Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
  • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
  • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
  • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate

Definitions

• the present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are nucleotide analogs, pharmaceutical compositions that include one or more nucleotide analogs and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a nucleotide analog, alone or in combination therapy with one or more other 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.
• Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active anti-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 compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• Some embodiments disclosed herein relate to a method of ameliorating and/or treating a hepatitis C viral (HCV) infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
• Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a HCV infection.
• Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a HCV infection.
• Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
• Other embodiments 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 ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• 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, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• Some embodiments disclosed herein relate to a method of inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
• Other embodiments 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 hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• 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, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for inhibiting replication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.
• a compound described herein or a pharmaceutically acceptable salt thereof for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof
• a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof
• Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.
• a compound described herein or a pharmaceutically acceptable salt thereof for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof
• a pharmaceutical composition that includes a compound described herein, in combination with an agent selected from an interferon, ribavirin
• Some embodiments disclosed herein relate to a method of inhibiting replication of a hepatitis C virus that can include administering to a subject identified as suffering from a HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, another antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.
• a compound described herein or a pharmaceutically acceptable salt thereof for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
• a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof
• the agent can be a compound, or a pharmaceutically acceptable salt thereof, selected from Compound 1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5012, 6001- 6078, 7000-7027 and 8000-8016, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or a pharmaceutically acceptable salt of the foregoing.
• the method can include administering a second agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.
• a second agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.
• Figure 1 shows example HCV protease inhibitors.
• Figure 2 shows example nucleoside HCV polymerase inhibitors.
• Figure 3 shows example non-nucleoside HCV polymerase inhibitors.
• Figure 4 shows example NS5A inhibitors.
• Figure 5 shows example other antivirals.
• Figure 6 shows example compounds of Formula (CC) and alpha- thiotriphosphates thereof, wherein Formula (CC) and alpha-thiotriphosphates thereof are described herein.
• Figure 7 shows example compounds of Formula (AA), wherein Formula (AA) is described herein.
• Figure 8 shows example compounds of Formula (BB), wherein Formula (BB) is described herein.
• Figure 9 shows example compounds of Formula (I), wherein Formula (I) is described herein.
• Figure 10 shows the gels from the assessment of incorporation of several compound with a uracil base by the human mitochondrial RNA polymerase.
• Figure 11 shows the gels from the assessment of incorporation of several compounds with a guanine base by the human mitochondrial RNA polymerase.
• Figures 12A-D shows the results of the inhibition of mitochondrial protein synthesis assays.
• any "R" group(s) such as, without limitation, R 1 , R 2 , R 3 , R 4 ,
• R 17 , R 18 , R A1 , R A2 , R A3 and R A4 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 cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R a and R b of an group are indicated to be "taken together,” it means that they are covalently 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, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl,
• C a to C b in which "a” and “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 cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to "b", inclusive, carbon atoms.
• a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 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, aryl, heteroaryl or heterocyclyl 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 "Ci-C 4 alkyl” or similar designations.
• C 1 -C 4 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-butyl, sec -butyl and t-butyl.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
• the alkyl group may be substituted or unsubstituted.
• 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 multi- 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, cycloheptyl 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 can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s).
• a cycloalkenyl group may be unsubstituted or substituted.
• aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic 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 C6-C14 aryl group, a C6-C1 0 aryl group, or a Ce aryl group.
• 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, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 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, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1 ,2,3-thiadiazole, 1 ,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine,
• heterocyclyl or “heteroalicyclyl” refers to 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 heterocycle 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 imides, cyclic thioimides 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 unsubstituted or substituted.
• heterocyclyl or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3- dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3- dithiolane, 1,4-oxathiane, tetrahydro- 1 ,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazoline, isox
• aralkyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group.
• the lower alkylene and aryl group of an aryl(alkyl) 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-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.
• a "(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
• the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl and (l,3-thiazinan-4-yl)methyl.
• Lower alkylene groups are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-(3 ⁇ 4-), ethylene (-CH 2 CH 2 -), 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 alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein.
• R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein.
• alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy.
• acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
• hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
• exemplary hydroxyalkyl groups include but are not limited to, 2 -hydroxy ethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2- dihydroxy ethyl.
• a hydroxyalkyl may be substituted or unsubstituted.
• haloalkyl 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, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -chloro-2-fluoromethyl and 2-fluoroisobutyl.
• a haloalkyl may be substituted or unsubstituted.
• haloalkoxy refers to an -O-alkyl 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, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1 -chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
• a haloalkoxy may be substituted or unsubstituted.
• a “sulfenyl” group refers to an "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• a sulfenyl may be substituted or unsubstituted.
• a “sulfonyl” group refers to an "SO 2 " group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
• R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl, as defined herein.
• An O-carboxy may be substituted or unsubstituted.
• An ester and C-carboxy may be substituted or unsubstituted.
• a thiocarbonyl may be substituted or unsubstituted.
• a "trihalomethanesulfonyl” group refers to an "X3CSO 2 -" group wherein each X is a halogen.
• a "trihalomethanesulfonamido” group refers to an "X 3 CS(0)2N(RA)-" group wherein each X is a halogen, and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• amino refers to a -NH 2 group.
• hydroxy refers to a -OH 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.
• S-sulfonamido refers to a "-S0 2 N(R A R B )" group in which R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• An S-sulfonamido may be substituted or unsubstituted.
• N-sulfonamido refers to a "RS02N(R A )-" group in which R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• An N-sulfonamido may be substituted or unsubstituted.
• An O-carbamyl may be substituted or unsubstituted.
• R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• An N-carbamyl may be substituted or unsubstituted.
• An O-thiocarbamyl may be substituted or unsubstituted.
• R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
• An N-thiocarbamyl may be substituted or unsubstituted.
• a C-amido may be substituted or unsubstituted.
• R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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.
• haloalkyl may include one or more of the same or different halogens.
• C 1 -C3 alkoxyphenyl 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 pyrimidine-base.
• examples include, but are not limited to, a ribonucleoside comprising a ribose moiety and a deoxyribonucleoside 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 heterocyclyl 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 triazole-base (for example, a 1,2,4-triazole).
• 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-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, uric acid and isoguanine.
• pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine).
• An example of an optionally substituted triazole-base is l,2,4-triazole-3-carboxamide.
• heterocyclic bases include diaminopurine, 8-oxo-N 6 -alkyladenine (e.g., 8-oxo-N 6 - methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N 4 ,N 4 -ethanocytosin, N 6 ,N 6 - ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos.
• a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).
• N-linked 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 is attached in an -N-linked amino acid, one of the hydrogens that is part of the main-chain amino or mono-substituted amino group is not present and the amino acid is attached via the nitrogen.
• 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 can be substituted
• -O-linked amino acid refers to an amino acid that is attached to the indicated moiety via the hydroxy from its main-chain carboxylic acid group.
• the amino acid is attached in an -O-linked amino acid, the hydrogen that is part of the hydroxy from its main-chain carboxylic acid group is not present and the amino acid is attached via the oxygen.
• O-linked amino acids can be substituted or unsubstituted.
