁇ -halo ketone 21b proceeds by the addition of an acid under basic conditions (e.g. Et 3 N).
  • Bromination of 22b proceeds upon treatment with pyridinium tribromide, and is followed by the addition of a second acid under basic conditions to provide the diester 22c.
  • Reaction of 22c with an amine or amine salt e.g. ammonium acetate affords the imidazole containing molecule 22d.
  • Oxidation of 22d can be accomplished in the presence of MnO 2 to provide 22e.
  • Scheme 23 shows a general synthesis of an E-V—C( ⁇ O)—P—W—P—R intermediate of the invention wherein, for illustrative purposes, R is a protecting group and W is a two aromatic ring unit.
  • Displacement of the ⁇ -halo ketone 21d proceeds by the addition of an acid under basic conditions (e.g. Et 3 N).
  • Reaction of 23a with an amine or amine salt affords the imidazole containing molecule 23b.
  • Oxidation of 23b can be accomplished in the presence of MnO 2 to provide 23c.
  • Scheme 25 shows a general synthesis of an E-V—C( ⁇ O)—P—W—P—C( ⁇ O)—V-E molecule of the invention wherein, for illustrative purposes, E is ethylcarbonylamino.
  • E is ethylcarbonylamino.
  • the treatment of either 25a or 25c with one or two equivalents respectively of propionyl chloride under basic conditions (e.g. sodium hydroxide) provides the molecule 25b or 25d.
  • Scheme 26 shows a general synthesis of an E-V—C( ⁇ O)—P—R and an R 1 —P—R molecule of the invention wherein, for illustrative purposes R is a haloimidazole.
  • R is a haloimidazole.
  • Treatment of the aldehyde 26a with glyoxal, in the presence of ammonium hydroxide provides the imidazole 26b.
  • Treatment with either N-bromosuccinamide or iodine provides the corresponding haloimidazole 26c and 26d respectively. Separation from the corresponding bis-halogenated compound can be accomplished by preparative HPLC chromatography.
  • the conversion of the bis-haloimidazole to the mono-haloimidazole can also be accomplished upon heating in the presence of sodium sulfite. Further functionalization of the P group can be accomplished upon removal of the protecting group and coupling with an appropriate acid (E-V—C( ⁇ O)—OH).
  • Scheme 27 shows an alternate general synthesis of an R 1 —P—W—P—R 2 intermediate of the invention wherein, for illustrative purposes, R 1 and R 2 are independent protecting groups and W is a two aromatic ring unit constructed via a transition metal mediated cyclization.
  • a brominating agent i.e. pyridinium tribromide
  • Displacement of the primary bromide then proceeds by the addition of an acid under basic conditions (e.g. K 2 CO 3 ) to provide 21d.
  • Conversion to 21f or 21g can be accomplished following methods described in Scheme 21.
  • Scheme 28 shows an alternate general synthesis of an E-V—C( ⁇ O)—P—W—P—R intermediate of the invention wherein, for illustrative purposes, R is a protecting group and W is a two aromatic ring unit.
  • a brominating agent i.e. pyridinium tribromide
  • Displacement of the primary bromide then proceeds by the addition of an acid under basic conditions (e.g. K 2 CO 3 ) to provide 22d.
  • Conversion to 22d or 22e can be accomplished following methods described in Scheme 22.
  • W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, optionally substituted aryl, optionally substituted heterocycle, and cyano;
  • he compound of formula (I) is represented by formula:
  • the compound of formula (I) is represented by formula:
  • At least one of E 1a and E 1b is —N(H)(alkoxycarbonyl). In one embodiment, at least one of E 1a and E 1b is —N(H)C( ⁇ O)OMe. In another embodiment, both of E 1a and E 1b are —N(H)C( ⁇ O)OMe.
  • At least one of E 1a and E 1b is —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl). In one embodiment, at least one of E 1a and E 1b is cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino. In another embodiment, E 1a and E 1b are each independently selected from cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino and methoxycarbonylamino.
