WO2011091152A1 - Inhibiteurs d'infection par le virus de l'hépatite c - Google Patents

Inhibiteurs d'infection par le virus de l'hépatite c Download PDF

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Publication number
WO2011091152A1
WO2011091152A1 PCT/US2011/021889 US2011021889W WO2011091152A1 WO 2011091152 A1 WO2011091152 A1 WO 2011091152A1 US 2011021889 W US2011021889 W US 2011021889W WO 2011091152 A1 WO2011091152 A1 WO 2011091152A1
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compound
formula
pharmaceutically acceptable
prodrug
metabolite
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PCT/US2011/021889
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English (en)
Inventor
Pablo Gastaminza
Francis V. Chisari
Suresh Mark Pitram
K. Barry Sharpless
Valery V. Fokin
Larissa B. Krasnova
Jiajia Dong
Original Assignee
Pablo Gastaminza
Chisari Francis V
Suresh Mark Pitram
Sharpless K Barry
Fokin Valery V
Krasnova Larissa B
Jiajia Dong
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Application filed by Pablo Gastaminza, Chisari Francis V, Suresh Mark Pitram, Sharpless K Barry, Fokin Valery V, Krasnova Larissa B, Jiajia Dong filed Critical Pablo Gastaminza
Publication of WO2011091152A1 publication Critical patent/WO2011091152A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/90—Xanthenes with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • HCV Hepatitis C virus
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5' untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
  • the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non- structural (NS) proteins of the virus. In the case of HCV, the generation of mature nonstructural proteins is effected by two viral proteases.
  • the viral genome also encodes a polymerase that catalyzes replication of viral RNA, in addition to other viral proteins, both functional and structural.
  • the present invention is directed to compounds and formulations that are effective for treatment of Hepatitis C virus (HCV) infections, such as in humans.
  • HCV Hepatitis C virus
  • compounds of the invention "kill" the virus, i.e., interfere with viral functions necessary for replication and propagation of the virus in a mammalian host.
  • compounds of the invention inhibit viral spread, reducing the virulence of the viral strain infecting a population of host cells, such as liver cells in a human patient.
  • the invention is also directed to methods of treatment using compounds of the invention.
  • the present invention provides a compound of formula (X): ( )
  • X is a 1,2-ethylene or a 1,3-propylene group which can be unsubstituted or substituted;
  • a dotted line indicates an optional double bond
  • Y is azido, NR, or 1,2,3-triazolyl, wherein R is hydrogen or (C 1 -C 6 )alkyl, provided that when Y is azido then R 7 , R 8 and R 9 are all absent;
  • Z 1 and Z 2 are each independently unsubstituted or substituted phenyl, wherein the phenyl group can be mono- or independently pluri- substituted with halo, haloalkyl, alkyl, alkenyl, alkynyl, azido, or (C 1 -C 3 )alkoxy; or Z 2 is NH 2 and Y, R 7 , R 8 , and R 9" are all absent;
  • R 1 and R 2" are independently at each occurrence hydrogen, (C 1 -C 6 )alkyl, (C 6 - Cio)aryl, or 3-8 membered heterocyclyl, wherein any alkyl, aryl, or heterocyclyl group can be substituted or unsubstituted; or
  • R 1 , R 2 , and carbon atoms to which they are bonded, wherein the optional double bond is present, can form a fused (C 6 -C 3 o)aryl that can be substituted or unsubstituted;
  • R 5 is absent, carbonyl, thiocarbonyl, or sulfonyl
  • R 6 is hydrogen, substituted or unsubstituted alkyl, cycloalkoxy, cycloalkylalkoxy, alkynyloxy, aralkoxy, heterocyclyloxy, cycloalkylamino, cycloalkylalkylamino, alkenylamino, arylamino, aralkylamino, heterocyclylamino, aroylamido, heteroaryl, or heteroarylalkyl;
  • R 5 and R 6 taken together can form a heterocyclyl
  • R is absent, hydrogen, carbonyl, thiocarbonyl, sulfonyl, or (C 1 -C 4 )alkylene;
  • R 8 is absent, NH, or O;
  • R 9 is alkynyl, alkanoyl, carboxamido, cycloalkyl, aryl, aroyl, heterocyclyl, carboxy, or carboxy-alkyl, wherein any alkynyl, alkanoyl, carboxamido, cycloalkyl, aroyl, heterocyclyl, or carboxy-alkyl can be substituted;
  • R 6 comprises a (C 1 -C 12 )alkylene diamine moiety bonded to two respective R 5 groups, wherein R 5 is carbonyl, thiocarbonyl, or sulfonyl; or, wherein for formula (XIB),
  • R 9 comprises a (C 1 -C 12 )alkylene diamine moiety bonded to two respective R 7 groups, wherein R 7 is carbonyl, thiocarbonyl, or sulfonyl, and R 8 is absent;
  • W is N or CH
  • Q is OH or NHR 20 ;
  • R is hydrogen, alkylaminocarbonyl or arylaminocarbonyl wherein any alkyl or aryl can be substituted;
  • R is aralkyl or alkoxycarbonyl
  • W and R 21 are as defined above and wherein R 20 comprises an alkylene bis(aminocarbonyl) group
  • W is N or CH and R 20 is hydrogen, alkylaminocarbonyl or
  • arylaminocarbonyl and R 21 is as defined above, wherein any alkyl or aryl can be substituted;
  • R is hydrogen or (C 1 -C6)alkyl
  • R 5 and R 6 are as defined above;
  • the present invention also provides a pharmaceutical composition.