• 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, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
• amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.
• phosphorothioate and phosphothioate refer to a compound of
• 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. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, 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; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g.
• methoxymethyl ether substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t- butyldimethylsilyl, tri-z ' so-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t- butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); 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 hemiacetal e.g., 1,3-dithiane or 1,3-dithiolane
• orthoesters e.g., those described herein
• triarylmethyl groups e.g., trityl; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4"-trimethoxytrityl (TMTr); and those described herein).
• 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-toluenesulfonic, 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, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, 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, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine
• 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-configuration 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.
• phosphorothioate include the following: and .
• all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine- bases.
• the 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 all 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.
• the compounds described herein exist in unsolvated 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 unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
• B 1 can be selected fr om an optionally substituted , an optionally
• R 1 can be selected from an optionally substituted Ci_6 alkyl, an optionally substituted C 2 -6 alkenyl, an optionally substituted C 2 -6 alkynyl and an optionally substituted C3-6 cycloalkyl; each can be absent or a single bond, provided that both
• R 2 can be halo, N 3 , -OR 7A or -N(R 7B R 7C ); R 4 can be absent; R 3 can be oxygen (O); and R p OH, an -O-optionally substituted Ci_6 alkyl.
• R p can be absent;
• R 2 can be halo, N 3 , -OR 7A or -N(R 7B R 7C );
• R 2 and R 3 can be each an oxygen atom which are linked together by a carbonyl
• R JD can be selected from O " , OH, an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, an -O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester
• R can be an optionally substituted Ci- 6 alkyl or an optionally substituted C3-6 cycloalkyl
• R &B and R 6C can be independently selected from hydrogen, an unsubstituted Ci_6 alkyl, an unsubstituted C3-6 alkenyl, an unsubstituted C3-6 alkynyl and an unsubstituted C3-6 cycloalkyl
• R can be NHR 6G
• R 6E can be hydrogen, halogen or NHR 6H
• R 6F can be NHR 61
• R 6H can be selected from hydrogen, an optionally substituted Ci_ 6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 cycl
• R and R'" can be independently hydrogen or an optionally substituted Ci_6 alkyl
• R 8 and R 12 can be independently an optionally substituted Ci_6 alkyl or an optionally substituted C3-6 cycloalkyl
• R 9 , R 10 and R 11 can be independently absent or hydrogen
• R 8A , R 9A , R 11A , R 12A , R 8B , R 9B , R 11B , R 12B , R p2 , R p3 , R p5 and R p6 can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl and an optionally substituted aryl
• R 14A , R 14B , R 15A , R 15B , R p8 and R p9 can be independently selected from hydrogen, an optionally substituted Ci-24 alkyl and an optionally substituted aryl; n can be 0 or 1 ; p, q, and r can be independently 1 or 2; s, t and u can be independently 3, 4 or 5; Z 1 , Z 1A , Z 1B and Z pl can be independently O (oxygen) or S (sulfur); and
• R 4 is and R 5A is O " or OH, then R 5B is O " , OH, , an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
• R 2 can be halo.
• R 2 can be fluoro or chloro.
• R 2 can be N3.
• R can be -OH.
• Suitable alkyl groups include, but are not limited to 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 cycloalkyl groups include, but are not limited to optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 2 can be -
• R and R' can be independently hydrogen or an optionally substituted Ci_ 6 alkyl.
• R and R can be both hydrogen, such that R can be -NH2.
• at least one of R 7B and R 7C can be an optionally substituted Ci_6 alkyl.
• R 7B and R 7C can be both an optionally substituted Ci_6 alkyl.
• R and R can be the same. In other embodiments, R and R can be different.
• R 3 can be -OH.
• R 1 can be an optionally substituted Ci_6 alkyl.
• R 1 can be an unsubstituted Ci_6 alkyl.
• R 1 can be unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted n- butyl, unsubstituted isobutyl, unsubstituted tert-butyl, unsubstituted pentyl (branched and straight-chained) or unsubstituted hexyl (branched and straight-chained).
• R 1 can be a substituted Ci_6 alkyl. Suitable substitutions are described herein. As an example, R 1 can be a halo-substituted Ci_6 alkyl (such as -CF 3 or -CH 2 CH 2 F). In other embodiments, R 1 can be an optionally substituted C2-6 alkenyl.
• Suitable alkenyl groups include, but are not limited to optionally substituted variants of the following: ethenyl, n-propenyl, isopropenyl, n- butenyl, isobutenyl, tert-butenyl, pentenyl (branched and straight-chained), hexenyl (branched and straight-chained), vinyl and allenyl.
• R 1 can be an optionally substituted C2-6 alkynyl.
• R 1 can be an optionally substituted C3-6 cycloalkyl, such as those described herein.
• Formula (I) can have the structure:
• R can be hydrogen. In other embodiments, R
• the compound of Formula (I) can be a monophosphate. In other embodiments, the compound of Formula (I) can be a thiomonophosphate. In some embodiments, the compound of Formula (I) can be a diphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiodiphosphate. In some embodiments, the compound of Formula (I) can be a triphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiotriphosphate. In some embodiments, R 4 can be
• R can be O " or OH. In other embodiments, R can be
• R 3A can be O " or OH
• R 3B can be ; and n can be 0.
• R can be R 3A can be O " or OH; can be and n can be 1.
• the substituents attached to the phosphorus can vary.
• a compound of Formula (I) can be a phosphoroamidate.
• a compound of Formula (I) can be a thiophosphoroamidate.
• a compound of Formula (I) can be a phosphorbisamidate.
• a compound of Formula (I) can be a thiophosphorbisamidate.
• R can be an optionally substituted N-linked amino acid. Various amino acids are suitable, including those described herein.
• R 5A can be an optionally substituted N-linked amino acid ester derivative.
• N-linked amino acid ester derivatives include, but are not limited to, 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.
• the N-linked amino acid ester derivative can be a C e alkyl ester derivative, for example, an isopropyl ester of alanine.
• the N-linked amino acid ester derivative can be a C3-6 cycloalkyl ester derivative, such as a cyclohexyl ester of alanine.
• R can have the structure wherein
• R can be selected from hydrogen, an optionally substituted Ci_6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci_6 alkyl) and an optionally substituted haloalkyl;
• R 14 can be selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C e haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted C 10 aryl and an optionally substituted aryl(Ci_6 alkyl);
• R 15 can be hydrogen or an optionally substituted Ci-4-alkyl; or R 14 and R 15 can be taken together to form an optionally substituted C3-6 cycloalkyl.
• R 14 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.
• R 14 can be an unsubstituted Ci_6-alkyl, such as those described herein.
• R 14 can be hydrogen.
• R 14 can be methyl.
• R 13 can be an optionally substituted Ci_6 alkyl.
• Ci-6-alkyls examples 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).
• R 13 can be methyl or isopropyl.
• R 13 can be ethyl or neopentyl.
• R can be an optionally substituted C3-6 cycloalkyl.
• optionally substituted C3-6 cycloalkyl examples include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 13 can be an optionally substituted cyclohexyl.
