WO2013142159A1 - Combinaisons pharmaceutiques comprenant un analogue thionucléotidique - Google Patents

Combinaisons pharmaceutiques comprenant un analogue thionucléotidique Download PDF

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WO2013142159A1
WO2013142159A1 PCT/US2013/030609 US2013030609W WO2013142159A1 WO 2013142159 A1 WO2013142159 A1 WO 2013142159A1 US 2013030609 W US2013030609 W US 2013030609W WO 2013142159 A1 WO2013142159 A1 WO 2013142159A1
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compound
formula
combination
pharmaceutically acceptable
compounds
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PCT/US2013/030609
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English (en)
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Lawrence M. Blatt
Leonid Beigelman
Hua Tan
Julian Alexander SYMONS
David Bernard Smith
Min Jiang
Tara Lynn Kieffer
Cornelis Arie RIJNBRAND
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Alios Biopharma, Inc.
Vertex Pharmaceuticals, Inc.
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Publication of WO2013142159A1 publication Critical patent/WO2013142159A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are a thiophosphoroarnidate nucleotide analog for use in combination therapy with one or more other agents. Also disclosed herein are methods of treating diseases and/or conditions with a thiophosphoroarnidate nucleotide analog in combination with one or more agents.
  • Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, have been the subject of widespread research for the treatment of viral infections and cancer.
  • Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active metabolites, which, in turn, may inhibit polymerases involved in viral or cell proliferation. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.
  • Some embodiments disclosed herein relate to a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection (for example, a hepatitis C viral infection) that can include administering to a subject suffering from the viral infection an effective amount of a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • Other embodiments described herein relate to using a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds, in the manufacture of a medicament for ameliorating and/or treating a viral infection (for example, a hepatitis C viral infection).
  • Still other embodiments described herein relate to a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds, that can be used for ameliorating and/or treating a viral infection (for example, a hepatitis C viral infection).
  • a viral infection for example, a hepatitis C viral infection.
  • Some embodiments disclosed herein relate to methods of ameliorati g and/or treating a viral infection (for example, a hepatitis C viral infection) that can include contacting a cell infected with the virus (such as the hepatitis C virus) with an effective amount of a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • a viral infection for example, a hepatitis C viral infection
  • a viral infection for example, a hepatitis C viral infection
  • a viral infection for example, a hepatitis C viral infection
  • a viral infection for example, a hepatitis C viral infection
  • a cell infected with the virus such as the hepatitis C virus
  • Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, that can be used for ameliorating and/or treating a viral infection (for example, a hepatitis C viral infection) by contacting a cell infected with the virus (such as the hepatitis C virus) with an effective amount of a combination of a compound of Formuia (A) and one or more compounds of Formula (C), or pharmaceuticall acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • a viral infection for example, a hepatitis C viral infection
  • a cell infected with the virus such as the hepatitis C virus
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include contacting a ceil infected with the virus (for example, a hepatitis C virus) with an effective amount of a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • a ceil infected with the virus for example, a hepatitis C virus
  • C pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • inventions described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, in the manufacture of a medicament for inhibiting replication of a virus (for example, a hepatitis C virus) that can include contacting a cell infected with the virus with an effective amount of a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • a virus for example, a hepatitis C virus
  • Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compound described herein, that can be used for inhibiting replication of a virus (for example, a hepatitis C vims) by contacting a cell infected with the virus with an effective amount of an effective amount of a combination of a compound of Formula (A) and one or more compounds of Formula (C), or pharmaceuticall acceptable salts, hydrates, and solvates of the aforementioned compounds.
  • a virus for example, a hepatitis C vims
  • Some embodiments described herein relate to a method of inhibiting a polymerase (for example, NS5B polymerase of a hepatitis C vims) that can include contacting a cell (for example, a cell infected with a hepatitis C virus) with an effective amount of a combination of one or more compounds described herein.
  • a polymerase for example, NS5B polymerase of a hepatitis C vims
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for inhibiting a polymerase (for example, S5B polymerase of a hepatitis C virus) that can include contacting a cell (for example, a cell infected with a hepatitis C vims) with an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for inhibiting a polymerase (for example, S5B polymerase of a hepatitis C virus) can include contacting a cell (for example, a ceil infected with a hepatitis C vims) that with an effective amount of said combination of compounds.
  • a polymerase for example, S5B polymerase of a hepatitis C virus
  • a cell for example, a ceil infected with a hepatitis C vims
  • Figure 1 shows example compounds of Formula (A), including Compounds 1033 through 1065.
  • Figure 2 shows example compounds of Formula (C), including Compounds 3000 through 3067, which includes HCV protease inhibitors, nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, NS5A inhibitors, and other antivirals.
  • T? 3 b A T? 4 , T K? 5 R 6 R 7 R 8 X? 10 ? 1 1 ? 12 R i 3 ? 14 R 15 ? 16 ? 1 7 R iA T? 2A ? 3A X? 3B iJ? 4A T3 5A
  • R° A R ?A , R SA and R" represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstituted. If two "R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R d and R D of an NR a R b group are indicated to be "taken together," it means that they are covIERly bonded to one another to form a ring:
  • R groups are not limited to the variables or substituents defined previously.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxy!, alkoxy, aryloxy, acyl, mercapto, ikylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbaniyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-suifonamido, C-carboxy, protected C-carboxy
  • C a to Q in which "a” arid “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.
  • the alkyl, alkenyl, alkynyl, ring of the cycloalkyi, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from "a" to "b", inclusive, carbon atoms.
  • a "Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, C3 ⁇ 4-, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH ⁇ CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no "a” and "b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycioalkynyi, ar l, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “ 1 to 20” refers to each integer in the given range: e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as "C 1 -C4 alkyl” or similar designations.
  • “C 1 -C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyf, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyi, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
  • the alkyl group may be substituted or unsubsti uted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or muiti- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyi and cyclooctyl.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may ⁇ be unsubstituted or substituted.
  • cycloalkynyi refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring.
  • the triple bonds cannot form a fully delocalized pi-electron system throughout ail the rings, When composed of two or more rings, the rings may be joined together in a fused fashion.
  • a cycloalkynyi group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multi cyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C,j-C] 4 aryl group, a C C io aryl group, or a , aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazoie, benzoxazole, 1 ,2,3-oxadiazoie, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazoie, pyrazole, benzopyrazole, isoxazole, benzoisoxazoie, isotfaiazole, triazoie, benzotriazole, thiadiazole, tetrazole, pyridine,
  • heterocyclyi or “heteroalicyclyl” refers to a three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system,
  • a heterocvcle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic iniides, cyclic thioimid.es and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized, Heterocyclyl or heteroalicyclic groups may be imsubstituted or substituted.
  • heterocyclyl or “heteroalicyclyl” groups include but are not limited to, 1 ,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxoiane, 1,3- dioxolane, 1,4-dioxolane, 1 ,3-oxathiane, i ,4 ⁇ oxathiin, 1 ,3-oxathiolane, 1 ,3-dithiole, 1,3- dithiolane, 1 ,4-oxathiane, tetrahydro- 1 ,4-thiazine, 2H-i ,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouraci!, trioxane, hexahydro ⁇ l ,3,5-triazine.
  • benzo-fused analogs e.g., benz
  • aralkyl and aryl(aikyi) refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenylalkyl, 3-phenylalkyl, and naphthylalkyl.
  • heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalky!, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrroiylalkyl, pyridylalkyl, isoxazolylaikyl, and imidazolylalkyl, and their benzo-fused analogs.
  • a "(heteroalicyclyi)alkyl” and “(heterocyciyT)alkyl” refer to a heterocyclic or a heteroalicyciylic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a (heteroalicyclyf)aikyl may be substituted or unsubstituted.
  • Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin ⁇ 4-y!propyl, (tetrahydro-2H ⁇ thiopyran-4-yl)methyl, and (1 ,3-thiazinan-4-yi)methyl,
  • Lower alkylene groups are straight-chained -C3 ⁇ 4- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (- €3 ⁇ 4-), ethylene i-C! ! ⁇ ( ' ! ! ⁇ ⁇ ). propylene ( ⁇ CH 2 CH 2 CH 2 -), and butylene (-CH 2 CH 2 CH 2 CH 2 -).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of "substituted.”
  • alkoxy refers to the formula -OR wherein R is an alky 1, an alkenyl, an alkynyl, a cyeloalkyl, a cycioalkenyi, a eycloalkynyi. aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl as defined herein.
  • a non- lirniiing list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methyl ethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy.
  • An alkoxy may be substituted or unsubstituted.
  • acyl refers to a hydrogen, alkyl, alkeny!, alkynyl, or aryl connected, as substituents, via a carbonyi group. Examples include forniyl, acetyl, propanoyl, benzoyl, and aeryi. An acyl may be substituted or unsubstituted.
  • hydroxyalkyi refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyi groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyi, 2-hydroxypropyi, and 2,2- dihydroxyethyl , A. hydroxyalkyi may be substituted or unsubstituted,
  • liaioaikyi refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl).
  • a halogen e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl.
  • groups include but are not limited to, chloromethyl, fiuoromethyl, difluoromethyl, triiluoromethyl, 1 -chloro-2-fluoromethy 1, and 2-fluoroisobutyl.
  • a liaioaikyi may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
  • groups include but are not limited to, chloromethoxy, f!uoromethoxy, difluoromethoxy, trifluoromethoxy, 1 -chloro-2-iluoromethoxy, and 2-fluoroisobutoxy.
  • A. haloalkoxy may be substituted or unsubstituted.
  • arylthio refers to RS-, in which R is an aryl, such as but not limited to phenyl.
  • R is an aryl, such as but not limited to phenyl.
  • An arylthio may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cvcloalkyl, cycloaikenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaiyi)alkyl or (heteroaiicyciyi)alkyl.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cvcloalkyl, cycloaikenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaiyi)alkyl or (heteroaiicyciyi)alkyl.
  • a sulfenyl may be substituted or unsubstituted.
  • a sulfinyl may be substituted or unsubstituted.
  • sulfonyF' group refers to an "S0 2 R" group in which R can be the same as defined with respect to sulfenyl.
  • R can be the same as defined with respect to sulfenyl.
  • a sulfonyl ma be substituted or unsubstituted.
  • An O- carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • a "trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein X is a halogen.
  • a "trihalomethanesulfonamido” group refers to an "X 3 CS(0)2 (R A )-" group wherein each X is a halogen and RA hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (he teroal icycly 1 )a Ikyl .
  • amino refers to a ⁇ NH 2 group
  • hydroxy refers to a Oi i group.
  • a "cyano" group refers to a "-CN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “mercapto” group refers to an "-SH” group.
  • carbonyl group refers to a C :::: 0 group.
  • S-sulfonamido refers to a "-S0 2 N(RARB)" group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroaiicyclyi)alkyl.
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonarnido refers to a u RS0 2 N(RA)-" group in which 11 and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroaiicyclyi)alkyl .
  • An N-sulfonamido may be substituted or unsubstituted.
  • An "O-carbamyl” group refers to a "-OC(-0)N(RARB)" group in which R and B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroaiicyclyi)alkyl .
  • An O-carbamyl may be substituted or unsubstituted.
  • N-carbamyl refers to an group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl.
  • An N-carbamyl may be substituted or unsubstituted.
  • O-thiocarbamyl refers to a group in which RA and R B can be independently hydrogen, alkyl, alkenyi, alkynyl, cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl ⁇ alkyl or (heteroaiicyclyi)alkyl.
  • An O-thiocarbamyl may be substituted or unsubstituted,
  • An N-thiocarbamyl may be substituted or unsubstituted,
  • R and A can be independently hydrogen, alkyl, alkenyi, alkynyl, cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.
  • An N-amido may be substituted or unsubstituted,
  • halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • substituents there may be one or more substituents present.
  • haloaikyi may include one or more of the same or different halogens.
  • C1-C3 aikoxyphenyi may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • nucleoside is used herein in its ordinary sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer thereof via a N- glycosidic bond, such as attached via the 9-position of a purine-base or the 1 -position of a pyrimidme-base.
  • Examples mciude but are not limited to, a ribomicleoside comprising a ribose moiety and a deoxyribonucieoside comprising a deoxyribose moiety.
  • a modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a carbon has been replaced with a sulfur or an oxygen atom.
  • a "nucleoside” is a monomer that can have a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.
  • nucleotide is used herein in its ordinary sense as understood by those skilled in the art, and refers to a nucleoside having a phosphate ester bound to the pentose moiety, for example, at the 5 '-position.
  • heterocyclic base refers to an optionally substituted nitrogen-containing heterocycly! that can be attached to an optionally substituted pentose moiety or modified pentose moiety
  • the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidine-base and an optionally substituted triazoie-base (for example, a 1 ,2,4-triazale).
  • purine- base is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers.
  • pyrimidine-base is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers.
  • a non-limiting list of optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkyl guanine (e.g., 7-rnethylguanme), theobromine, caffeine, uric acid and isoguanine.
  • pyrimidine -bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-aIkylcytosine (e.g., 5-methylcytosine).
  • An example of an optionally substituted triazole-base is l ,2,4-triazoie-3-carboxamide.
  • heterocyclic bases include diaminopurine, 8-oxo-N 6 -alkyladenine (e.g., 8-oxo-N°- methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N " -ethanocytosin, N 6 ,N '" '- ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-iluorouracii and 5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos.
  • diaminopurine 8-oxo-N 6 -alkyladenine (e.g., 8-oxo-N°- methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N " -ethanocytosin, N 6 ,
  • a heterocyclic base can be optionally substituted with an amine or an enoi protecting group(s).
  • amino acid refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group.
  • amino acid refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, a-amino acids, ⁇ -amino acids, ⁇ -amino acids and ⁇ -amino acids.
  • Suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutaniine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamiiia-aminobutyric acid, eitruiline, heta-alanine, alpha-ethyl-giycine, alpha-propyl-g!ycine and norleucine.
  • N- linked amino acids can be substituted or unsubstituted.
  • ester derivative refers to an amino acid in which a main-chain carboxylic acid group has been converted to an ester group,
  • N-linked amino acid ester derivatives include substituted and
  • phosphate is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example, as used herein, the terms “monophosphate,” “diphosphate,” and “triphosphate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms,
  • protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions.
  • Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmte, Protective Groups in Organic Chemistry Plenum Press, 1.973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups.
  • the protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art.
  • a non- limiting list of protecting groups include benzyl; substituted benzyl; aikylcarbonyis and alkoxycarbonyis (e.g., t-butoxycarbonyi (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyi); substituted methyl ether (e.g., niethoxymethyi ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsiiyl, triethylsilyl, triisopropyisilyl, t- butyldimethylsilyl.