  • At least one of V 1a and V 1b is:
  • E 1a -V 1a taken together are R 9a or wherein E 1b -V 1b taken together are R 9b .
  • at least one of P 1a and P 1b is selected from:
  • P 1a and P 1b are each independently selected from:
  • At least one of —V 1a —C( ⁇ O)—P 1a — and —P 1b —C( ⁇ O)—V 1b — is:
  • At least one of —V 1a —C( ⁇ O)—P 1a — and —P 1b —C( ⁇ O)—V 1b — is:
  • —V 1a —C( ⁇ O)—P 1a — and —P 1b —C( ⁇ O)—V 1b — are each independently:
  • one of —V 1a —C( ⁇ O)—P 1a — and —P 1b —C( ⁇ O)—V 1b — is:
  • the disclosure provides a compound of formula:
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the crude oil was purified by silica gel chromatography (2% to 5% to 10% MeOH/CH 2 Cl 2 ) to provide (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (6.38 g, 70%).
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • reaction was poured directly onto a silica gel column and purified by flash column chromatography (hexanes/DCM) to yield 8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (1.22 g, 97% yield) as an off-white solid.
  • the mixture was degassed with a stream of argon for ten minutes.
  • the degassed reaction was heated under argon to 90° C. for 2.5 hours then cooled to room temperature and diluted with ethyl acetate.
  • the organics were washed with water and brine, dried with magnesium sulfate and concentrated.
  • reaction was then heated to 85° C. for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO 4 ) and concentrated.
  • reaction was then heated to 85° C. for 2.5 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO 4 ) and concentrated.
  • This compound was made in an analogous manner to methyl ⁇ (2S)-1-[(2R)-2-(5- ⁇ 2-[(2S)-1- ⁇ (2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl ⁇ pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl ⁇ -1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl ⁇ carbamate, substituting 7-hydroxy-1-tetralone for 5-hydroxy-1-tetralone in the first step of the sequence.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 95° C. under argon for 7 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • the resulting mixture was degassed and then heated to 85° C. for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with saturated sodium bicarbonate and brine, dried over MgSO 4 and concentrated.
  • the mixture was degassed with bubbling N 2 for 10 min the heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO 3 and brine. The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the mixture was degassed with bubbling N 2 for 10 min the heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO 3 and brine. The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the mixture was degassed with bubbling N 2 for 10 min the heated to 95° C. for 14 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO 3 and brine. The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the mixture was degassed with bubbling N 2 for 10 min the heated to 95° C. for 5 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO 3 and brine. The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the resulting crude bromohydrin was suspended in DCM (200 mL) and treated with activated MnO 2 (62.7 g, 722 mmol). After stirring for 15 h at RT, the reaction mixture was filtered over celite and the filter cake was rinsed several times with DCM. The combined filtrate ( ⁇ 400 mL) was treated with MeOH ( ⁇ 100 mL) and the mixture was gradually concentrated under reduced pressure, causing solid material to precipitate from solution. When the liquid volume reached ⁇ 200 mL, the solid was filtered off and rinsed with MeOH.
  • concentration/precipitation/filtration/rinsing sequence was performed 2 ⁇ more, resulting in the collection of 3 crops of powdered 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.49 g, 56% over 2 steps).
  • the stirred reaction mixture was heated to 110° C. for 4.5 h, then cooled to RT and diluted with EtOAc.
  • the organic phase was washed 3 ⁇ with saturated aqueous NaHCO 3 , then dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the solution was degasses with argon for 5 min and heated, with stirring, to 85° C. for 6 h.
  • the solution was cooled to room temperature and diluted with EtOAc.
  • the organic layer was washed with water and brine.
  • the aqueous layers were backextracted with EtOAc (3 ⁇ ).
  • the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the solution was degasses with argon for 5 min and heated, with stirring, to 85° C. for 6 h.