• R 13 can be an optionally substituted aryl, such as phenyl and naphthyl.
• R 13 can be an optionally substituted aryl(Ci_6 alkyl).
• R 13 can be an optionally substituted benzyl.
• R 13 can be an optionally substituted C e haloalkyl, for example, CF 3 .
• R 15 can be hydrogen. In other embodiments, R 15 can be an optionally substituted C 1-4 alkyl, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R 15 can be methyl. In some embodiments, R 14 and R 15 can be taken together to form an optionally substituted C3-6 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the carbon to which R 14 and R 15 are attached may be a chiral center.
• the carbon to which R 14 and R 15 are attached may be a (R)-chiral center. In other embodiments, the carbon to which R 14 and R 15 are attached may be a -chiral center.
• R can be an -O-optionally substituted aryl.
• R 5B can be an -O-optionally substituted phenyl. When the phenyl is substituted, the ring can be substituted 1, 2, 3 or more than 3 times. Suitable mono-substituted phenyl groups include, ortho-substituted phenyl, meta-substituted phenyl and para-substituted phenyl.
• R 5B can be an -O-unsubstituted aryl.
• R 5B can be an -O-optionally substituted naphthyl.
• R 5B can be an -O-optionally substituted heteroaryl.
• R 5B can be an -O-optionally substituted quinolinyl.
• R 5B can be an -O-optionally substituted heterocyclyl.
• R 5B is an optionally substituted N-linked amino acid, such as those described for R 5A .
• R 5B is an optionally substituted N- linked amino acid ester derivative, for example, those described herein.
• R 5B is an optionally substituted N-linked amino acid ester derivative, for example, those described herein.
• R can have the structure wherein R can be selected from hydrogen, an optionally substituted Ci-6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci_6 alkyl) and an optionally substituted haloalkyl; R 17 can be selected from hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted Ci_6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted C 10 aryl and an optionally substituted aryl(Ci_6 alkyl); and R 18 can be hydrogen or an optionally substituted Ci-4-alkyl; or R 17 and R 18 can be taken together to form an optionally substituted C3-6 cycloalkyl.
• R 17 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.
• R 17 can be an unsubstituted Ci_6-alkyl, such as those described herein.
• R 17 can be hydrogen.
• R 17 can be methyl.
• R 16 can be an optionally substituted Ci_6 alkyl.
• Ci-6-alkyls examples 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).
• R 16 can be methyl or isopropyl.
• R 16 can be ethyl or neopentyl.
• R 16 can be an optionally substituted C3-6 cycloalkyl.
• optionally substituted C3-6 cycloalkyl examples include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 16 can be an optionally substituted cyclohexyl.
• R 16 can be an optionally substituted aryl, such as phenyl and naphthyl.
• R 16 can be an optionally substituted aryl(Ci_6 alkyl).
• R 16 can be an optionally substituted benzyl.
• R 16 can be an optionally substituted Ci_6 haloalkyl, for example, CF 3 .
• R 18 can be hydrogen. In other embodiments, R 18 can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R 18 can be methyl. In some embodiments, R 17 and R 18 can be taken together to form an optionally substituted C3-6 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on
• the groups that are selected for R and R may be a chiral center.
• the carbon to which R 17 and R 18 are attached may be a (R)-chiral center.
• the carbon to which R 17 and R 18 are attached may be a (S)-chiral center.
• R can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R 5B can be an -O- optionally substituted aryl.
• R 5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R 5B can be an - O-optionally substituted heteroaryl.
• R 5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R 5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
• R can be .
• R 8A and R 9A can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl; and R 10A can be selected from hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted -0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O- heteroaryl and an optionally substituted -O-monocyclic heterocyclyl.
• R 8A and R 9A can be hydrogen.
• at least one of R 8A and R 9A can be an optionally substituted C 1-24 alkyl or an optionally substituted aryl.
• R 10A can be hydrogen. In other embodiments, R 10A can be an optionally substituted C 1-24 alkyl. In some embodiments, R 10A can be an unsubstituted C 1-4 alkyl. In still other embodiments, R 10A can be an optionally substituted aryl. In yet still other embodiments, R 10A can be -0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally ssuubbssttiittuutteedd --0O-monocyclic heterocyclyl. In some embodiments, R can be an unsubstituted O-C i_4 alkyl.
• R can be .
• R 8ts and R yt> can be independently selected from hydrogen, an optionally substituted Ci -24 alkyl and an optionally substituted aryl; and R 10B can be selected from hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted -0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O- heteroaryl and an optionally substituted -O-monocyclic heterocyclyl.
• R 8B and R 9B can be hydrogen.
• R 8B and R 9B can be an optionally substituted C 1-24 alkyl or an optionally substituted aryl.
• R 10B can be hydrogen.
• R 10B can be an optionally substituted Ci -24 alkyl.
• R 10B can be an unsubstituted C 1-4 alkyl.
• R 10B can be an optionally substituted aryl.
• R 10B can be -0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl.
• R 10B can be an unsubstituted -
• R 5A can be and R 5B can be
• R 5A can be , wherein R 11A and R 12A can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl; R 13A can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted -0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl; and Z 1A can be independently O (oxygen) or S (sulfur). In some embodiments, R and R can be hydrogen.
• R 11A and R 12A can be an optionally substituted C 1-24 alkyl or an optionally substituted aryl.
• R 13A can be an optionally substituted C 1-24 alkyl.
• R 13A can be an unsubstituted C 1-4 alkyl.
• R 13A can be an optionally substituted aryl.
• R 13A can be an optionally substituted - O-Ci-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl.
• R 13A can be an unsubstituted -O-C 1-4 alkyl.
• Z 1A can be O (oxygen). In other embodiments, Z 1A can be or S (sulfur).
• R 5B can be , wherein R 1 and R can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl; R 13B can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted -0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl; and Z 1B can be independently O (oxygen) or S (sulfur). In some embodiments, R 11B and R 12B can be hydrogen.
• R 11B and R 12B can be an optionally substituted C 1-24 alkyl or an optionally substituted aryl.
• R 13B can be an optionally substituted C 1-24 alkyl.
• R can be an unsubstituted C 1-4 alkyl.
• R can be an optionally substituted aryl.
• R 13B can be an optionally substituted— 0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl.
• R 13B can be an unsubstituted -O-C 1-4 alkyl.
• Z 1B can be O (oxygen).
• Z 1B can be or S (sulfur).
• R 5A can be and R 5B can be ) ⁇ Z 1 B ⁇ R 13B
• R 5A can be .
• R 14A can be hydrogen.
• R 14A can be an optionally substituted C 1-24 alkyl.
• R 14A can be an optionally substituted aryl.
• R 14A can be a Ci-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).
• p can be 1. In other embodiments, p can be 2.
• R 5B can be .
• R 14B can be hydrogen.
• R 14B can be an optionally substituted C 1-24 alkyl.
• R 14B can be an optionally substituted aryl.
• R 14B can be a Ci_6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).
• q can be 1. In other embodiments, q can be 2. In
• R 5A can be and R 5B can be
• R 5A can be .