  • esters e.g., benzoate ester
  • carbonates e.g., methoxyrnethylcarbonate
  • sulfonates e.g.
  • acyclic ketal e.g., dimethyl acetal
  • cyclic ketals e.g., 1,3-dioxane, 1 ,3-dioxolanes, and those described herein
  • acyclic acetal e.g., those described herein
  • acyclic liemiacetal e.g., 1 ,3-dithiane or 1,3-dithiolane
  • orthoesters e.g., those described herein
  • triarylmethyl groups e.g., trityi; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4"-trimethoxytrityl (TMTr); and those described herein).
  • leaving group refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates and halogens.
  • Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed,, Andrew Streitwieser and Clayton Heathcock ( 1981), pages 169-171 ; and Organic Chemistry, 5 th ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups,
  • pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, iris(hydroxymethyl)methyiamine, Cj-C? alkylamine, cydohexyiamine, triethanol amine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, iris(hydroxymethyl)methyiamine, Cj-C? alkylamine
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise.
  • a group of items linked with the conjunction Or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.
  • each center may independently be of R-configuration or S-conflguration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses ail potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates,
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like, in other embodiments, the compounds described herein exist in unsoivated form.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like.
  • Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol,
  • the compounds provided herein can exist in unsoivated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsoivated forms for the purposes of the compounds and methods provided herein.
  • B l can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group
  • R ! can be selected from O " , OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative
  • R 2 can be selected from an optionally substituted aryl, an optionally substituted
  • heteroaryl an optionally substituted heterocyclyl and , wherein R 19 , R"' and R " can be independently absent or hydrogen, and n can be 0 or 1 ; provided that when R ! is
  • R ",a and R JL1 can be independently selected from hydrogen, deuterium, an optionally substituted Ci-6 alkyl, an optionally substituted C?-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C 1-6 haloalkyi and an.
  • R 1 ⁇ 4 and R ih can be taken together to form an optionally substituted C3- cycloalkyl
  • R ⁇ can be selected from hydrogen, azido, an optionally substituted Ci- 6 alkyl, an optionally substituted C 2-6 alkenyl and an optionally substituted C 2-6 alkynyl
  • R 2 can be an optionally substituted heteroaryl.
  • l can be an optionally substituted heterocyclyl.
  • R z can be an optionaily substituted aryl.
  • R 2 can be an optionally substituted phenyl or an optionally substituted naphthyl. If R 2 is a substituted phenyl or a substituted naphthyl, the phenyl ring and the naphthyl ring(s) can be substituted one or more times.
  • Suitable substituents that can be present on optionally substituted phenyl and an optionally substituted naphthyl include electron-donating groups and electron-withdrawing groups.
  • R 2 can be a para-substituted phenyl, in other embodiment, R can be an unsubstituted phenyl or an unsubstituted naphthyl.
  • R " wherein R ! 9 , R 20 and R J > can be independently absent or hydrogen, and n can be 0 or 1. In some embodiments, 11 can be 0. In other embodiments, n can be 1 .
  • R can be an a-thiodiphosphate.
  • R _i can be an ⁇ -thiotriphosphate.
  • At least one of R 19 , R iJ and J can be absent. In other embodiments, at least one of R i , R 2b and R i can be hydrogen. In some embodiments, R '*! and R J can be absent. In other embodiments, R 20 and R 21 can be hydrogen. In some embodiments, R 19 , R 2u and R l can be absent. In some embodiments, R i9 , R 20 and R i can be hydrogen. Those skilled in the art understand that when any of R' 9 , "° and R" 1 are absent the oxygen atom to which R' 9 , R"° and R '!i are associated with can have a negative charge.
  • the oxygen atom to which R 20 is associated with can be O " .
  • one or more the phosphorus atoms can he a chiral center.
  • the alpha-phosphorus (the phosphorus nearest to the pentose ring) can be a chiral center.
  • the alpha-phosphorus can be a (R)-stereocenter.
  • the alpha-phosphorus can be a (S)-stereocenter.
  • ll 1 can be absent.
  • R ! can be hydrogen.
  • R 1 can be an optionally substituted N-Iinked a-amino acid.
  • R 1 can be an optionally substituted N-linked a-amino acid ester derivative.
  • Various amino acids and amino acid ester derivatives can be used, including those described herein.
  • Suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • Additional suitable amino acids include, but are not limited to, alpha-ethyl-glycine, alpha- propyl-glycine and beta-alanine
  • N-linked amino acid ester derivatives include, but are not limited to, an ester derivatives of any of the following amino acids: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • Additional examples of N-linked amino acid ester derivatives include, but are not limited to, an ester derivative of any of the following amino acids: alpha-ethyl-glycine, alpha- propyl-glycine and beta-alanine.
  • R 1 can be an ester derivative of alanine.
  • R* can be selected from alanine methyl ester, alanine ethyl ester, alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester.
  • the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester derivative can be in the [.-configuration. In other embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester derivative can be in the D-conflguration.
  • R 3 when R 3 is an optionally substituted N-linked a- amino acid or an optionally substituted N-linked a-amino acid ester derivative, then R 2 can be selected from optionally substituted aryi, an optionally substituted heteroaryl and an optionally substituted heterocyciyl.
  • R " when R' is an optionally substituted N-linked a-amino acid ester derivative, then R " can be an optionall substituted aryl.
  • II 1 when an optionally substituted N-linked a-amino acid ester derivative, then R 2 can be an optionally substituted heteroaryl.
  • R 3 when R 3 is an optionally substituted N-linked a-amino acid ester derivative, then R can be an optionally substituted heterocyciyl.
  • R can have the structure wherein
  • R 2 can be selected from hydrogen, an optionally substituted Ci-6-aikyl, an optionally substituted C?.6 cycloaikyl, an optionally substituted aryl, an optionally substituted aryl(Ci-6 alkyl) and an optionally substituted Ci_6 haioalkyl; and R 7" ' can be selected from hydrogen, an optionally substituted Ct-6 alkyl, an optionally substituted Ct-g haioalkyl, an optionally substituted C3-6 cycloaikyl, an optionally substituted C aryl, an optionally substituted Cut aryl and an optionally substituted or R 23 and R 24 can be taken together to form an optionally substituted C3..6 cycloaikyl,
  • R 2j can be an optionally substituted Ci-g-alkyl.
  • suitable optionally substituted Ci-6-aIkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutvl, tert-butyi, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).
  • R "3 can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino, in some embodiment, R' " ' can be an unsubstituted Ci-g-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutvl, tert-butyl, pentyl (branched and straight- chained), and hexyl (branched and straight-chained). In an embodiment, R 2j can be methyl.
  • R 22 can be an optionally substituted Ci-e alkyl.
  • optionally substituted include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyi, tert-butyi, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).
  • R can be methyl or isopropyl.
  • R i can be ethyl or neopentyl.
  • R 22 can be an optionally substituted C 3 -6 cycloaikyl.
  • optionally substituted C 3- 6 cycloaikyl examples include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyi, and cyclohexyl.
  • R 22 can be an optionally substituted cyclohexyl.
  • R 2 " can be an optionall substituted aryl, such as phenyl and naphthyl.
  • R 22 can be an optionally substituted alkyl).
  • ⁇ can be an optionally substituted benzyl.
  • R " " can be an optionally substituted d-6 haioalkyl, for example, CF 3 .
  • R 24 can be hydrogen.