  • the pharmaceutical composition includes a pharmaceutically acceptable carrier; and a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.
  • the pharmaceutical composition further includes one or more additional compounds having anti-Hepatitis C virus activity.
  • Hepatitis C virus activity can be interferon, ribavirin, or a combination thereof.
  • the one or more additional compounds can be an inhibitor of a HCV protease, or an inhibitor of a HCV polymerase.
  • the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon ⁇ , or a combination thereof.
  • the one or more additional compounds having anti- Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5 '-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.
  • the present invention further provides a method of treating an animal inflicted with Hepatitis C Virus infection.
  • the method includes administering to an animal in need of such treatment an effective amount of a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.
  • the invention provides a method of treatment of an HCV infection in a host animal, such as a human patient, afflicted with an HCV strain that is resistant, or has developed resistance, to inhibitors of HCV viral protease or HCV viral polymerase.
  • the protease(s) and polymerase(s) of viruses, such as HCV are targeted by many varieties of medicinal compounds, and it is possible, or even likely, that resistance to these mechanisms of action may develop among viral populations.
  • the compounds of the invention target a viral component other than one of these enzyme systems, the inventors believe that cross-resistance is unlikely.
  • inventive compounds can be used in treatment of HCV strains that are already resistant, in treatment of HCV strains wherein development of protease or polymerase inhibitor resistant strains is of concern, and in combination therapy comprising use of a protease inhibitor, a polymerase inhibitor, or both, in conjunction with a compound of the invention.
  • the compounds of the invention can also be used to prevent viral spread in a population of cells that has been exposed to an inoculum of HCV.
  • the compounds of the invention are believed to inhibit the transmission of the virus from an infected cell to an uninfected cell. Therefore, in various embodiments, a method of preventing viral spread is provided, comprising administering an effective amount of a compound of the invention to a patient exposed to an inoculum of HCV.
  • the method further includes administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or simultaneously with a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.
  • the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof.
  • the one or more additional compounds can be an inhibitor of a HCV protease, or an inhibitor of a HCV polymerase.
  • the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon ⁇ , or a combination thereof.
  • the one or more additional compounds having anti- Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5 '-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.
  • the animal is a human.
  • the present invention also provides a method of killing or inhibiting Hepatitis C Virus.
  • the method includes contacting the Hepatitis C Virus with an effective amount of a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.
  • the contacting is in vitro. In various embodiments, the contacting is in vivo.
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
  • stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated herein.
  • any of the groups described herein, which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
  • substituents within the compounds described herein are present to a recursive degree.
  • "recursive substituent” means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim.
  • One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • Recursive substituents are an intended aspect of the disclosed subject matter.
  • One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents.
  • the total number should be determined as set forth above.
  • the inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ( 2 H), or tritium ( H) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as U C, 12 C, 13 C, or 14 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 14 N, or 15 N.
  • a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected.
  • a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14 N and
  • a molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule.
  • isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
  • the isotopes, radiolabeled or stable can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry.
  • the isotopic forms are incorporated into precursors as required for use in any particular synthetic route.
  • 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
  • o-nitrophenoxyacetyl a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyl
  • phenoxycarbonyl 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,
  • phenylthiocarbonyl and the like phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR', OC(0)N(R') 2 , CN, NO, N0 2 , ON0 2 , azido, CF 3 , OCF 3 , R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R') 2 , SR', SOR', S0 2 R', S0 2 N(R') 2 , S0 3 R', C(0)R', C(0)C(0)R', C(0)CH 2 C(0)R', C(S)R', C(0)OR', OC(0)R', C(0)N(R') 2 , OC(0)N(R') 2 , C(S)N(R') 2 , (CH 2 )o- 2 N(R')C(0)R', (CH 2 ) 0 - 2 N(
  • R' can be hydrogen or a carbon- based moiety, and wherein the carbon-based moiety can itself be further substituted.