• R 15A can be hydrogen.
• R 15A can be an optionally substituted C 1-24 alkyl.
• R 15A can be an optionally substituted aryl, for example, an optionally substituted phenyl.
• R 15A can be an optionally substituted Ci-6 alkyl.
• R 15A can be an unsubstituted Ci-6 alkyl.
• s can be 3.
• s can be 4.
• s can be 5.
• R Da can be .
• R 15B can be hydrogen.
• R 15B can be an optionally substituted C 1-24 alkyl.
• R 15B can be an optionally substituted aryl, for example, an optionally substituted phenyl.
• R 15B can be an optionally substituted Ci_6 alkyl.
• R 15B can be an unsubstituted Ci_6 alkyl.
• t can be 3.
• t can be 4.
• t can be and R 5B can be
• R 5A and/or R 5B can be isopropyloxycarbonyloxymethoxy (POC) group. In some embodiments, R 5A and/or R 5B can be pivaloyloxymethoxy (POM) group. In some embodiments, R 5A and R 5B can be both a isopropyloxycarbonyloxymethoxy (POC) group, and form a bis(isopropyloxycarbonyloxymethoxy) (bis(POC)) prodrug.
• POC isopropyloxycarbonyloxymethoxy
• POM pivaloyloxymethoxy
• R 5A and R 5B can be both a isopropyloxycarbonyloxymethoxy (POC) group, and form a bis(isopropyloxycarbonyloxymethoxy) (bis(POC)) prodrug.
• R 5A and R 5B can be both a pivaloyloxymethoxy (POM) group, and form a bis(pivaloyloxymethoxy) (bis(POM)) prodrug.
• R 5A and R 5B can be both a S-acylthioethyl (SATE)-O- group and form a SATE ester prodrug.
• R 5A and R 5B can be the same. In other embodiments, R 5A and R 5B can be different.
• R 3 can be oxygen (O); and R p can be R 1 1 V ⁇ , wherein Z p can be oxygen (O) or sulfur l can be selected from O " , OH, an -O-optionally substituted Ci-6 alkyl. , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative.
• Formula (I) can have the structure:
• R pl can be O " .
• R pl can be OH.
• R pl can be an -O-optionally substituted C e alkyl.
• R pl can be a substituted or an unsubstituted version of the following: methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched or straight chained) and hexoxy (branched or straight chained).
• R p can R p and R p can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl; and R p4 can be selected from hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted— 0-C 1-24 alkyl, an optionally substituted - O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl.
• R p2 and R p3 can be hydrogen.
• R p2 and R p3 can be an optionally substituted C 1-24 alkyl or an optionally substituted aryl.
• R p4 can be an optionally substituted C 1-24 alkyl.
• R p4 can be an unsubstituted C 1-4 alkyl.
• R p4 can be an optionally substituted aryl.
• R p4 can be an optionally substituted— O-Ci-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl.
• R p4 can be an unsubstituted— 0-C 1-4 alkyl.
• R p can be wherein R p5 and
• R p can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl
• R p? can be independently selected from hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted— 0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl
• Z pl can be independently O (oxygen) or S (sulfur).
• R p5 and R p6 can be hydrogen.
• R p5 and R p6 can be an optionally substituted C 1-24 alkyl or an optionally substituted aryl.
• R p? can be an optionally substituted C 1-24 alkyl. .
• R p? can be an unsubstituted C 1-4 alkyl.
• R p? can be an optionally substituted aryl.
• R p? can be an optionally substituted— 0-C 1-24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O- monocyclic heterocyclyl.
• Z pl can be O (oxygen). In other embodiments, Z pl can be or S (sulfur). In some embodiments, R pl can be isopropyloxycarbonyloxymethyloxy (POC) group. In some embodiments, R pl can be pivaloyloxymethyloxy (POM) group. [0118] In some embodiments, R pl can be In some embodiments, R p can be hydrogen. In other embodiments, R p can be an optionally substituted Ci-24 alkyl. In still other embodiments, R p8 can be an optionally substituted aryl.
• R p8 can be a Ci_6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight- chained).
• r can be 1. In other embodiments, r can be 2.
• R p can be In some embodiments, R p can be hydrogen. In other embodiments, R p can be an optionally substituted Ci-24 alkyl. In still other embodiments, R p9 can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R p9 can be an optionally substituted Ci-6 alkyl. In some embodiments, R p9 can be an unsubstituted Ci_6 alkyl. In some embodiments, u can be 3. In other embodiments, u can be 4. In still other embodiments, u can be 5. In some embodiments, R pl can be a S-acylthioethyl (SATE) group and form a SATE ester prodrug.
• SATE S-acylthioethyl
• R pl can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
• R pl can be optionally substituted version of the following: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof.
• R pl can be selected from N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester and N-leucine isopropyl ester.
• R pl can have the structure wherein R pl ° can be selected from hydrogen, an optionally substituted Ci_6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci_6 alkyl) and an optionally substituted haloalkyl; R pl 1 can be selected from hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted Ci_6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted C1 0 aryl and an optionally substituted aryl(Ci_6 alkyl); and R pl2 can be hydrogen or an optionally substituted Ci-4-alkyl; or R pl 1 and R pl2 can be taken together to form an optionally substituted C3-6 cycloalkyl.
• R pl 1 When R pl 1 is substituted, R pU 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.
• R pl 1 can be an unsubstituted Ci-6-alkyl, such as those described herein.
• R pl 1 can be hydrogen.
• R pl 1 can be methyl.
• R pl ° can be an optionally substituted Ci_6 alkyl.
• Ci-6-alkyls examples 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).
• R pl ° can be methyl or isopropyl.
• R pl ° can be ethyl or neopentyl.
• R pl ° can be an optionally substituted C3-6 cycloalkyl.
• optionally substituted C3-6 cycloalkyl examples include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• R pl ° can be an optionally substituted cyclohexyl.
• R pl ° can be an optionally substituted aryl, such as phenyl and naphthyl.
• R pl ° can be an optionally substituted aryl(Ci_6 alkyl).
• R pl ° can be an optionally substituted benzyl.
• R pl ° can be an optionally substituted Ci_6 haloalkyl, for example, CF 3 .
• R pl2 can be hydrogen.
• R pl2 can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
• R pl2 can be methyl.
• R pl 1 and R pl2 can be taken together to form an optionally substituted C3-6 cycloalkyl.
• optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• the carbon to which R pl 1 and R pl2 are attached may be a chiral center.
• the carbon to which R pl 1 and R pl2 are attached may be a (R)-chiral center.
• the carbon to which R pU and R pl2 are attached may be a (5)-chiral center.
• the nucleobase can vary.
• B 1 can be uracil. In some embodiments,
• B 1 can be an optionally substituted . In some embodiments, B 1 can be
• B 1 can be an optionally substituted
• R 6A can be an optionally substituted Ci_6 alkyl.
• R 6A can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained).
• R can be an optionally substituted C3-6 cycloalkyl, for example, optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• B 1 can be guanine. In some embodiments, B 1 can be
• B 1 can be an optionally substituted .