  • R 24 can be an optionally substituted Ci.i-aikyL such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • R 24 can be methyl.
  • ⁇ ' and R 24 can be taken together to form an optionally substituted CM cycloalkyl. Examples of optionally substituted C3.
  • cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cvclopentyl, and cvclohexyl.
  • the carbon to which R 2" ' and I "4 are attached may be a chiral center.
  • the carbon to which R 2j and R 24 are attached may be a (R)-chirai center.
  • the carbon to which R 2" ' and R “ 4 are attached may be a (S)-chiral center.
  • R 3a and R 3 ° can be the same.
  • R 3a and R:' b can be different.
  • R ia and R jb can be both hydrogen.
  • at least one of R 3i and R 3b can be an optionally substituted Cj . -6-alkyl; and the other of R ja and R ⁇ j0 can be hydrogen.
  • Suitable optionally substituted C , aikyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, pentyi (branched and straight-chained), and hexyl (branched and straight-chained).
  • at least one of R a and R b can be methyl, and the other of R a and R 3b can be hydrogen.
  • at least one of R ja and R 3b can be an optionally substituted Ci-6-haloalkyl, and the other of R 3a and R' b can be hydrogen.
  • R:' a and R ib can be taken together to form an optionally substituted ⁇ cycloaikyl.
  • the 5'- carbon can be a (R)-stereocenter. in other embodiments, the 5 '-carbon can be an (S) ⁇ stereocenter.
  • R 4 can be hydrogen. In other embodiments, R 4 can be azido. in still other embodiments, R 4 can be an optionally substituted G..6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyi, isobutyl, tert-butyl, pentyi (branched and straight- chained), and hexyl (branched and straight-chained). In some embodiments, R 4 can be an optionally substituted C2-6 alkenyl. In some embodiments, R can be an optionally substituted C?-6 alkynyl.
  • the substituents attached to the 2 '-carbon and the 3 ' -carbon can also vary.
  • s can be hydrogen.
  • R 5 can be halogen.
  • R 5 can be azido.
  • R 5 can be cyano.
  • R ' can be an optionally substituted Cj-g alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).
  • R 5 can be -OR' 0 , wherein R 10 can be hydrogen
  • R 5 can be -OR' 0 , wherein R 10 can be an optionally substituted C 1-6 alkyl.
  • R 6 can be hydrogen. In other embodiments, R° can be halogen. In still other embodiments, R° can be azido, in yet still other embodiments, R" can be cyano. In some embodiments, R 6 can be an optionally substituted Ci ⁇ alkyl. In other embodiments, R 6 can be -OR' 2 , wherein R 12 can be hydrogen.
  • R° can be -OR 12 , wherein R 12 can be an optionally substituted Ci-6 alkyl
  • R 1 *' can be an optionally substituted Ci-6 alkyl are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched).
  • suitable optionally substituted alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl pentyl (branched and straight-chained), and hexyl (branched and straight-chained).
  • suitable optionally substituted C3-6 cycloalkyls include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R' can be hydrogen. In other embodiments, R' can be halogen. In still other embodiments, R 7 can be azido. In yet still other embodiments, R ' ' can be cyano. In some embodiments, R 7 can be an optionally substituted Ci- ⁇ alkyl. In other embodiments, R 7 can be -OR 14 . In an embodiment, when R 1" is hydrogen, R ' can be a hydroxy group. In still other embodiments, when R 14 is an optionally substituted Ci-6 alkyl, R' can be an optionally substituted Cw alkoxy.
  • R ' ' being -OR 14 , wherein R 14 can be an optionally substituted Cj- alkyl
  • R 14 can be an optionally substituted Cj- alkyl
  • examples, of R ' ' being -OR 14 , wherein R 14 can be an optionally substituted Cj- alkyl include, but are not limited to, are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched).
  • R l ? is an optionally substituted C3-6 cycloalkyl.
  • suitable Ci-6 alkyl and C ..6 cycloalkyl groups are described herein.
  • R 6 and R' can both be hydroxy.
  • at least one of R' and R' can be a halogen.
  • R' and R 8 can both be a halogen.
  • R' can be a halogen and R 8 can be an optionally substituted C 1-6 aikyi, such as those described herein,
  • R' can be hydrogen and R 8 can be a halogen.
  • R° and R 7 can be a hydroxy and R 8 ca be an optionally substituted C t - alkyl
  • R° can be hydroxy
  • R' can be hydroxy, H or halogen
  • R 8 can be an optionally substituted C3.6 alkyl.
  • R 38 , R jb , R 4 , R 5 and R 9 can be hydrogen in any of the embodiments described in this paragraph.
  • B 1 can be a optionally substituted adenine, an optionally substituted guanine, and optionally substituted thymine, optionally substituted cytosine, or an optionally substituted uracil in any of the embodiments described in this paragraph,
  • R 9 can be hydrogen. In other embodiments, R can be azido. In still other embodiments, R 9 can be cyano. In yet still other embodiments, R 9 can be an optionally substituted C « alkyl, such as those described herein, in some embodiments, R 9 can be -QR i8 . In some embodiments, when R 9 is -OR 18 , R 9 can be a hydroxy group. In other embodiments, when R 9 is -OR 18 , R 9 can be an optionally substituted C ⁇ ..e alkoxy.
  • optionally substituted C3-6 alkoxy examples include the following: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), and hexoxy (branched and straight-chained).
  • amine and/or amino groups may be protected with a suitable protecting group.
  • an amino group may be protected by transforming the amine and/or amino group to an amide or a carbamate,
  • an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can have one of the following structures:
  • R B2 can be halogen or NHR* 2 , wherein R 3 ⁇ 4 i is selected from hydrogen, an optionally substituted d-6 a kyl, an optionally substituted C 2 .
  • the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the definition of "substituted.”
  • Suitable optionally substituted alkyl groups that can be present on an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups are described herein, and include, optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight- chained).
  • B 1 can be selected from adenine, guanine, thymine, cytosine and uracil.
  • R 2 can be ⁇ -L ⁇ . In other embodiments, can be
  • B 1 can be other embodiment
  • B can be in some embodiments.
  • B can be in some embodiments.
  • B 1 can be in still other embodiments, B can be
  • B 1 can be In some embodiments.
  • R " when R " is a substituted or unsubstituted
  • R" is a substituted or unsubstituted ph enyl and R' is
  • R 1 when R 1 is O " or OH, then R 2 cannot be .
  • at least one of and R jb cannot be hydrogen, in some embodiments, I is not azido.
  • R " when R " is not azido, then R ' ' and R 8 are not both halogen.
  • R 4 when R 4 is azido, then B 1 is not an optionally substituted uracil, optionally substituted uracil with one or more protected amino groups, an optionally substituted cytosine or optionally substituted cytosine with one or more protected amino groups.
  • R° cannot be azido.
  • R 1 is a methyl ester of glycine, alanine, valine, or phenylalanine;
  • R "1 is p-chlorophenyl or p-nitrophenyi;
  • B 1 is thymine;
  • R 3s , R jb , R 4 , R b , R 7 , R 8 , and R 9 are all hydrogen; then R 6 cannot be azido.
  • at least one of R 6 and R ? cannot be hydroxy.
  • R 6 cannot be hydroxy
  • R 7 cannot be hydroxy
  • both of R 6 and R 7 cannot be hydroxy.