  • a substituent When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as O, S, C(O), S(O), or S(0) 2 can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR' 2 ) n wherein n is 1, 2, 3, or more, and each R' is independently selected.
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
  • spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic denotes a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group.
  • the carbocycle has 3 to 8 ring members, whereas in other words
  • the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N-l substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • a carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • cycloalkyl alkyl groups also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
  • Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 C ⁇ C(CH 3 ), and -CH 2 C ⁇ C(CH 2 CH 3 ) among others.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or -CH 2 -CH 2 -S-S-CH 3 .
  • a “cyclohetero alkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • a cycloheteroalkyl ring can also be termed a “heterocyclyl,” described below.
  • -CH CH-N(CH 3 )-CH 3
  • -CH 2 -CH CH-CH 2 -SH
  • -CH CH-0-CH 2 CH 2 -0-CH 3 .
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused
  • (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non- aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 - heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridiny
  • Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein.
  • haloalkyl group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
  • haloalkoxy includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3- dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (C x -C y )perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(C 1 -C 6 )perfluoroalkyl, more preferred is -(C 1 -C3)perfluoroalkyl, most preferred is -CF 3 .
  • (C x -C y )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(C 1 -C 6 )perfluoroalkylene, more preferred is -(C 1 -C 3 )perfluoroalkylene, most preferred is -CF 2 -.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • the group is a "formyl” group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • the term "amine” also includes ammonium ions as used herein.
  • amino group is a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group.
  • An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • ammonium ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide includes C- and N-amide groups, i.e., -C(0)NR 2 , and -NRC(0)R groups, respectively.
  • Amide groups therefore include but are not limited to carbamoyl groups (-C(0)NH 2 ) and formamide groups (-NHC(O)H).
  • a "carboxamido” group is a group of the formula C(0)NR 2 , wherein R can be H, alkyl, aryl, etc.
  • azido refers to an N 3 group.
  • An “azide” can be an organic azide or can be a salt of the azide (N 3 ⁇ ) anion.
  • nitro refers to an N0 2 group bonded to an organic moiety.
  • nitroso refers to an NO group bonded to an organic moiety.
  • nitrate refers to an ON0 2 group bonded to an organic moiety or to a salt of the nitrate (N0 3 ⁇ ) anion.
  • urethane (or “carbamyl”) includes N- and O-urethane groups, i.e.,
  • sulfonamide includes S- and N-sulfonamide groups, i.e., -SO 2 NR 2 and -NRSO 2 R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • amidine or “amidino” includes groups of the formula -C(NR)NR 2 .
  • an amidino group is -C(NH)NH 2 .
  • guanidine or “guanidino” includes groups of the formula
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • the compounds of the present invention may take the form of salts.
  • the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be “pharmaceutically-acceptable salts.” The term
  • pharmaceutically- acceptable salt refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
  • pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates .
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,A ⁇ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
  • salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization.. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I).
  • pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J.
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non- stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • prodrug refers to any pharmaceutically acceptable form of compound of the invention which, upon administration to a patient, provides a compound of the invention .
  • prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form a compound of the invention.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • the compounds of the invention herein possess antiviral activity against HCV, or are metabolized to a compound that exhibits such activity.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub- combinations of the above-listed embodiments.
  • isolated compound refers to a preparation of a compound of a specified formula, or a mixture of compounds, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an “isolated compound” refers to a preparation of a compound or a mixture of compounds, which contains the named compound or mixture of compounds in an amount of at least 10 percent by weight of the total weight.
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
  • a compound or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido-imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom.
  • the equilibrium is an example of tautomerism.
  • a structure depicted herein as one tautomer is intended to also include the other tautomer.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer.
  • the Cahn-Ingold-Prelog ranking is A > B > C > D.
  • the lowest ranking atom, D is oriented away from the viewer.
  • the present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
  • Isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques.
  • a racemic mixture of a compound of the invention, or a chiral intermediate thereof is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan).
  • a suitable chiral column such as a member of the series of DAICEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan).
  • the column is operated according to the manufacturer's instructions.
