SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF

[0001] Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57.

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SEQLISTING_—65. TXT, created Feb. 13, 2014, which is 1 Kb in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

[0003] 1. Field

[0004] 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.

[0005] 2. Description

[0006] 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.

[0007] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0008] 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.

[0009] 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).

[0010] 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).

[0011] 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. 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. 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. In some embodiments, 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. In some embodiments, 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.

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0025] As used herein, any “R” group(s) such as, without limitation, R¹, R², R³, R⁴, R^5A, R^5B, R^6A, R^6B, R^6C, R^6D, R^6E, R^6F, R^6G, R^6H, R^7A, R^7B, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, 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 NR^aR^b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together” with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defined previously.

[0026] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that 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, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

[0027] As used herein, “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. Thus, for example, a “C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—. 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.

[0028] As used herein, “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 “C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-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.

[0029] As used herein, “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.

[0030] As used herein, “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.

[0031] As used herein, “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.

[0032] As used herein, “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.

[0033] As used herein, “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. For example, the aryl group can be a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0034] As used herein, “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. For example, 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). Furthermore, the term “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. Examples of 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, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

[0035] As used herein, “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. Examples of such “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-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

[0036] As used herein, “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.

[0037] As used herein, “heteroaralkyl” 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.

[0038] 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 (1,3-thiazinan-4-yl)methyl.

[0039] “Lower alkylene groups” are straight-chained —CH₂— tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene (—CH₂CH₂CH₂CH₂—). 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.”

[0040] As used herein, “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. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0041] As used herein, “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.

[0042] As used herein, “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-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0043] As used herein, “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). Such 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.

[0044] As used herein, “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). Such 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.

[0045] 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. A sulfenyl may be substituted or unsubstituted.

[0046] A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0047] A “sulfonyl” group refers to an “SO₂R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0048] An “O-carboxy” group refers to a “RC(═O)O—” group in which 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.

[0049] The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0050] A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0051] A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein each X is a halogen.

[0052] A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_A)—” 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.

[0053] The term “amino” as used herein refers to a —NH₂ group.

[0054] As used herein, the term “hydroxy” refers to a —OH group.

[0055] A “cyano” group refers to a “—CN” group.

[0056] The term “azido” as used herein refers to a —N₃ group.

[0057] An “isocyanato” group refers to a “—NCO” group.

[0058] A “thiocyanato” group refers to a “—CNS” group.

[0059] An “isothiocyanato” group refers to an “—NCS” group.

[0060] A “mercapto” group refers to an “—SH” group.

[0061] A “carbonyl” group refers to a C═O group.

[0062] An “S-sulfonamido” group refers to a “—SO₂N(R_AR_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. An S-sulfonamido may be substituted or unsubstituted.

[0063] An “N-sulfonamido” group refers to a “RSO₂N(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. An N-sulfonamido may be substituted or unsubstituted.

[0064] An “O-carbamyl” group refers to a “—OC(═O)N(R_AR_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. An O-carbamyl may be substituted or unsubstituted.

[0065] An “N-carbamyl” group refers to an “ROC(═O)N(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. An N-carbamyl may be substituted or unsubstituted.

[0066] An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_AR_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. An O-thiocarbamyl may be substituted or unsubstituted.

[0067] An “N-thiocarbamyl” group refers to an “ROC(═S)N(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. An N-thiocarbamyl may be substituted or unsubstituted.

[0068] A “C-amido” group refers to a “—C(═O)N(R_AR_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. A C-amido may be substituted or unsubstituted.

[0069] An “N-amido” group refers to a “RC(═O)N(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. An N-amido may be substituted or unsubstituted.

[0070] The term “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.

[0071] Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example “haloalkyl” may include one or more of the same or different halogens. As another example, “C₁-C₃ alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0072] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).

[0073] The term “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.

[0074] The term “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.

[0075] As used herein, the term “heterocyclic base” refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety. In some embodiments, 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). The term “purine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term “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. Examples of 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 1,2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (e.g., 8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Pat. Nos. 5,432,272 and 7,125,855, which are incorporated herein by reference for the limited purpose of disclosing additional heterocyclic bases. In some embodiments, a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).

[0076] The term “—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. When the 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.

[0077] The term “—N-linked amino acid ester derivative” refers to an amino acid in which a main-chain carboxylic acid group has been converted to an ester group. In some embodiments, the ester group has a formula selected from alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— and aryl(alkyl)-O—C(═O)—. A non-limiting list of ester groups include substituted and unsubstituted versions of the following: methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—, n-butyl-O—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—, neopentyl-O—C(═O)—, cyclopropyl-O—C(═O)—, cyclobutyl-O—C(═O)—, cyclopentyl-O—C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—, benzyl-O—C(═O)— and naphthyl-O—C(═O)—. N-linked amino acid ester derivatives can be substituted or unsubstituted.

[0078] The term “—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. When 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.

[0079] As used herein, the term “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable 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.