  • the solution was cooled to room temperature and diluted with EtOAc.
  • the organic layer was washed with water and brine.
  • the aqueous layers were backextracted with EtOAc (3 ⁇ ).
  • the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the aqueous layer was backextracted with CH 2 Cl 2 .
  • the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude residue was purified by preparative reverse phase HPLC (10% to 50% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics.
  • the addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid.
  • the precipitate was filtered through a membrane filter and washed with water.
  • the solution was degasses with argon for 5 min and heated, with stirring, to 90° C. for 6 h.
  • the solution was cooled to room temperature and diluted with EtOAc.
  • the organic layer was washed with water and brine.
  • the aqueous layers were backextracted with EtOAc (3 ⁇ ).
  • the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics.
  • the remaining solution was basified with aqueous bicarbonate and extracted with CH 2 Cl 2 (3 ⁇ ).
  • the crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water.
  • the solution was degasses with argon for 5 min and heated, with stirring, to 90° C. for 6 h.
  • the solution was cooled to room temperature, diluted with EtOAc, and filtered through celite.
  • the filtrate was concentrated under reduced pressure and purified by silica column chromatography (2% to 25% CH 2 Cl 2 /MeOH) and preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics.
  • the aqueous layer was basified with aqueous sodium bicarbonate and extracted with CH 2 Cl 2 (3 ⁇ ).
  • the crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water.
  • the solution was degasses with argon for 5 min and heated, with stirring, to 90° C. for 6 h.
  • the solution was cooled to room temperature, diluted with EtOAc, and filtered through celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc.
  • the organic solution was washed water and brine and the aqueous layers were backextracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the aqueous layer was backextracted with CH 2 Cl 2 , and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude residue was purified by preparative reverse phase HPLC (10% to 58% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics.
  • the addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid.
  • the precipitate was filtered through a membrane filter and washed with water.
  • the product was purified by reverse phase HPLC.
  • the product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate.
  • the eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (30.7 mg) MS (ESI) m/z 869.9 [M+H] + .
  • the product was purified by reverse phase HPLC.
  • the product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate.
  • the eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (24 mg).
  • Example BO Compound tert-butyl (2S,4S)-2-[5-(2- ⁇ (2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl ⁇ -1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate) but using (2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid in place of (2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid.

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US13/831,116 US20130309196A1 (en) 2012-05-16 2013-03-14 Antiviral compounds
ES13726936.1T ES2628350T3 (es) 2012-05-16 2013-05-15 Compuestos antivíricos inhibidores de NS5A de HCV
PCT/US2013/041201 WO2013173488A1 (en) 2012-05-16 2013-05-15 Antiviral compounds inhibitors of hcv ns5b
EP17160683.3A EP3239153B1 (en) 2012-05-16 2013-05-15 9-(1h-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazole derivatives and their use as inhibitors of hcv ns5a
CN201380029171.0A CN104487442B (zh) 2012-05-16 2013-05-15 Hcv ns5a的抗病毒化合物抑制剂
KR1020147034784A KR102078233B1 (ko) 2012-05-16 2013-05-15 항바이러스성 화합물
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MX2014013660A MX362060B (es) 2012-05-16 2013-05-15 Compuestos antivirales inhibidores del virus de hepatitis c (vhc) ns5b.