  • the preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for
  • Treating refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
  • treating includes (i) preventing a pathologic condition from occurring (e.g., prophylaxis); (ii) inhibiting the pathologic condition or arresting its development; (iii) relieving the pathologic condition; and/or (iv) diminishing symptoms associated with the pathologic condition
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result .
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • terapéuticaally effective amount is intended to include an amount of a compound described herein, or an amount of the combination of compounds described herein, e.g., to treat or prevent the disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme ReguL, 22:27 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased activity, or some other beneficial effect of the combination compared with the individual components.
  • infection refers to the invasion of the host by germs including viruses that reproduce and multiply, causing disease by local cell injury, release of poisons, or germ-antibody reaction in the cells.
  • the infection can be in a mammal (e.g., human).
  • the term "metabolite” refers to any compound produced in vivo or in vitro from the parent drug of the invention, or any of its prodrugs that are converted biologically to a parent drug of the invention and then to a further biotransformation product of the parent drug.
  • the term "patient” refers to a warm-blooded animal, and preferably a mammal, such as, for example, a cat, dog, horse, cow, pig, mouse, rat, or primate, including a human.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • One diastereomer or one enantiomer of a compound disclosed herein may display superior biological activity compared with the other.
  • separation of the diastereomeric mixture or the racemic material can be achieved by HPLC, optionally using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Tucker et al., J. Med. Chem., 37, 2437 (1994), for the resolution of enantiomers.
  • a chiral compound described herein may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Huffman et al., J. Org. Chem., 60: 1590 (1995).
  • ⁇ denotes microgram
  • mg denotes milligram
  • g denotes gram
  • ⁇ _/' denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • ⁇ denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes nanometer
  • the invention as disclosed herein provides a compound, a composition and a method for the treatment of hepatitis C in humans or other host animals, that includes administering an effective amount of a compound of the invention as described herein or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, optionally in a pharmaceutically acceptable carrier as a pharmaceutical composition of the invention.
  • the compounds of this invention either possess antiviral (i.e., anti-Hepatitis C virus) activity, or are metabolized to a compound that exhibits such activity.
  • the invention provides a method of inhibiting an HCV protease enzyme comprising contacting the enzyme with an effective amount of a compound of the invention.
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the invention provides pharmaceutical combinations.
  • a combination of the invention further includes one or more additional compounds having anti-Hepatitis C virus activity.
  • the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof.
  • the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a,
  • lymphoblastoid interferon ⁇ lymphoblastoid interferon ⁇ , or a combination thereof.
  • the one or more additional compounds having anti-Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.
  • the one or more additional compounds having anti-Hepatitis C virus activity can be an inhibitor of a HCV protease, such as an inhibitor of the NS3 protease, or can be an inhibitor of a HCV polymerase, such as the NS5B polymerase.
  • the present invention also provides a method of treating an animal inflicted with
  • the method includes administering to an animal in need of such treatment a compound of the invention and a pharmaceutically acceptable salt, a prodrug, or a metabolite thereof.
  • the animal can be a human being.
  • the method further includes administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or
  • the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof.
  • the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon ⁇ , or a combination thereof.
  • the one or more additional compounds having anti-Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.
  • the animal is a human.
  • the invention provides a method of treatment of an HCV infection in a host animal, such as a human patient, afflicted with an HCV strain that is resistant, or has developed resistance, to inhibitors of HCV viral protease or HCV viral polymerase.
  • the protease(s) and polymerase(s) of viruses, such as HCV are targeted by many varieties of medicinal compounds, and it is possible, or even likely, that resistance to these mechanisms of action may develop among viral populations.
  • the compounds of the invention target a viral component other than one of these enzyme systems, the inventors believe that cross-resistance is unlikely.
  • inventive compounds can be used in treatment of HCV strains that are already resistant, in treatment of HCV strains wherein development of protease or polymerase resistant strains is of concern, and in combination therapy comprising use of a protease inhibitor, a polymerase inhibitor, or both, in conjunction with a compound of the invention.
  • the compounds of the invention can also be used to prevent viral spread in a population of cells that has been exposed to an inoculum of HCV.
  • the compounds of the invention are believed to inhibit the transmission of the virus from an infected cell to an uninfected cell. Therefore, in various embodiments, a method of preventing viral spread is provided, comprising administering an effective amount of a compound of the invention to a patient exposed to an inoculum of HCV.