[0080] The terms “phosphorothioate” and “phosphothioate” refer to a compound of the general formula

its protonated forms (for example,

and

and its tautomers (such as

[0081] As used herein, the term “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.

[0082] The terms “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-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); 4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

[0083] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, 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. Pharmaceutical salts 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. 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.

[0084] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ preferred, ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, 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. Likewise, 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. Similarly, 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.

[0085] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0086] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

[0087] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. For example all tautomers of a phosphate and a phosphorothioate groups are intended to be included. Examples of tautomers of a phosphorothioate include the following:

Furthermore, 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.

[0088] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0089] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0090] It is understood that 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. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in 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. In addition, 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.

[0091] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0092] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein: B¹ can be selected from an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

R¹ can be selected from an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl and an optionally substituted C_3-6 cycloalkyl; each - - - - - - - - can be absent or a single bond, provided that both - - - - - - - - are each absent or both - - - - - - - - are each a single bond; when both - - - - - are each a single bond, then R² can be halo, N₃, —OR^7A or —N(R^7BR^7C); R⁴ can be absent; R³ can be oxygen (O); and R^p can be

wherein Z^p can be oxygen (O) or sulfur (S) and R^p1 can be selected from O⁻, OH, an —O-optionally substituted C_1-6 alkyl.

an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; when both - - - - - are each absent, then R^p can be absent; R² can be halo, N₃, —OR^7A or —N(R^7BR^7C); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be each an oxygen atom which are linked together by a carbonyl group; and R⁴ can be hydrogen or

R^5A can be selected from O⁻, OH, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester derivative,

R^5B 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 derivative,

R^6A can be an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl; R^6B and R^6C can be independently selected from hydrogen, an unsubstituted C_1-6 alkyl, an unsubstituted C_3-6 alkenyl, an unsubstituted C_3-6 alkynyl and an unsubstituted C_3-6 cycloalkyl; R^6D can be NHR^6G; R^6E can be hydrogen, halogen or NHR^6H; R^6F can be NHR^6I; R^6G can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A1 and —C(═O)OR^A2; R^6H can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A3 and —C(═O)OR^A4; R^6I can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A5 and —C(═O)OR^A6; X¹ can be N (nitrogen) or —CR^6J, R^6J can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl and an optionally substituted C_2-6 alkynyl; R^A1, R^A2, R^A3, R^A4, R^A5 and R^A6 can be independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_6-10 aryl, heteroaryl, heterocyclyl, aryl(C_1-6 alkyl), heteroaryl(C_1-6 alkyl) and heterocyclyl(C_1-6 alkyl); R^7A can be hydrogen or —C(═O)R¹²; R^7B and R^7C can be independently hydrogen or an optionally substituted C_1-6 alkyl; R⁸ and R¹² can be independently an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl; R⁹, R¹⁰ and R¹¹ 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 C_1-24 alkyl and an optionally substituted aryl; R^10A, R^10B, R^13A, R^13B, R^p4 and R^p7 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; R^14A, R^14B, R^15A, R^15B, R^p8 and R^p9 can be independently selected from hydrogen, an optionally substituted C_1-24 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; Z¹, Z^1A, Z^1B and Z^p1 can be independently O (oxygen) or S (sulfur); and provided that when R⁴ 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.

[0093] The substituents attached to the 2′-carbon can vary. In some embodiments, R² can be halo. For example, R² can be fluoro or chloro. In other embodiments, R² can be N₃. In some embodiments, R² can be —OH. In other embodiments, R² can be OR^7A, wherein R^7A can be —C(═O)R¹², and R¹² can be an optionally substituted C_1-6 alkyl. 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). In yet still other embodiments, R² can be OR^7A, wherein R^7A can be —C(═O)R¹², and R¹² can be an optionally substituted C_3-6 cycloalkyl. Suitable cycloalkyl groups include, but are not limited to optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiment, R² can be —N(R^7BR^7C), wherein R^7B and R^7C can be independently hydrogen or an optionally substituted C_1-6 alkyl. In some embodiments, R^7B and R^7C can be both hydrogen, such that R² can be —NH₂. In other embodiments, at least one of R^7B and R^7C can be an optionally substituted C_1-6 alkyl. In some embodiments, R^7B and R^7C can be both an optionally substituted C_1-6 alkyl. In some embodiments, R^7B and R^7C can be the same. In other embodiments, R^7B and R^7C can be different.

[0094] Various substituents can be attached to the 3′-carbon of the pentose ring. In some embodiments, R³ can be —OH. In other embodiments, R³ can be —OC(═O)R⁸, wherein R⁸ can be an optionally substituted C_1-6 alkyl such as those described herein. In still other embodiments, R³ can be —OC(═O)R⁸, wherein R⁸ can be an optionally substituted C_3-6 cycloalkyl. Examples of suitable optionally substituted C_3-6 cycloalkyl groups are described herein.

[0095] In some embodiments, R² and R³ can each be an oxygen atom and the oxygen atoms can be linked together by a carbonyl group. In other embodiments, R² and R³ can be both —OH. In other embodiments, R² can be halo and R³ can be —OH. In still other embodiments, R² can be halo and R³ can be —OC(═O)R⁸.