NZ725365A NZ725365A (en) 2012-05-16 2013-05-15 Antiviral compounds inhibitors of hcv ns5b
PL17160683T PL3239153T3 (pl) 2012-05-16 2013-05-15 Pochodne 9-(1H-imidazol-5-ilo)-1,11-dihydroizochromeno[4',3':6,7]nafto[1,2-d]imidazolu i ich zastosowanie jako inhibitorów NS5A HCV
JP2015512796A JP6209209B2 (ja) 2012-05-16 2013-05-15 抗ウイルス化合物
EA201790963A EA034749B1 (ru) 2012-05-16 2013-05-15 Противовирусные соединения
CN201610856469.4A CN106432254B (zh) 2012-05-16 2013-05-15 Hcv ns5a的抗病毒化合物抑制剂
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SI201330651T SI2850085T1 (sl) 2012-05-16 2013-05-15 Antivirusne spojine inhibitorjev hcv ns5a
PT137269361T PT2850085T (pt) 2012-05-16 2013-05-15 Compostos antivirais inibidores de hcv ns5a
SG10201703451RA SG10201703451RA (en) 2012-05-16 2013-05-15 Antiviral compounds
EA201492002A EA028026B1 (ru) 2012-05-16 2013-05-15 Противовирусное соединение, содержащая его фармацевтическая композиция и способ лечения
PT17160683T PT3239153T (pt) 2012-05-16 2013-05-15 Derivados de 9-(1h-imidazol-5-il)-1,11-di-hidroisocromeno-[4',3':6,7]nafto[1,2-d]imidazole e sua utilização como inibidores da ns5a do vhc
AU2013262874A AU2013262874B2 (en) 2012-05-16 2013-05-15 Antiviral compounds
BR112014028221-8A BR112014028221B1 (pt) 2012-05-16 2013-05-15 Compostos antivirais, composição farmacêutica que os compreende e uso
ES17160683T ES2738012T3 (es) 2012-05-16 2013-05-15 Derivados de 9-(1H-imidazol-5-il)-1,11-dihidroisocromeno[4',3':6,7]nafto[1,2-D]imidazol y su utilización como inhibidores de HCV NS5A
CN201811468769.0A CN109970749A (zh) 2012-05-16 2013-05-15 Hcv ns5a的抗病毒化合物抑制剂
SI201331447T SI3239153T1 (sl) 2012-05-16 2013-05-15 Derivati 9-(1H-imidazol-5-il)-1,11-dihidroizokromeno(4',3':6,7)nafto(1,2-D) imidazol in njihova uporaba kot inhibitorji HCV NS5A
IN2459MUN2014 IN2014MN02459A (hr) 2012-05-16 2013-05-15
EP13726936.1A EP2850085B1 (en) 2012-05-16 2013-05-15 Antiviral compounds inhibitors of hcv ns5a
KR1020207003891A KR20200017557A (ko) 2012-05-16 2013-05-15 항바이러스성 화합물
PL13726936T PL2850085T3 (pl) 2012-05-16 2013-05-15 Antywirusowe związki inhibitorowe hcv ns5a
US14/316,573 US20140316144A1 (en) 2012-05-16 2014-06-26 Antiviral compounds
IL235645A IL235645A0 (en) 2012-05-16 2014-11-11 Antiviral compounds inhibit hcv ns5b
HK15105957.3A HK1205126A1 (en) 2012-05-16 2015-06-23 Antiviral compounds inhibitors of hcv ns5b hcvns5b
US14/925,203 US9682989B2 (en) 2012-05-16 2015-10-28 Antiviral compounds
US15/590,846 US20170342085A1 (en) 2012-05-16 2017-05-09 Antiviral compounds
JP2017124206A JP6408656B2 (ja) 2012-05-16 2017-06-26 抗ウイルス化合物、ｈｃｖ ｎｓ５ｂの阻害剤
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HK18104656.7A HK1245262B (zh) 2012-05-16 2018-04-10 9-(1氫-咪唑-5-基)-1，11-二氫異苯並吡喃並[4'，3'：6，7]萘並[1，2-d]咪唑衍生物及其作為hcv ns5a抑制劑的用途
US16/209,860 US10800789B2 (en) 2012-05-16 2018-12-04 Antiviral compounds
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CA2873485A1 (en) 2013-11-21
US9682989B2 (en) 2017-06-20
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SG10201703451RA (en) 2017-06-29
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US20190337960A1 (en) 2019-11-07
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