  • the invention provides a compound of formula (X):
  • X is a 1,2-ethylene or a 1,3-propylene group which can be unsubstituted or substituted;
  • a dotted line indicates an optional double bond
  • Y is azido, NR, or 1,2,3-triazolyl, wherein R is hydrogen or (C 1 -C6)alkyl, provided that when Y is azido then R 7 , R 8 and R 9 are all absent;
  • Z 1 and Z 2 are each independently unsubstituted or substituted phenyl, wherein the phenyl group can be mono- or independently pluri- substituted with halo, haloalkyl, alkyl, alkenyl, alkynyl, azido, or (C 1 -C 3 )alkoxy; or Z 2 is NH 2 and Y, R 7 , R 8 , and R 9" are all absent; R 1 and R 2" are independently at each occurrence hydrogen, (C 1 -C6)alkyl, (C 6 - C 10 )aryl, or 3-8 membered heterocyclyl, wherein any alkyl, aryl, or heterocyclyl group can be substituted or unsubstituted; or
  • R 1 , R 2 , and carbon atoms to which they are bonded, wherein the optional double bond is present, can form a fused (C6-C 30 )aryl that can be substituted or unsubstituted;
  • R 5 is absent, carbonyl, thiocarbonyl, or sulfonyl
  • R 6 is hydrogen, substituted or unsubstituted alkyl, cycloalkoxy, cycloalkylalkoxy, alkynyloxy, aralkoxy, heterocyclyloxy, cycloalkylamino, cycloalkylalkylamino, alkenylamino, arylamino, aralkylamino, heterocyclylamino, aroylamido, heteroaryl, or heteroarylalkyl;
  • R 5 and R 6 taken together can form a heterocyclyl
  • R is absent, hydrogen, carbonyl, thiocarbonyl, sulfonyl, or (C 1 -C 4 )alkylene;
  • R 8 is absent, NH, or O;
  • R 9 is alkynyl, alkanoyl, carboxamido, cycloalkyl, aryl, aroyl, heterocyclyl, carboxy, or carboxy-alkyl, wherein any alkynyl, alkanoyl, carboxamido, cycloalkyl, aryl, aroyl, heterocyclyl, or carboxy-alkyl can be substituted;
  • R 6 comprises a (C 1 -C 1 2)alkylene diamine moiety bonded to two respective R 5 groups, wherein R 5 is carbonyl, thiocarbonyl, or sulfonyl; or, wherein for formula (XIB),
  • R 9 comprises a (C 1 -C 12 )alkylene diamine moiety bonded to two respective R 7 groups, wherein R 7 is carbonyl, thiocarbonyl, or sulfonyl, and R 8 is absent;
  • W is N or CH
  • Q is OH or NHR 20 ;
  • R 20 is hydrogen, alkylaminocarbonyl or arylaminocarbonyl wherein any alkyl can be substituted;
  • R 21 is aralkyl or alkoxycarbonyl
  • W and R are as defined above and wherein R 20 comprises an alkylene bis(aminocarbonyl) group
  • W is N or CH and R 20 is hydrogen, alkylaminocarbonyl or
  • arylaminocarbonyl and R 21 is as defined above, wherein any alkyl or aryl can be substituted;
  • R is hydrogen or (C 1 -C 6 )alkyl
  • R 5 and R 6 are as defined above;
  • R 6 can be cycloalkoxy, cycloalkylalkoxy, alkynyloxy, , aralkoxy, or heterocyclyloxy. More specifically, the compound of formula (X) can be any of the following structures:
  • R 6 can be cycloalkylamino or alkenylamino. More specifically, the compound of formula (X) can be any of the following structures:
  • R 6 can be arylamino, aralkylamino, or aroylamido. More specifically, the compound of formula (X) can be any of the following structures:
  • R 6 can be substituted or unsubstituted alkyl. More specifically, the compound of formula (X) can be any of the following structures:
  • R 6 can be substituted heteroarylalkyl. More specifically, a compound of formula (X) can be any of the following structures:
  • R 5 and R 6 together can form a heterocyclyl. More specifically, a compound of formula (X) can be any of the following structures:
  • R 9 can be cycloalkyl. More specifically, a compound of formula (X) can be any of the following structures: or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof.
  • R 9 can be aroyl. More specifically, a compound of formula (X) can be any of the following structures: or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof.
  • R9 can be alkynyl. More specifically, a compound of formula (X) can be any of the following structures:
  • R 9 can be aryl substituted with azido. More specifically, a compound of formula (X) can be any of the following structures:
  • R 9 can be carboxyl, heteroaryl, or cycloalkyl. More specifically, a compound of formula (X) can be any of the following structures:
  • R 9 can be alkanoyl, carboxamido, aryl, or heterocyclyl. More specifically, a compound of formula (X) of claim 23 of any of the following structures:
  • Z 1 , Z 2 , or both can comprise an azidophenyl group. More specifically, a compound of formula (X) can be the following structure: or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof.