• R 6B can be selected from hydrogen, an unsubstituted
• Ci-6 alkyl an unsubstituted C3-6 alkenyl, an unsubstituted C3-6 alkynyl and an unsubstituted C3-6
• R 6B can be an unsubstituted Ci_6 alkyl.
• R ot> can be methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained).
• R 6B can be an unsubstituted C3-6 alkenyl.
• R 6B can be an unsubstituted C3-6 alkynyl.
• R 6B can be an unsubstituted C3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• B 1 can be an optionally substituted
• B can be unsubstituted In some embodiments,
• R can be hydrogen.
• R can be an unsubstituted Ci_6 alkyl.
• R 6C can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained).
• R 6C can be an ethyl.
• R 6C can be an unsubstituted C3-6 alkenyl.
• R 6C can be an unsubstituted C3-6 alkynyl.
• R 6C can be hydrogen.
• R can be an unsubstituted Ci_6 alkyl.
• R 6C can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or
• C3-6 cycloalkyl for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• B 1 can be
• X 1 can be N (nitrogen) or -CR 6J ;
• R 6J can be selected from hydrogen, halogen, an optionally substituted Ci_6 alkyl, an optionally substituted C 2 -6 alkenyl and an optionally substituted C 2 -6 alkynyl;
• R 6D can be NHR 6G ;
• R 6E can be hydrogen, halogen or NHR 6H ;
• X can be N (nitrogen). In other embodiments, X can be - CR 61 , wherein CR 61 can be selected from hydrogen, halogen, an optionally substituted C e alkyl, an optionally substituted C 2 -6 alkenyl and an optionally substituted C 2 -6 alkynyl. In some embodiments, X 1 can be CH. In some embodiments, R 6D and R 6E can be both NH2. In other embodiments, at least one of R 6D and R 6E can be H 2 . In some embodiments, R 6D can be NHR 6G , wherein R 6G can be an optionally substituted Ci_6 alkyl. In some embodiments, R 6E can be hydrogen.
• R 6E can be halogen.
• R 6E can be NHR 6H , wherein R 6H can be an optionally substituted C e alkyl.
• R 6E can be NHR 6H , wherein
• R 6D and R 6E can be the same. In other embodiments, R 6D and R 6E can be different.
• B 1 can be cytosine. In some embodiments, B 1 can be
• R can be NHR ;
• R A5 and R A6 are independently selected from the group consisting of Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C6-10 aryl, heteroaryl, heterocyclyl, aryl(Ci_6 alkyl), heteroaryl(Ci_6 alkyl) and heterocyclyl(Ci_6 alkyl).
• R A5 and R A6 can also be C3-6 cycloalkyl, C3-6 cycloalkenyl, C6-10 aryl or heteroaryl, heterocyclyl. Additionally, R A5 and R A6 can be aryl(Ci_6 alkyl), heteroaryl(Ci_6 alkyl) or heterocyclyl(Ci_6 alkyl).
• Z 1 can be O (oxygen). In other embodiments, Z 1 can be S (sulfur).
• R 2 is not halo. In some embodiments, R 2 is not fluoro. In some embodiments, R 5B is not an -O-optionally substituted aryl. In some embodiments, R 5B is not an -O-unsubstituted aryl. In some embodiments, R 5A is not N-alanine isopropyl ester. In some embodiments, R 1 is not an optionally substituted Ci_6 alkyl. For example, R 1 is not an unsubstituted Ci_6 alkyl, such as methyl. In some embodiments, B 1 is not an optionally substituted uracil, for example, a halo-substituted uracil. In some embodiment, when both
• R 4 cannot be selected from H and wherein R 5B is an -O-unsubstituted aryl; R is and Z 1 is oxygen.
• R 2 is not halo (such as fluoro) when B 1 is uracil.
• a compound of Formula (I) is not a compound in WO 2013/092481 (filed December 17, 2012).
• Example structures of a compound of Formula (I) include the following:
• R 3 can be OH. In some embodiments of this paragraph,
• R pl can be -O-unsubstituted Ci_6 alkyl.
• R 4 can be H.
• R 4 can be a phosphoroamidate group.
• R 4 can be a phosphate group (such as a mono-, di- or tri-phosphate).
• R 4 can be a thiophosphoroamidate group.
• R 4 can be thiophosphate group (such as an alpha-thiomono-, alpha-thiodi- or alpha-thiotri-phosphate).
• R pl can be -O-ethyl, -O-isopropyl or -O-isobutyl.
• Examples of compounds of Formula (I) include the following:
• Examples of compounds of Formula (I) include the following:
• R 4 being R 5A ;
• R 5A being an optionally substituted N- linked amino acid or an optionally substituted N-linked amino acid ester derivative; and
• R 5B being an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, an -O- optionally substituted heterocyclyl, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.
• the groups attached to the phosphorus can be removed by simple hydrolysis. Inside the cell, the phosphate thus released may then be metabolized by cellular enzymes to the diphosphate or the active triphosphate. Likewise, the thio-phosphate may be metabolized to the alpha-thiodiphosphate or the alpha-thiotriphosphate. Furthermore, in some embodiments, varying the substituents on a compound described herein, such as compound of Formula (I), can help maintain the efficacy of such the compound by reducing undesirable effects, such as isomerization.
• the phosphorylation of a thio-monophosphate of a compound of Formula (I), or pharmaceutically acceptable salt thereof can be stereoselective.
• a thio-monophosphate of a compound of Formula (I) can be phosphorylated to give an alpha-thiodiphosphate and/or an alpha-thiotriphosphate compound that can be enriched in the (R) or (S) diastereomer with respect to the 5 '-0-phosphorous atom.
• one of the (R) and (5) configuration with respect to the 5 '-0-phosphorous atom of the alpha- thiodiphosphate and/or the alpha-thiotriphosphate compound can be present in an amount > 50%, > 75%, > 90%, > 95% or > 99% compared to the amount of the other of the (R) or (S) configuration with respect to the 5'-0-phosphorous atom.
• phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof can result in the formation of a compound that has the (R)-configuration at the 5'-0-phosphorous atom.
• phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof can result in formation of a compound that has the (5)- configuration at the 5'-0-phosphorous atom.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can act as a chain terminator of HCV replication.
• compounds of Formula (I) can contain a moiety at the 2 '-carbon position such that once the compound is incorporated into an RNA chain of HCV no further elongation is observed to occur.
• a compound of Formula (I) can contain a 2 '-carbon modification wherein R 1 is a non-hydrogen group selected from an optionally substituted Ci_6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C3-6 cycloalkyl.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have increased metabolic and/or plasma stability.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be more resistant to hydrolysis and/or more resistant to enzymatic transformations.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have increased metabolic stability, increased plasma stability, can be more resistant to hydrolysis and/or can be more resistant to enzymatic transformations compared to a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4' -position.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have improved properties.