  • B 1 can be an optionally substituted heterocyclic base as described above;
  • R 1 can be selected from O " , OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
  • R 2 can be
  • R 19 and R _1 can be independently absent or hydrogen, and n can be 0 or 1 ; provided that when Ii ! is
  • R R " 8 and R JD can be hydrogen;
  • R ' can be hydrogen;
  • R 3 can be selected from hydrogen, halogen, an optionally substituted C 1-6 aikyl and -OR " J ;
  • R 6 and R 7 can be both oxygen atoms and linked together by a carbonyl group
  • R 8 can be selected from hydrogen, halogen, an optionally substituted alkyl and -OR 16
  • R 9 can be hydrogen
  • R kl , R 12 , R 14 and R i6 can be independently selected from hydrogen and an optionally substituted ( * ; ..., alkyl; and ⁇ R li and R 13 can be independently selected from an optionally substituted Cu; alkyl and an optionally substituted C3-6 cycloalkyl.
  • Some embodiments disclosed herein relate to a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein: B' can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group
  • R 1 c n be selected from O " , OH, an optionally substituted N-linked amino acid and an optionally substituted -linked amino acid ester
  • ⁇ can be selected from an optionally substituted a yl and
  • R 59 , R 0 and R 21 can be independently absent or hydrogen, and n can be 0 or 1 ; provided
  • R can be hydrogen
  • R J can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl and -OR 10
  • R 6 and R can be both oxygen atoms and linked together by a carbonyl group
  • R' can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl and -OR 16
  • li 9 can be hydrogen
  • R 10 , R L; , R' 4 and R itJ can be independently selected from hydrogen and an optionally substituted Cj_,j alkyl
  • Formula (A) can be a compound of Formula (la), wherein: B 1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group selected from cytosine, uridine, thymidine, guanine and adenine; R 1 can be selected from O " , OH, and an optionally substituted N-iinked amino acid ester derivative of alanine, valine, or leucine; R "; can be selected from an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted pyridyl, an
  • R 19 , R 20 and R independently can be hydrogen or absent, and n can be 0 or 1 ; provided that when R 1 is O " or
  • R " can be an optionally substituted Cue alkyl; R can be hydrogen; R ' and R "* can be independently hydrogen or an optionally substituted (. * ; complicat,. alkyl; and R lj and R l 3 can be independently an optionall substituted Ci_e alkyl,
  • B 1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group
  • R 1 can be selected from O " , OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative
  • R 2 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and , wherein R i 9 , R 20 and R 21 can be independently absent or hydrogen.
  • n can be 0 or 1 ; provided that when R is O " or OH, then R" is R J
  • R can be independently selected from hydrogen, an optionally substituted Cw alkyl, an optionally substituted C2- aikenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C 1-6 haloalkyl and ar l( (.
  • R 4 can be selected from hydrogen, azido, an optionally substituted Ci_6 alkyi, an optionally substituted C 2- 6 aikenyl and an optionally substituted C 2- 6 alkynyl
  • R can be both oxygen atoms and linked together by a carbonyi group;
  • R 9 can be selected from hydrogen, azido, cyano, an optionally substituted Ci-6 alkyi and -OR 1 8 ;
  • R'°, R 12 , R 14 , R 16 and R 18 can be independently selected from hydrogen and an optionally substituted Ci_6 alkyl;
  • R 1 1 , R 13 , R s 5 and R 1 ' can be independently an optionally substituted C 0 alkyl and an optionally substituted C3.
  • cycloalkyl
  • a compound of Formula (A) can be a single diastereomer, In other embodiments, a compound of Formula (A) can be a mixture of diastereomers. In some embodiments, a compound of Formula (A ) can be a 1 : 1 mixture of two diastereomers. In some embodiments, a compound of Formula (A) can be diasteriometrically enriched (for example, one diastereomer can be present at a. concentration of > 55%, > 75%, > 80%, > 90%, > 95%, > 98%, or > 99% as compared to the total concentration of the other diastereomers),
  • Compounds of Formula (C) are therapeutic compounds that include HCV protease inhibitors, nucleoside HCV polymerase inhibitors, non-nucieoside HCV polymerase inhibitors, S5A inhibitors, and other antivirals, Examples of compounds of Formula (C) are provided in Figure 2.
  • a composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, can act as a chain terminator of HCV replication.
  • incorporation of compound of Formula (A) containing a moiety at the 2' -carbon position can terminate further elongation of the RNA chain of HCV.
  • a compound of Formula (A) can contain a 2' -carbon modification when 8
  • R of Formula (A) is a non-hydrogen group selected from halogen or an optionally substituted C h alky],
  • a composition containing a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof can have increased metabolic and/or plasma stability.
  • a composition containing a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds can have increased metabolic and/or plasma stability.
  • a non-limiting list of example properties include, but are not limited to, increased biological half life, increased bioavailability, increase potency, a sustained in vivo response, increased dosing intervals, decreased dosing amounts, decreased cytotoxicity, reduction in required amounts for treating disease conditions, reduction in viral load, reduction in time to seroreversion (i.e., the virus becomes undetectable in patient serum), increased sustained viral response, a reduction of morbidity or mortality in clinical outcomes, increased subject compliance, decreased liver conditions (such as liver fibrosis, liver cirrhosis and/or liver cancer), and compatibility with other medications.
  • a composition containing a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof can have a biological half life of greater than 24 hours, e.g., a biological half life in the range of about 40 to 46 hours for some compounds of Formula (A).
  • a composition containing a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof can have more potent antiviral activity (for example, a lower IC5 0 in an HCV replicon assay) as compared to the current standard of care.
  • a pharmaceutical composition can include a single diastereomer of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, (for example, a single diastereomer is present in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the other diastereomers).
  • a pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition can include a concentration of one diastereomer of > 50%, > 60%, > 70%, > 80% ⁇ , > 90%, > 95%, or > 98%», as compared to the total concentration of the other diastereomers.
  • a pharmaceutical composition includes a 1:1 mixture of two diastereomers of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • composition refers to a mixture of one or more compounds disclosed herein with one or more chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, niethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • physiologically acceptable defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent '" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered, by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human bl ood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • Combination therapies contemplated include use of a compound of Formula (A) selected from those listed in Figure 1 and a compound (e.g., an HCV protease inhibitor, nucleoside HCV polymerase inhibitor, non-nucleoside HCV polymerase inhibitor, NS5A inhibitor, or other antiviral) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1
  • a compound e.g., an HCV protease inhibitor, nucleoside HCV polymerase inhibitor, non-nucleoside HCV polymerase inhibitor, NS5A inhibitor, or other antiviral
  • combination therapies contemplated include use of a compound of Formula (A) selected from those listed in Figure 1 and a compound of Formula (C) selected from 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041 , 3042, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1 and a compound of Formula (C) selected from 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041 , 3042, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064,
  • combination therapies contemplated include use of a compound selected from Compound 1033 through Compound 1065 and a compound selected from 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041 , 3042, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061 , 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds,
  • Combination therapies also contemplated include use of a compound of Formula (A) selected from those listed in Figure 1 and two different compounds of Formula (C) (e.g., HCV protease inhibitors, nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, NS5A inhibitors, or other antivirals) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • Other combination therapies contemplated include use of a compound selected from Compound 1033 through Compound 1065 and two different compounds selected from Compund 3000 through Compound 3067.
  • Still other combination therapies contemplated include use of a compound of Formula (A) selected from those listed in Figure 1, a first compound of Formula (C) (e.g., HCV protease inhibitors, nucleoside HC V polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, NS A inhibitors, or other antivirals) selected from those listed in Figure 2 and a second compound of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are different.