  • Z 1 , Z 2 , or both can comprise an alkynylphenyl. More specifically, a compound of formula (X) can be the following structure
  • Y can be azido. More specifically, a compound of formula (X) can be any of the following structures:
  • the inventive compound can be a dimer of formula (XIA) or (XIB)
  • a dimer of formula (XI A) or (XIB) can be any of the following structures:
  • a compound of the invention can be a compound of formula (XX). More specifically, a compound of formula (XX) can be any of the following structures:
  • a compound of the invention can be a dimer of formula (XXI). More specifically, a compound of formula (XXI) can be any of the following formulas:
  • a compound of the invention can be a compound of formula (XXII). More specifically, a compound of formula (XXII) can be of the following formula:
  • a compound of the invention can be a compound of formula (XXIII). More specifically, a compound of formula (XXIII) can be of the following structure:
  • a compound of the invention can be a compound of formula (XXIV). More specifically, a compound of formula (XXIV) can be of the following structure:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of the invention.
  • the carrier can be any of those known in the art in which the compound of the invention has suitable stability for the use contemplated, as is discussed below.
  • the invention provides a composition further comprising one or more additional compounds having anti-Hepatitis C virus activity.
  • the one or more additional compounds c anti-Hepatitis C virus activity can be an interferon, ribavirin, or a combination thereof.
  • the one or more additional compounds having anti-Hepatitis C virus activity can be an inhibitor of an HCV protease, or an inhibitor of an HCV polymerase, or both.
  • the interferon can be interferon a2b, pegylated interferon a, consensus interferon, interferon a2a,
  • lymphoblastoid interferon ⁇ lymphoblastoid interferon ⁇ , or a combination thereof.
  • the one or more additional compounds having anti- Hepatitis C virus activity can be interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, microRNA agonists or antagonists, or a combination thereof.
  • the invention provides a method of treating an animal infected with Hepatitis C Virus, comprising administering to the animal an effective amount of a compound of the invention, or any pharmaceutically acceptable salt, solvate, hydrate, prodrug, or metabolite thereof.
  • the strain of the Hepatitis C Virus with which the animal is infected is resistant or is known to be capable of developing resistance to an anti-HCV therapy.
  • treating can comprise inhibiting viral spread within the animal after exposure of the animal to an infectious inoculum of the virus.
  • treating can comprise inhibiting the Hepatitis C virus wherein the strain of the Hepatitis C virus infecting the animal is a strain that has developed resistance to an inhibitor of a Hepatitis C virus protease or of a Hepatitis C virus polymerase.
  • a method of the invention can further comprise administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or simultaneously with the compound of the invention, or a
  • the one or more additional compounds having anti-Hepatitis C virus activity can be an interferon, ribavirin, or a combination thereof.
  • the interferon can be interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastiod interferon ⁇ , or a combination thereof.
  • the one or more additional compounds having anti-Hepatitis C virus activity can be interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.
  • the animal being treated for HCV infection is a human.
  • the invention provides a method of killing, inhibiting, or blocking viral spread of a Hepatitis C Virus, comprising contacting the Hepatitis C Virus with an effective amount of a compound of claim 1, or any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or metabolite thereof sufficient to inhibit or kill, inhibit, or block viral spread of the Hepatitis C Virus.
  • the contacting is in vitro, as in experimental studies. In various embodiments, the contacting is in vivo, as in treatment of patients.
  • the invention provides a use of a compound of the invention in preparation of a medicament for the treatment of Hepatitis C virus.
  • Solution percentages express a weight to volume relationship, and solution ratios express a volume to volume relationship, unless stated otherwise.
  • Flash chromatography was carried out on silica gel (Si0 2 ) according to Still's flash chromatography technique (J. Org. Chem., 43, 2923, (1978).
  • Suitable aromatic aldehydes include, for example benzaldehyde,
  • benzeneacetaldehyde 2-bromobenzaldehyde, 2-methoxybenzaldehyde, 2,3- dimethoxybenzaldehyde, benzeneacetaldehyde, 4-(methylthio)benzaldehyde, 1- naphthaldehyde, anthracene-9-carboxaldehyde, 1-pyrenecarboxaldehyde, 9H-fluorene-2- carboxaldehyde, 4-butoxybenzaldehyde, and the like, or combinations thereof.