• 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 seroconversion (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 compound of Formula (I), or a pharmaceutically acceptable salt thereof can have a biological half-life of greater than 24 hours.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have a biological half-life greater than a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4' -position.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have more potent antiviral activity (for example, a lower EC5 0 in an HCV replicon assay) as compared to the current standard of care.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof does not significantly inhibit mitochondrial function of the mitochondrial RNA polymerase.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof is incorporated in the human mitochondrial RNA polymerase less than 10% compared to the natural 5 '-triphosphate nucleotide with the same B 1 .
• the presence of a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate in a compound of Formula (I) can increase the stability of the compound by inhibiting its degradation. Also, in some embodiments, the presence of a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can make the compound more resistant to cleavage in vivo and provide sustained, extended efficacy.
• a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can facilitate the penetration of the cell membrane by a compound of Formula (I) by making the compound more lipophilic.
• a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can have improved oral bioavailability, improved aqueous stability and/or reduced risk of byproduct-related toxicity.
• a compound of Formula (I) can be compared to a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4'- position.
• Compounds of Formula (I) can be prepared using various methods known to those skilled in the art. Examples of methods are shown in Schemes 1 and 2. Suitable phosphorus containing precursors can be commercially obtained or prepared by synthetic methods known to those skilled in the art. Examples of general structures of phosphorus containing precursors are shown in Schemes 1 and 2, and include phosphorochloridates and thiophosphorochloridates. Suitable phosphorochloridates and thiophosphorochloridates are commercially available and/or can be synthetically prepared.
• a compound of Formula (I) can be generated from a compound of Formula (A) and a compound of Formula (B) or a compound of Formula (A) and a compound of Formula (C) using an organometallic reagent, such as a Grignard reagent.
• organometallic reagent such as a Grignard reagent.
• Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnesium bromides.
• an appropriate base can be used to form a compound of Formula (I).
• suitable bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole)).
• the sulfur can be added in various manners.
• the sulfur can be part of the phosphorus containing
• R 5B_p Qi precursor for example, R 5A .
• one of the oxygens attached to the phosphorus can be exchanged with a sulfur using a sulfurization reagent.
• Suitable sulfurization agents are known to those skilled in the art, and include, but are not limited to, elemental sulfur, Lawesson's reagent, cyclooctasulfur, 3H-l,2-Benzodithiole-3-one-l, l-dioxide (Beaucage's reagent), 3-((N,N-dimethylaminomethylidene)amino)-3H-l,2,4-dithiazole-5-thione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).
• a phosphorus containing precursor can be coupled to the nucleoside, for example, a compound of Formula (A).
• any leaving groups can be cleaved under suitable conditions, such as hydrolysis.
• R la , R 2a , R 3a and B la can be the same as R 1 , R 2 , R 3 and B 1 as described herein for Formula (I).
• Further phosphorus containing groups can be added using methods known to those skilled in the art, for example using a pyrophosphate.
• one or more bases can be used during the addition of each phosphorus-containing group. Examples of suitable bases are described herein.
• R 2 and R 3 can be each an oxygen atom, wherein the oxygen atoms are linked together by a carbonyl groups.
• a compound of Formula (I), wherein R 2 and R 3 are both hydroxy groups can be treated with 1,1'- carbonyldiimidazole (CDI).
• a compound of Formula (I), wherein R 2 and R 3 are both hydroxy groups can be treated with an alkyl anhydride (e.g., acetic anhydride and propionic anhydride) or an alkyl acid chloride (e.g., acetylchloride).
• a catalyst can be used to facilitate the reaction.
• Suitable catalyst is 4- dimethylaminopyridine (DMAP).
• DMAP 4- dimethylaminopyridine
• alkyl acid e.g. acetic acid and propionic acid
• carbodiimides include, but are not limited to, ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).
• one or more the groups attached to the pentose ring can be protected with one or more suitable protecting groups.
• suitable protecting groups such as triarylmethyl and/or silyl groups.
• triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr),.
• Suitable silyl groups include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-zso-propylsilyloxymethyl and [2- (trimethylsilyl)ethoxy]methyl.
• R 2 and/or R 3 can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclic ketal.
• Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2- oxacyclopentylidene orthoester, dimethoxymethylene orthoester, 1 -methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester 1,2- dimethoxyethylidene orthoester, and alpha-methoxybenzylidene orthoester;
• suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3- (benzyloxy)propyl acetal, benzylidene acetal, 3,4-dimethoxybenzylidene acetal and p- acetoxybenzylidene acetal; and suitable cyclic ketals include 1-t-butylethylidene ketal, 1- phen
• a pharmaceutical composition that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
• the pharmaceutical composition can include a single diastereomer of a compound of Formula (I), or a pharmaceutically acceptable salt 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).
• the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), 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.
• the pharmaceutical composition includes a 1 : 1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• composition refers to a mixture of one or more compounds disclosed herein with other 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, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
• Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
• a pharmaceutical composition is suitable for human and/or veterinary applications.
• 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 blood.
• 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.
• 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 tableting 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 counterions.
• 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 drugs, or the approved product insert.
• Compositions that can include a compound 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 one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof.
• Other embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject identified as suffering from the disease or condition an effective amount of one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof.
• Some embodiments disclosed herein relates to a method of ameliorating or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein (for example, a compound of Formula (I)), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
• Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein.
• Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a HCV infection by administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein.
• Some embodiments disclosed herein relate to methods of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
• Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• Some embodiments disclosed herein relate to methods of inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
• Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for inhibiting replication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
• the compound can be a compound of Formula (I), or a pharmaceutical acceptable salt thereof, wherein R 4 is hydrogen.
• the compound can be a compound of Formula (I), wherein compound of Formula (I) is a mono, di, or triphosphate, or a pharmaceutically acceptable salt of the foregoing.
• the compound can be a compound of Formula (I), wherein compound of Formula (I) is a thiomonophosphate, alpha-thiodiphosphate, or alpha-thiotriphosphate, or a pharmaceutically acceptable salt of the foregoing.
• the compound can be a compound of Formula (I), wherein compound of Formula (I) is phosphoroamidate or phosphorbisamidate, or a pharmaceutically acceptable salt of the foregoing.
• the compound can be a compound of Formula (I), wherein compound of Formula (I) is thiophosphoroamidate or thiophosphorbisamidate, or a pharmaceutically acceptable salt of the foregoing.
• the compound of Formula (I), or a pharmaceutical acceptable salt thereof, that can be used to ameliorating and/or treating a viral infection (for example, a HCV infection) and/or inhibit replication of a virus (such as a HCV virus) can be any of the embodiments provided in any of the embodiments described in paragraphs [0090]-[0138].
• 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 described herein relate to a method of inhibiting NS5B polymerase activity that can include contacting a cell infected with hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof. Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include administering to a subject infected with hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit a RNA dependent RNA polymerase, and thus, inhibit the replication of HCV RNA. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit a HCV polymerase (for example, NS5B polymerase).
• Some embodiments described herein relate to a method of 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 to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof), wherein the liver condition is caused by a HCV infection.
• Some embodiments described herein relate to a method of increasing liver function in a subject having a HCV infection that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof).
• this method can include slowing or halting the progression of liver disease.