  • a first compound of Formula (C) e.g., HCV protease inhibitors, nucleoside HC V polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, NS A inhibitors, or other antivirals
  • a second compound of Formula (C) selected from those listed in Figure 2
  • combination therapies contemplated include use of a compound selected from Compound 1033 through Compound 1065; a first compound selected from Compound 3000 through Compound 3067; and a second compound selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 is different from the second compound selected from Compound 3000 through Compound 3067.
  • the pharmaceutically active ingredients of the combination therapy can be contained in a single unit dosage form, in two unit dosage forms, or in three unit dosage forms.
  • a single unit dosage form can be provided containing a compound of Formula (A) selected from those listed in Figure 1 and a compound of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds
  • a single unit dosage form can be provided containing a compound of Formula (A) selected from those listed in Figure 1 and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds
  • two unit dosage forms can be provided, with one containing a compound of Formula (A) selected from those listed in Figure 1 and the other containing a compound of Formula (C) selected from those listed in Figure 2, or a pharma ceutically acceptable salt, hydrate, or solvate of the aforementioned compounds,
  • two unit dosage forms can be provided, with one containing a compound of Formula (A) selected from those listed in Figure 1 , and the other containing two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • two unit dosage forms can be provided, with one containing a compound of Formula (A) selected from those listed in Figure 1 and a first compound of Formula (C) selected from those listed in Figure 2, and the other containing a second compound of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first and second compound are not the same.
  • three unit dosage forms ca be provided, with one unit dosage form containing a compound of Formula (A) selected from those listed in Figure 1 and two additional unit dosage forms, each containing a different compound of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabieting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterfoils.
  • the liposomes can be targeted to and taken up selectively by the organ.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drags, or the approved product insert.
  • Compositions that can include one or more compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Some embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject an effective amount of a combination of compounds described herein.
  • such methods include administering an effective amount of a combination of a compound of Formula (A), and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • such methods include administering an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • such methods include administering an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • such methods include administering an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065 and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds
  • such methods include administering an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C) and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) is different from the second of Formula (C).
  • such methods include administering an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067 and a second compound selected from Compound 3000 through Compound 3067, or a phannaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 is different from the second compound selected from Compound 3000 through Compound 3067.
  • FIG. 1 Another embodiments disclosed herein relates to a method of ameliorating or treating a viral infection that can include administering an effecti ve amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the viral infection can be caused by a vims selected from an adenovirus, an Alphaviridae, an Arbovirus, an Astrovirus, a Bunyaviiidae, a Coronaviridae, a Fiioviridae, a Flaviviridae, a Hepadnaviridae, a Herpesviridae, an Alp aherpesvirinae, a Betaherpesvirinae, a Gammaherpesvirinae, a Norwalk Vims, an Astroviridae, a Caliciviridae, an Orthomyxoviridae, a Paramyxoviridae, a Paramyxoviruses, a Rubulavirus, a Morhilli virus, a Papovaviridae, a Parvoviridae, a Picornaviridae, an Aplithoviridae, a Cardioviridae, an Enteroviridae,
  • the viral infection can be a hepatitis C viral (HCV) infection.
  • HCV is an enveloped positive strand RNA virus in the Flaviviridae family.
  • NS5B is believed to be an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
  • Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection (for example, an HCV infection) that can include contacting a ceil infected with the virus with an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for ameliorating and/or treating a viral infection (for example, an HCV infection) that can include contacting a cell infected with the virus with an effective amount of said combination of compounds described herein.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for ameliorating and/or treating a viral infection (for example, an HCV infection) by contacting a cell infected with the virus with an effective amount of said combination of compounds described herein.
  • a viral infection for example, an HCV infection
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, In some embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, In other embodiments, including those of this paragraph, the combination can include an effecti ve amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051, 3052, 30
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same,
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • Some embodiments disclosed herein relate to methods of inhibiting replication of a virus (such as a hepatitis C virus) that can include contacting a cell infected with the vims with an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for inhibiting replication of a vims (such as a hepatitis C virus) that can include contacting a cell infected with the virus with an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for inhibiting replication of a virus (such as a hepatitis C virus) by contacting a ceil infected with the virus with an effective amount of said combination of compounds.
  • a virus such as a hepatitis C virus
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination ca include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a. pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combina tion can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061 , 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and two different compounds of Formula (Q selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination ca include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • Some embodiments described herein relate to a method of inhibiting an RNA dependent RNA polymerase can include contacting a cell (for example, a cell infected with HCV) with an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for inhibiting an RNA dependent RNA polymerase that can include contacting a ceil (for example, a cell infected with HCV) with an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for inhibiting an RNA dependent RNA polymerase that can include contacting a cell (for example, a cell infected with HCV) with an effective amount of said combination of compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, in some embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041 , 3042, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061 , 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, In other embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected irom Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include contacting a ceil (for example, a cell infected with HCV) with an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for inhibiting NS5B polymerase activity that can include contacting a cell (for example, a cell infected with HCV) with an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for inhibiting NS5B polymerase activity that can include contacting a cell (for example, a ceil infected with HCV) with an effective amount of said combination of compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041 , 3042, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforemen tioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Conipund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • Some embodiments described herein relate to a method of inhibiting an HCV polymerase (for example, NS5B polymerase) can include contacting a cell (for example, a ceil infected with HCV) with an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for inhibiting an HCV polymerase (for example, S5B polymerase) that can inciude contacting a cell (for example, a cell infected with HCV) with an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for inhibiting an HCV polymerase (for example, NS5B polymerase) that can include contacting a ceil (for example, a cell infected with HCV) with an effective amount of said combination of compounds.
  • an HCV polymerase for example, NS5B polymerase
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 Docough Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforemen tioned compounds, In some embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and two different compounds of Formula (C) selected from those listed in Figure 2.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • Some embodiments described herein relate to a method of ameliorating and/or treating HCV infection in a subject suffering from an HCV infection that can include administering to the subject an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combmation of compounds described herein in the manufacture of a medicament for ameliorating and/or treating HCV infection in a subject suffering from an HCV infection that can include administering to the subject an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for ameliorating and/or treating HCV infection in a subject suffering from an HCV infection that can include administering to the subject an effective amount of said combination of compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharma ceutically acceptable salt, hydra te, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1, and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Fonnula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same,
  • Some embodiments described herein relate to a method of ameliorating and/or treating a condition selected from liver fibrosis, liver cirrhosis, and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering an effective amount of a combination of compounds described herein,
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for ameliorating and/or treating a condition selected from liver fibrosis, liver cirrhosis, and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for ameliorating and/or treating a condition selected from liver fibrosis, liver cirrhosis, and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering an effective amount of said combination of compounds.
  • the one or more conditions selected from liver fibrosis, liver cirrhosis and liver cancer can be the result of an HCV infection.
  • the combination can include an effective amount of a combination of a compound of Fonnula (A) selected from those listed in Figure 1 , and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Fonnula (A) selected from those listed in Figure 1 , and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combination can include an effective amount of a.
  • a cause of liver fibrosis, liver cirrhosis, and/or liver cancer can be an HCV infection.