  • Suitable heteroaromatic aldehydes include, for example, l-pyrrol-2-aldehyde, 1- pyrrol-3-aldehyde, furan-2-aldehyde, furan-3-aldehyde, thiophene-2-aldehyde, thiophene- 3-aldehyde, 4-pyridinecarboxaldehyde, 3-pyridinecarboxaldehyde, 2- pyridinecarboxaldehyde, 4,6-dimethyl-2-pyridinecarboxaldehyde, 4-methyl- pyridinecarboxaldehyde, pyrimidine-2-aldehyde, pyrimidine-4-aldehyde, 2-methyl- pyrimidine-4-aldehyde, 6-methylpyridine-2-aldehyde, pyrazine-2-aldehyde, pyridazine- 3-aldehyde, pyridazine-4-aldehyde, l-methylbenzimid
  • compositions of the compounds of the invention alone or in combination with another medicament.
  • compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts and mixtures thereof.
  • compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein.
  • the compositions can appear in
  • compositions include a compound of the invention and a
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier or when the carrier serves as a diluent, it can be solid, semi- solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols,
  • polyhydroxyethoxylated castor oil peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • sterile oils can be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi-dose containers.
  • the formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the formulations can also be formulated for controlled release or for slow release.
  • compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted
  • Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide- polyglycolide.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides) .
  • the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application.
  • a liquid carrier preferably an aqueous carrier
  • the carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that can be prepared by conventional tabletting techniques can contain:
  • Active compound 250 mg
  • a typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
  • the compounds of the invention can be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition.
  • mammals include also animals, both domestic animals, e.g.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used.
  • a typical dosage is about 10 mg to about 1000 mg per day.
  • the exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 ⁇ g to about 1250 mg, preferably from about 250 ⁇ g to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • Target cells were seeded the day before (10 4 cells/well/ 96- well).
  • the chemical library was provided in a 96- well format in DMSO solutions at lOmM concentration.
  • the compounds were diluted to a final concentration of 20 ⁇ in complete medium (DMEM+10%FCS).
  • Compound and virus dilutions were mixed 1: 1 and added to clone 2 cells, which were incubated in the presence of the virus (400 FFU/well) and compound (10 ⁇ ) for 72 hours at 37°C. After this incubation period, the cells were fixed at room temperature (RT) with a 4% paraformaldehide solution in phosphate buffered saline (PBS, pH 7) for 20 minutes. The fixed cells were processed for colorimetric analysis as follows.
  • a dilution ( ⁇ g/ml) of a recombinant human IgG anti-E2 is added in incubation buffer (0.3% TritonXlOO, 3% bovine serum albumin (BSA) in PBS) for 1 hour at room temperature.
  • the cells are washed four times with 200 ⁇ of PBS and incubated with the appropriate dilution (1: 15000) of the secondary antibody conjugated to horseradish peroxidase (HRP, Goat anti-human IgG-HRP; Jackson Immunoresearch, Stanford, CA) for 1 hour at room temperature.
  • HRP horseradish peroxidase
  • the cells are washed again four times with 200 ⁇ of PBS and the remaining peroxidase activity is evaluated by adding 3,3',5,5'-tetramethylbenzidine (TMB; Pierce, Rockford, IL) to the cells in the presence of hydrogen peroxide.
  • TMB 3,3',5,5'-tetramethylbenzidine
  • the oxidation of TMB leads to the generation of a blue product that absorbs light at 650 nm.
  • the reaction can be stopped by the addition of 1 volume of IN H 2 SO 4 , which generates a yellow product with an optimal absorbance of 450 nm.
  • Each plate includes a standard curve with serial 2-fold dilutions of the virus to ensure appropriate colorimetric value transformation and negative controls (uninfected cells) to determine the background of the assay.
  • the screening technology described above does not discriminate between an antiviral compound and a false-positive result, as both should be associated with a reduced O.D.45o nm signal.
  • the readout relies on viable, proliferating cells. Since the virus requires actively dividing cells for efficient replication and viral antigen quantitation relies on the presence of similar amounts of cells in the well, a non-specific toxic effect of a given compound should lead to a false-positive readout. To avoid problem, the impact of the compounds on cell viability was evaluated.
  • IC 50 inhibitory concentration 50
  • LD 50 lethal dose 50
  • IC 50 serial dilutions of the different antiviral compounds were assayed using the colorimetric assay.