• the course of the disease can be reversed, and stasis or improvement in liver function is contemplated.
• liver fibrosis, liver cirrhosis and/or liver cancer can be treated; liver function can be increased; virus-caused liver damage can be reduced or eliminated; progression of liver disease can be slowed or halted; the course of the liver disease can be reversed and/or liver function can be improved or maintained by contacting a cell infected with hepatitis C virus with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.)
• a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• 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 that there are eleven (numbered 1 through 1 1) main genotypes of HCV, although others have classified 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 1 la).
• an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof can be effective to treat at least one genotype of HCV.
• a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
• a compound described herein for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof
• a compound of Formula (I), or a pharmaceutical acceptable salt thereof can be more effective against a larger number of HCV genotypes than the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable salt thereof, can be 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 alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase and/or other indicator of disease response.
• successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can reduce the incidence of liver cancer in HCV infected subjects.
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is an amount that is effective to reduce HCV viral titers to undetectable levels, for example, 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 effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is an amount that is effective to reduce HCV viral load compared to the HCV viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be an amount that is effective to reduce HCV viral load to lower than about 25 international units/mL serum.
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is an amount that is effective to achieve a reduction in HCV 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 the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the HCV viral load can be measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion).
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof 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 the hepatitis C virus relative to pre-treatment levels in a subject, as determined after completion of the treatment regime (for example, 1 month after completion).
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in a reduction of the replication of the hepatitis C virus 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 compound of Formula (I), or a pharmaceutically acceptable salt thereof can result in a reduction of the hepatitis C virus 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 the hepatitis C virus replication compared to the reduction of the hepatitis C virus reduction achieved by pegylated 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 pegylated interferon.
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof 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 200, less than about 100, less than about 25, or less than about 15 international units 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.
• HCV RNA e.g., less than about 500, less than about 200, less than about 100, less than about 25, or less than about 15 international units per milliliter serum
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof 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
• a non- limiting list of examples of markers includes measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) using known methods.
• ALT serum alanine aminotransferase
• AST aspartate aminotransferase
• ALP alkaline phosphatase
• 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 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal.
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with 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 IFN-alpha-based and/or 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 HCV ( ⁇ 0.5 log IU/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); and "relapsers” (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).
• non-responders i.e., subjects in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV ( ⁇ 0.5 log IU/mL), for example, a previous IFN
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered to a treatment failure subject suffering from HCV.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered to a non-responder subject suffering from HCV.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered to a relapsed subject suffering from HCV.
• infectious agents can develop resistance to one or more therapeutic agents.
• resistance refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(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 compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered to a subject infected with an HCV strain that is resistant to one or more different anti-HCV agents (for example, an agent used in a conventional standard of care).
• development of resistant HCV strains is delayed when a subject is treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of HCV strains resistant to other HCV drugs (such as an agent used in a conventional standard of care).
• an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof 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.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be provided to a subject that is hypersensitive to interferon and/or ribavirin.
• viral load rebound refers to a sustained >0.5 log IU/mL increase of viral load above nadir before the end of treatment, where nadir is a >0.5 log IU/mL decrease from baseline.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered to a subject experiencing viral load rebound, or can prevent such viral load rebound when used to treat the subject.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof 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.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be provided to a subject that discontinued a HCV therapy because of one or more adverse effects or side effects associated with one or more other HCV agents (for example, an agent used in a conventional standard of care).
• Table 1 provides some embodiments of the percentage improvement obtained using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to the standard of care. Examples include the following: in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving the standard of care; and in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving the standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art. Table 1
• 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.
• treating 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. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
• 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 mg 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.
• the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered less frequently compared to the frequency of administration of an agent within the standard of care.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered one time per day.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered one time per day to a subject suffering from a HCV infection.
• the total time of the treatment regime with a compound of Formula (I), or a pharmaceutically acceptable salt thereof can 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 ED5 0 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 (MEC).
• MEC minimal effective concentration
• 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 administration or selective uptake, the effective local concentration of the drug 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 to the route of administration. 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, cell 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.
• the compounds disclosed herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, can be used in combination with one or more additional agent(s).
• Examples of additional agents that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof include, but are not limited to, agents currently used in a conventional standard of care for treating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of Formula (AA), (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (AA), or a pharmaceutically acceptable salt thereof), compounds of Formula (BB) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (BB), or a pharmaceutically acceptable salt thereof), compounds of Formula (CC) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (CC), or a pharmaceutically acceptable salt thereof), and/or combinations thereof.
• agents currently used in a conventional standard of care for treating HCV include, HCV protease inhibitors, HCV polymerase inhibitor
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used with one, two, three or more additional agents described herein.
• a non-limiting list of examples of combinations of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in Tables A, B, C, D and E.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with an agent(s) currently used in a conventional standard of care therapy.
• a compound disclosed herein can be used in combination with Pegylated interferon-alpha- 2a (brand name PEGASYS®) and ribavirin, Pegylated interferon-alpha-2b (brand name PEG- INTRON®) and ribavirin, Pegylated interferon-alpha-2a, Pegylated interferon-alpha-2b, or ribavirin.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be substituted for an agent currently used in a conventional standard of care therapy.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in place of ribavirin.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with an interferon, such as a pegylated interferon.
• an interferon such as a pegylated interferon.
• suitable interferons include, but are not limited to, Pegylated interferon-alpha-2a (brand name PEGASYS®), Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferon alfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or a combination thereof.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with a HCV protease inhibitor.
• HCV protease inhibitors include the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS- 650032, SCH 503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH- 2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof.
• HCV protease inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof include VP-19744, PSI- 879, VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479, R-1626, R-7182, MK-0608, ⁇ -8014, ⁇ -8018, A-848837, A-837093, BILB-1941, VCH-916, VCH- 716, GSK-71 185, GSK-625433, XTL-2125 and those disclosed in PCT Publication No.
• HCV protease inhibitors include the compounds numbered 1001-1016 in Figure 1.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with a HCV polymerase inhibitor.
• the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor.
• nucleoside inhibitors examples include, but are not limited to, RG7128, PSI-7851, PSI-7977, ⁇ -189, PSI-352938, PSI-661, 4'-azidouridine (including known prodrugs of 4'-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinations thereof.
• a non-limiting list of example nucleoside inhibitors includes compounds numbered 2001-2012 in Figure 2.
• non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof.
• a non-limiting list of example non-nucleoside inhibitors includes the compounds numbered 3001-3014 in Figure 3.
• HCV polymerase inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof include VX-500, VX-813, VBY-376, TMC- 435350, EZ-058, EZ-063, GS-9132, ACH-1095, IDX-136, IDX-316, ITMN-8356, ITMN-8347, ITMN-8096, ITMN-7587, VX-985, and those disclosed in PCT Publication No. WO 2012/142085.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with a NS5A inhibitor.
• NS5A inhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof.
• a non-limiting list of example NS5A inhibitors includes the compounds numbered 4001-4012 in Figure 4.
• Additional NS5A inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof include A-832, PPI-1301 and those disclosed in PCT Publication No. WO 2012/142085.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with other antiviral compounds.