  • Some embodiments described herein relate to a method of increasing liver function in a subject having an HCV infection that can include administering to the subject an effective amount of a combination of compounds described herein.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for increasing liver function in a subject having an HCV infection that ca include administering to the subject an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that, can be used for increasing liver function in a subject having an HCV infection that can include administering to the subject, an effective amount of said combination of compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041 , 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1
  • the combination can include an effective amount of a combination of a compound of Formula ( A) selected from those listed in Figure 1 , and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, in other embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), and a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same.
  • the combinati on can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • Other embodiments described herein relate to using a combination of compounds described herein in the manufacture of a medicament for reducing or eliminating further virus-caused liver damage in a subject having an HCV infection by administering an effective amount of said combination of compounds.
  • Still other embodiments described herein relate to a combination of compounds described herein that can be used for reducing or eliminating further virus-caused liver damage in a subject having an HCV infection by administering an effective amount of said combination of compounds, in some embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforemen tioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and one or more compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and a compound selected from Compound 3015, 3016, 3025, 3026, 3027, 3028, 3037, 3038, 3039, 3040, 3041, 3042, 3048, 3049, 3050, 3051 , 3052, 3053, 3054, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065 and 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • a compound of Formula (A) selected from those listed in Figure 1
  • the combination can include an effective amount of a combination of a compound of Formula (A) selected from those listed in Figure 1 , and two different compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, and two different compounds selected from Compound 3000 through Compound 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds.
  • the combination can include an effective amount of a combination of a compound of Formula (A), a first compound of Formula (C), arid a second compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound of Formula (C) and the second compound of Formula (C) are not the same, in yet stil l other embodiments, including those of this paragraph, the combination can include an effective amount of a combination of a compound selected from Compound 1033 through Compound 1065, a first compound selected from Compound 3000 through Compound 3067, and a second compound selected from Compound 3000 through Compund 3067, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds, wherein the first compound selected from Compound 3000 through Compound 3067 and the second compound selected from Compound 3000 through Compound 3067 are not the same.
  • this method or use can include slowing or halting the progression of liver disease.
  • genotypes of HCV there are a variety of genotypes of HCV, and a variety of subtypes within each genotype. For example, at present it is known tha there are eleven (numbered 1 through 11) main genotypes of HCV, alth ough others have classifi ed the genotypes as 6 main genotypes. Each of these genotypes is further subdivided into subtypes (la-lc; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a- 7b; 8a-8b; 9a; 10a; and 11a).
  • a combination therapy as described herein can be effective to treat at least one genotype of HCV.
  • a combination therapy described herein e.g., a combination therapy including a compound of Formula (A) selected from those listed in Figure 1 and one or more compounds of Formula (C) selected from those listed in Figure 2, or a pharmaceutically acceptable salt, hydrate, or solvate of the aforementioned compounds
  • a combination therapy described herein e.g., a combination therapy including a compound of Formula (A) selected from those listed in Figure 1 and one or more compounds of Formula (C) listed in Figure 2 can be effective to treat 3 or more, 5 or more, 7 or more of 9 more genotypes of HCV.
  • a combination therapy described herein e.g., a combination therapy including a compound of Formula (A) selected from those listed in Figure 1 and one or more compounds of Formula (C) listed in Figure 2 is more effective against a larger number of HCV genotypes than the standard of care
  • a combination therapy described herein e.g., a combination therapy including a compound of Formula (A) from those listed in Figure 1 and one or more compounds of Formula (C) listed in Figure 2 is more effective against a particular HCV genotype than the standard of care (such as genotype 1, 2, 3, 4, 5 and/or 6).
  • Suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, a reduction in the rate of liver function decrease, stasis in liver function, improvement in liver function, reduction in one or more markers of liver dysfunction, including alanme transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase, and/or other indicator of disease response.
  • a combination therapy described herein e.g., a combination therapy including a compound of Formula (A) selected from those listed in Figure 1 and one or more compounds of Formula (C) listed in Figure 2, or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds
  • a combination therapy described herein can reduce the incidence of liver cancer in HCV patients.
  • an amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (Cj), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds is an amount that is effective to reduce viral titers to undetectable levels, to about 100 to about 500, to about 50 to about 100, to about 10 to about 50, or to about 15 to about 25 international units/mL serum.
  • an amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds is an amount that is effective to reduce viral load compared to the viral load before administration of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds.
  • the viral load is measured before administration of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, and again after completion of the treatment regime with a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds (for example, 1 month after completion).
  • an amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be an amount that is effective to reduce viral load to lower than about 100 genome copies/mL serum.
  • an a ount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds is an amount that is effective to achieve a reduction in viral titer in the serum of the subject in the range of about 1.5- log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5-log reduction compared to the viral load before administration of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds.
  • the viral load can be measured before administration of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, and again after completion of the treatment regime with a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds (for example, 1 month after completion).
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can result in at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of 1 1( V relative to pre-treatment levels in a subject, as determined after completion of the treatment regime (for example 1 month after completion).
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (Q), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can result in a reduction of the replication of HCV relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold.
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can result in a reduction of HCV replication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3,5 log or 3.5 to 4 log more reduction of HCV replication compared to the reduction of HCV replication achieved by pegyiated interferon in combination with ribavirin, administered according to the standard of care, or may achieve the same reduction as that standard of care therapy in a shorter period of time, for example, in one month, two months, or three months, as compared to the reduction achieved after six months of standard of care therapy with ribavirin and pegyiated interferon,
  • an amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the subject's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
  • non-detectable or substantially non-detectable HCV RNA e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum
  • an amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can reduce a level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated subject, or to a placebo-treated subject.
  • markers are known to those skilled in the art and include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • immunological-based methods e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • ELISA enzyme-linked immunosorbent assays
  • markers includes measuring the levels of serum alanine aminotransferase (ALT), asparatate aminotransferacse (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) using known methods.
  • ALT serum alanine aminotransferase
  • AST asparatate aminotransferacse
  • ALP alkaline phosphatase
  • GTT gamma-
  • an ALT level of less than about 45 IU/L (international units/liter), an AST in the range of 10-34 IU L, ALP in the range of 44-147 IU/L, GGT in the range of 0- 1 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal.
  • an effective amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula ( €)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds is an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to within what is considered a normal level.
  • Subjects who are clinically diagnosed with HCV infection include "naive" subjects (e.g., subjects not previously treated for HCV, particularly those who have not previously received I FN -alpha-based andVor ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" subjects).
  • Treatment failure subjects include "non-responders” (i.e., subjects in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HC V ( ⁇ 0.5 log lU/mL), for example, a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a.
  • previous pegylated IFN-alpha and ribavirin combination therapy i.e., subjects who were previously treated for HCV, for example, who received a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
  • a combination as described herein of a compound of Formula (A) arid one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered to a treatment failure subject suffering from HCV
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered to a non-responder subject suffering from HCV
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered to a relapsed subject suffering irom HCV.
  • infectious agents can develop resistance to one or more therapeutic compounds.
  • resistance refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic compound(s).
  • the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain.
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered to a subject infected with a HCV strain that is resistant to one or more different anti-HCV agents,
  • development of resistant HCV strains is delayed when patients are treated with a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, or a pharmaceutically acceptable salt thereof, compared to the development ofHCV strains resistant to other HCV drugs.
  • an effective amount of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered to a subject for whom other anti-HCV medications are contraindicated.
  • administration of pegylated interferon alpha in combination with ribavirin is contraindicated in subjects with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) and other subjects at risk from the hematologic side effects of current therapy.