  • Serial 2-fold dilutions of the compound were prepared. These solutions (50 ml) were mixed with 50 ml of an 8.10 J FFU/ml virus dilution in complete medium containing final compound concentrations starting at 50 ⁇ . The mixture was transferred into a 96- well plate containing 10 4 clone 2 cells per well seeded the day prior to the experiment. The cultures were incubated for a period of 72 hours at 37°C, after which the cells were fixed and processed for colorimetric analysis as described above.
  • IC 50 is defined as the compound concentration that should reduce HCV by 50%, based on the values obtained after O.D. transformation with the standard curve.
  • cell viability was measured in the presence of increasing concentrations of the antiviral compounds.
  • Cell viability may be determined by measuring the mitochondrial metabolic capacity of the cells at any given time point. This may be achieved by culturing metabolically active cells with a modified soluble tetrazolium salt Thiazolyl Blue Tetrazolium Bromide also called MTT (Sigma- Aldrich, St.Louis, MO), which transforms MTT into formazan, a purple precipitate. This transformation, dependent on mitochondrial dehydrogenases, was quantified within 2-4 hours using a colorimetric assay that is read at 570 nm.
  • the LD 50 of a particular compound was determined similarly to the IC 50 .
  • Serial dilutions of the compound typically from 100 ⁇ to 100 nanoM
  • Cell viability was analyzed by adding MTT (5 ⁇ g/ml final concentration) and measuring the resulting formazan content, after resuspension in 100% DMSO, at 570 nm in a microplate spectrophotometer.
  • LD 50 values were obtained by plotting the colorimetric values (O.D.57o nm ) versus the compound concentration and determining the concentration that rendered 50% of the activity observed in the control. This procedure is widely used for determination of cell viability because it is rapid, simple and yields highly reproducible results.

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Abstract

L'invention porte sur des composés pharmaceutiques, sur des compositions, sur des combinaisons et sur des procédés de traitement d'une infection par le virus de l'hépatite C. Les composés de l'invention sont efficaces pour tuer, inhiber ou bloquer la propagation virale d'un virus de l'hépatite C. L'invention porte également sur des procédés de préparation et sur des procédés d'utilisation.
PCT/US2011/021889 2010-01-22 2011-01-20 Inhibiteurs d'infection par le virus de l'hépatite c WO2011091152A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014036443A2 (fr) * 2012-08-31 2014-03-06 Novadrug, Llc Carboxamides hétérocyclyle pour le traitement de maladies virales

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4068070A (en) * 1974-07-16 1978-01-10 Fuji Chemical Industry Co., Ltd. α-Cyanoamine compounds and a process for producing the same
US6407122B1 (en) * 1997-12-02 2002-06-18 Pharmacia & Upjohn S.P.A. Amino-benzothiazole derivatives
WO2003028721A2 (fr) * 2001-09-26 2003-04-10 Aventis Pharma S.A. Composes de benzimidazole substitue et utilisation de ceux-ci pour le traitement du cancer
US20080132550A1 (en) * 2003-07-21 2008-06-05 Aventis Pharmaceuticals Inc. Heterocyclic compounds as p2x7 ion channel blockers
US7410979B2 (en) * 2003-11-19 2008-08-12 Rigel Pharmaceuticals, Inc. Synergistically effective combinations of dihaloacetamide compounds and interferon or ribavirin against HCV infections

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4068070A (en) * 1974-07-16 1978-01-10 Fuji Chemical Industry Co., Ltd. α-Cyanoamine compounds and a process for producing the same
US6407122B1 (en) * 1997-12-02 2002-06-18 Pharmacia & Upjohn S.P.A. Amino-benzothiazole derivatives
WO2003028721A2 (fr) * 2001-09-26 2003-04-10 Aventis Pharma S.A. Composes de benzimidazole substitue et utilisation de ceux-ci pour le traitement du cancer
US20080132550A1 (en) * 2003-07-21 2008-06-05 Aventis Pharmaceuticals Inc. Heterocyclic compounds as p2x7 ion channel blockers
US7410979B2 (en) * 2003-11-19 2008-08-12 Rigel Pharmaceuticals, Inc. Synergistically effective combinations of dihaloacetamide compounds and interferon or ribavirin against HCV infections

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014036443A2 (fr) * 2012-08-31 2014-03-06 Novadrug, Llc Carboxamides hétérocyclyle pour le traitement de maladies virales
WO2014036443A3 (fr) * 2012-08-31 2014-04-24 Novadrug, Llc Carboxamides hétérocyclyle pour le traitement de maladies virales
US9511070B2 (en) 2012-08-31 2016-12-06 Novadrug, Llc Heterocyclyl carboxamides for treating viral diseases

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