• other antiviral compounds include, but are not limited to, Debio-025, MIR- 122, cyclosporin A and/or combinations thereof.
• a non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5012 in Figure 5.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with a compound of Formula (AA), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (AA), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2013/0164261, published June 27, 2013, the contents of which are incorporated by reference in its entirety):
• 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 absent or selected from hydrogen, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and , wherein R , R and R can be independently absent or hydrogen, and n can be 0 or 1; provided that when R AAl is O " or OH, then R AAI is absent,
• hydrogen or R can be selected from hydrogen, halogen,
• R and R can be both an oxygen atom which are linked together by a carbonyl group;
• R > J AA5 can be selected from an optionally substituted C2-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C3-6 cycloalkyl; or
• R AA5 together can form -(Ci_ 6 alkylVO- or -0-(Ci_ 6 alkyl)-; R ⁇ and R ⁇ 11 can be
• a non-limiting list of examples of compounds of Formula (AA) includes the compounds numbered 7000-7027 in Figure 7.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (BB), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0165286, published June 28, 2012, the contents of which are incorporated by reference in their entireties):
• B can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group
• X BB can be O (oxygen) or S (sulfur)
• R BB1 can be selected from -Z BB -R BB9 , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative
• Z BB can be selected from O (oxygen), S (sulfur) and N(R BB1 °)
• R BB2 and R BB3 can be independently selected from hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted Ci_6 haloalkyl and an optionally substituted aryl(Ci_6 alkyl); or R BB2 and R BB3 can be taken together to form a group selected from an optionally substituted C3-6 cycloalkyl, an optionally substituted
• R BB9 can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(Ci_ 6 alkyl), an optionally substituted heteroaryl(Ci_ 6 alkyl) and an optionally substituted heterocyclyl(Ci_ 6
• R BB14 and R BB16 can be independently an optionally substituted Ci_6 alkyl or an optionally substituted C3-6 cycloalkyl.
• at least one of R BB2 and R BB3 is not hydro gen.
• a non-limiting list of example compounds of Formula (BB) includes the compound numbered 8000-8016 in Figure 8.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with a compound of Formula (CC), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (CC), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0071434, published March 22, 2012, the contents of which are incorporated by reference in its entirety):
• B CC1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group
• R CC1 can be selected from O " , OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative
• R CC2 can be selected from an optionally substituted aryl, an optionally substituted
• heteroaryl an optionally substituted heterocyclyl and , wherein
• R , R and R can be independently absent or hydrogen, and n can be 0 or 1;
• R LL2 R CC3a and R CC3b can be independently selected from hydrogen, deuterium, an optionally substituted Ci_6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted Ci_6 haloalkyl and aryl(Ci_6 alkyl); or R and R can be taken together to form an optionally substituted C 3 -6 cycloalkyl;
• R CC4 can be selected from hydrogen, azido, an optionally substituted Ci_6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl;
• R CC6 can be selected from hydrogen, halogen,
• R CC18 CC10 CC12 from hydrogen, azido, cyano, an optionally substituted Ci_6 alkyl and -OR ;
• R , R , R , R and R can be independently selected from hydrogen and an optionally substituted Ci_ 6 alkyl;
• R ccu , R CC13 , R CC15 and R CC1? can be independently selected from an optionally substituted Ci_6 alkyl and an optionally substituted C 3 -6 cycloalkyl.
• R CC3a , R CC3b , R CC4 , R CC5 , R CC7 , R CC8 and R CC9 are all hydrogen, then R CC6 is
• R CC3a is hydrogen
• R CC3b is hydrogen
• R CC4 is H
• R CC5 is OH or H
• R CC6 is hydrogen, OH, or -
• R CC8 is hydrogen, OH or OCH 3
• R ⁇ y is H and B is an optionally substituted adenine, an optionally substituted guanine, an optionally substituted uracil or an optionally substituted hypoxanthine.
• a non-limiting list of examples of compounds of Formula (CC) includes the compounds numbered 6000-6078 in Figure 6.
• Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
• Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include administering to a subject suffering from the HCV infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
• agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds can include administering to a subject suffering from the HCV infection
• Some embodiments described herein relate to a method of inhibiting the replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
• a compound of Formula (I) or a pharmaceutically acceptable salt thereof
• Some embodiments described herein relate to a method of inhibiting the replication of a hepatitis C virus that can include administering to a subject infected with the hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered with one or more additional agent(s) together in a single pharmaceutical composition.
• a compound of Formula (I), or a pharmaceutically acceptable salt the thereof can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition.
• one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
• the dosing amount(s) and dosing schedule(s) when using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents are within the knowledge of those skilled in the art.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective amounts and dosing protocols as described herein.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prior to all additional agents.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prior to at least one additional agent.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered concomitantly with one or more additional agent(s).
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered subsequent to the administration of at least one additional agent.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered subsequent to the administration of all additional agents.
• the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in an additive effect.
• the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a synergistic effect.
• the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a strongly synergistic effect.
• the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) is not antagonistic.
• 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.
• additive effect means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.
• a potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof) may be a reduction in the required amount(s) of one or more compounds of Figures 1-8 (including pharmaceutically acceptable salts thereof) 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 one or more compounds of Figures 1-8 (including pharmaceutically acceptable salts thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• a disease condition disclosed herein for example, HCV
• the amount of a compound in Figures 1-8 can be less compared to the amount of the compound in Figures 1-8 (including a pharmaceutically acceptable salt thereof), needed to achieve the same viral load reduction when administered as a monotherapy.
• Another potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof) is that the use of two or more compounds having different mechanism of actions 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 compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof) may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in Figures 1 -8 (including pharmaceutically acceptable salts thereof) thereof; different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof); little to no significant effects on cytochrome P450; little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof)
• a non-limiting list of example combination of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, with one or more additional agent(s) are provided in Tables A, B, C, D and E.
• Each numbered X and Y compound in Tables A, B, C, D and E has a corresponding name and/or structure provided in Figures 1-8.
• the numbered compounds in Tables A, B, C, D and E includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions containing the compounds or a pharmaceutically acceptable salt thereof.
• 1001 includes the compound corresponding to 1001, pharmaceutically acceptable salts thereof, and pharmaceutical compositions that include compound 1001 and/or a pharmaceutically acceptable salt thereof.
• the combinations exemplified in Tables A, B, C, D and E are designated by the formula X:Y, which represents a combination of a compound X with a compound Y.
• the combination designated as 1001 :9004 in Table A represents a combination of compound 1001 with compound 9004, including pharmaceutically acceptable salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004).
• the combination designated as 1001 :9004 in Table A represents the combination of Telaprevir
• each of the combinations provided in Tables A, B, C, D and E can be used with one, two, three or more additional agents described herein.
• the combination of agents can be used to treat, ameliorate and/or inhibit a virus and/or a viral infection, wherein the virus can be HCV and the viral infection can be an HCV viral infection.
• Table A Example combinations of a compound X with a compound Y.
• Table B Example combinations of a compound X with a compound Y.

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