  • hemoglobinopathies e.g., thalassemia major, sickle-cell anemia
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be provided to a subject that is hypersensitive to interferon or ribavirin.
  • viral load rebound refers to a sustained >0,5 log lU/niL increase of viral load above nadir before the end of treatment, where nadir is a >0.5 log lU/mL decrease from baseline.
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered to a subject experiencing viral load rebound, or can prevent such viral load rebound when used to treat the subject,
  • a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can decrease the number and/or severity of side effects that can be observed in HCV patients being treated with ribavirin and pegylated interferon according to the standard of care.
  • side effects include, but are not limited to fever, malaise, tachycardia, chills, headache, arthralgias, myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritability, confusion, depression, severe depression, suicidal ideation, anemia, low white blood cell counts, and thinning of hair, in some embodiments, a combmation as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (Q), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, can be provided to a subject that discontinued an HCV therapy because of one or more adverse effects or side effects associated with one or more other HCV agents.
  • Table A provides some embodiments of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, compared to the standard of care, Examples include the following: in some embodiments, a combination as described herein of a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, results in a percentage of non-responders that is 10% less than the percentage of non-responders receiving the standard of care; in some embodiments, a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, results in a number of side effects that is in the range of
  • a "subject” refers to an animal that is the object of treatment, observation or experiment
  • "Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans, In some embodiments, the subject is human.
  • the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy.
  • treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
  • an effective amount of compound is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated.
  • an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled, in the medical arts will recognize.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
  • the dosage may range broadly, depending upon the desired effects and the therapeutic indication, Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 nig and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject, in some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years, in some embodiments, a combination therap including a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutical iy acceptable salts, hydrates, or solvates of the aforementioned compounds, can be administered less frequently compared to the frequency of administration of an agent within the standard of care, in some embodiments, a combination therapy including a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 ( Formula (C)) can be administered one time per day.
  • a combination therapy including a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be administered one time per day to a subject suffering from an HCV infection.
  • the total time of the treatment regime with a combination therapy including a combination as described herein of a compound of Formula (A) and one or more compounds selected from those of Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be less compared to the total time of the treatment regime with the standard of care.
  • human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250%) of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • dosages may be calculated as the free base.
  • the compounds disclosed herein in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration ( EC).
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. in cases of local admmistration or selective uptake, the effective local concentration of the drag may not be related to plasma concentration.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and the route of admmistration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, ceil line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • combination therapies that can include an effective amount of a combination of compounds described herein (e.g., a combination as described herein of a compound of Formula (A) and one or more compounds selected from those listed in Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds), and one or more pharmaceutically acceptable carriers, diluents, excipients or combinations thereof.
  • a combination of compounds described herein e.g., a combination as described herein of a compound of Formula (A) and one or more compounds selected from those listed in Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds
  • pharmaceutically acceptable carriers diluents, excipients or combinations thereof.
  • Combination therapies contemplated include use of a compound of Formula (A) selected from those listed in Figure 1 and two different compounds (e.g., HCV protease inhibitors, nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, NS5A inhibitors, or other antivirals) selected from those listed in Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds.
  • two different compounds e.g., HCV protease inhibitors, nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors, NS5A inhibitors, or other antivirals
  • a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof can be administered prior to all compounds (such as those listed in Figure 2), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds.
  • a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof can be administered prior to at least one compound (such as those listed in Figure 2), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds.
  • a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof can be administered concomitantly with one or more compound(s) (such as those listed in Figure 2), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, in yet still other embodiments, a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, can be administered subsequent to the administration of at least one agents (such as those listed in Figure 2), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, in some embodiments, a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, can be administered subsequent to the administration of all other agents (such as those listed in Figure 2), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds.
  • the combination of a compound of Formula (A) with one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can result in an additive effect.
  • the combination of a compound of Formula (A), with one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can result in a synergistic effect.
  • the combination of a compound of Formula (A), with one or more compounds selected from Figure 2 (Formula (Cj), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can result in a strongly synergistic effect.
  • the combination of a compound of Formula (A), with one or more compounds selected from Figure 2 (Formula (C) ⁇ , or pharmaceutically acceptable salts, hydrates, or sol vates of the aforemen tioned compounds is not antagonistic ,
  • the term "antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e., as a single compound).
  • the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.
  • the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.
  • a potential advantage of utilizing a combination of a compound of Formula (A) with one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds may be a reduction in the required amount(s) of the compound(s) that is effective in treating a disease condition disclosed herein (for example, HCV), as compared to the amount required to achieve same therapeutic result when the compound(s) from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, is administered without a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • a disease condition disclosed herein for example, HCV
  • the amount of the agent from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds can be less compared to the amount of the compound from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, needed to achieve the same viral load reduction when administered as a monotherapy.
  • Another potential advantage of utilizing a compound of Formula (A), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, with one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds, is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.
  • Additional advantages of utilizing a combination as described herein of a combination of a compound Formula (A) with one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds may include little to no cross resistance between a combination of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and the one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds; different routes for elimination of a combination of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and the one or more compounds selected from Figure 2 (Formula (C)), or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compounds; little to no overlapping toxicities between a combination of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
  • Compound 1002 encompasses a mixture of diastereomers including Compound 1003 and Compound 1004, each of which are depicted below.
  • Each numbered compound in Tables B and C has a corresponding name and/or structure provided in Figures 1 and 2.
  • the numbered compounds in Tables B and C include pharmaceutically acceptable salts, hydrates, and solvates of the compounds and pharmaceutical compositions containing the compounds or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
  • 1033 includes the compound corresponding to 1033, pharmaceutically acceptable salts, hydrates, and solvates of the aforementioned compound, and pharmaceutical compositions that include compound 1033, or pharmaceutically acceptable salts, hydrates, or solvates of the aforementioned compound.
  • the combinations exemplified in Table B are designated by the Formula A:C, which represents a combination of a compound of Formula ( A) with a compound of Formula (C).
  • the combinations exemplified in Table C are designated by the Formula A:C:C, which represents a combination of a compound of Formula (A) with a first compound of Formula (C) with a second compound of Formula (C).
  • the combination designated as 1033:3001 :3002 in Table C represents a combmation of compound 1033 with compound 3001 and with compound 3002, including pharmaceutically acceptable salts, hydrates, and solvates of compound 1033, 3001, and/or 3002, and pharmaceutical compositions including compound 1033, 3001, and/or 3002 (including pharmaceutical compositions that include pharmaceutically acceptable salts, hydrates, and solvates of compound 1033, 3001 , and/or 3002),
  • pharmaceutical compositions including compound 1033, 3001, and/or 3002 including pharmaceutical compositions that include pharmaceutically acceptable salts, hydrates, and solvates of compound 1033, 3001 , and/or 3002
  • the combination of compounds can be used to treat, ameliorate and/or inhibit a virus and/or a viral infection, wherein the vims can be HCV and the viral infection can be an HCV viral infection.

Abstract

L'invention concerne des compositions pharmaceutiques qui peuvent comprendre un analogue thionucléotidique pour être utilisées dans une thérapie combinée à d'autres agents, l'invention concerne également des procédés de traitement de maladies et/ou de conditions avec une composition pharmaceutique qui peut comprendre un analogue thionucléotidique dans une thérapie en association avec d'autres agents.
PCT/US2013/030609 2012-03-21 2013-03-12 Combinaisons pharmaceutiques comprenant un analogue thionucléotidique WO2013142159A1 (fr)

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