[0096] In some embodiments, R¹ can be an optionally substituted C_1-6 alkyl. In some embodiments, R¹ can be an unsubstituted C_1-6 alkyl. For example, R¹ 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). In some embodiments, R¹ can be a substituted C_1-6 alkyl. Suitable substitutions are described herein. As an example, R¹ can be a halo-substituted C_1-6 alkyl (such as —CF₃ or —CH₂CH₂F). In other embodiments, R¹ can be an optionally substituted C_2-6 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. In still other embodiments, R¹ can be an optionally substituted C_2-6 alkynyl. In yet still other embodiments, R¹ can be an optionally substituted C_3-6 cycloalkyl, such as those described herein.

[0097] In some embodiments, both - - - - - - can be each absent, R^p can be absent; R² can be halo, N₃, —OR^7A or —N(R^7BR^7C); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be each an oxygen atom which are linked together by a carbonyl group; and R⁴ can be hydrogen or

When both - - - - - - are absent, Formula (I) can have the structure:

In some embodiments, R⁴ can be hydrogen. In other embodiments, R⁴ can be

In some embodiments, 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, R⁴ can be

R^5A can be O⁻ or OH; and R^5B can be O⁻ or OH. In other embodiments, R⁴ can be

[0098]

and n can be 0. In still other embodiments, R⁴ can be

[0099]

and n can be 1. The substituents attached to the phosphorus can vary. In some embodiments, a compound of Formula (I) can be a phosphoroamidate. In other embodiments, a compound of Formula (I) can be a thiophosphoroamidate. In still other embodiments, a compound of Formula (I) can be a phosphorbisamidate. In yet still other embodiments, a compound of Formula (I) can be a thiophosphorbisamidate.

[0100] In some embodiments, R^5A can be an optionally substituted N-linked amino acid. Various amino acids are suitable, including those described herein. Examples of 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. In other embodiments, R^5A can be an optionally substituted N-linked amino acid ester derivative. Examples of 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. In some embodiments, the N-linked amino acid ester derivative can be a C_1-6 alkyl ester derivative, for example, an isopropyl ester of alanine. In other embodiments, the N-linked amino acid ester derivative can be a C_3-6 cycloalkyl ester derivative, such as a cyclohexyl ester of alanine.

[0101] In some embodiments, R^5A can have the structure

wherein R¹³ can be selected from hydrogen, an optionally substituted C_1-6-alkyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C_1-6 alkyl) and an optionally substituted haloalkyl; R¹⁴ can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_1-6 haloalkyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryl and an optionally substituted aryl(C_1-6 alkyl); and R¹⁵ can be hydrogen or an optionally substituted C_1-4-alkyl; or R¹⁴ and R¹⁵ can be taken together to form an optionally substituted C_3-6 cycloalkyl.

[0102] When R¹⁴ is substituted, R¹⁴ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R¹⁴ can be an unsubstituted C_1-6-alkyl, such as those described herein. In some embodiments, R¹⁴ can be hydrogen. In other embodiments, R¹⁴ can be methyl. In some embodiments, R¹³ can be an optionally substituted C_1-6 alkyl. Examples of optionally substituted C_1-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In some embodiments, R¹³ can be methyl or isopropyl. In some embodiments, R¹³ can be ethyl or neopentyl. In other embodiments, R¹³ can be an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R¹³ can be an optionally substituted cyclohexyl. In still other embodiments, R¹³ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹³ can be an optionally substituted aryl(C_1-6 alkyl). In some embodiments, R¹³ can be an optionally substituted benzyl. In some embodiments, R¹³ can be an optionally substituted C_1-6 haloalkyl, for example, CF₃. In some embodiments, R¹⁵ can be hydrogen. In other embodiments, R¹⁵ 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, R¹⁵ can be methyl. In some embodiments, R¹⁴ and R¹⁵ can be taken together to form an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R¹⁴ and R¹⁵, the carbon to which R¹⁴ and R¹⁵ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁴ and R¹⁵ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R¹⁴ and R¹⁵ are attached may be a (S)-chiral center.

[0103] Examples of suitable

groups include the following:

[0104] In some embodiments, R^5B can be an —O-optionally substituted aryl. For example, 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. In other embodiments, R^5B can be an —O-unsubstituted aryl. Alternatively, R^5B can be an —O-optionally substituted naphthyl. In other embodiments, R^5B can be an —O-optionally substituted heteroaryl. For example, R^5B can be an —O-optionally substituted quinolinyl. In still other embodiments, R^5B can be an —O-optionally substituted heterocyclyl.

[0105] In some embodiments, R^5B is an optionally substituted N-linked amino acid, such as those described for R^5A. In other embodiments, R^5B is an optionally substituted N-linked amino acid ester derivative, for example, those described herein. In some embodiments, R^5B can have the structure

wherein R¹⁶ can be selected from hydrogen, an optionally substituted C_1-6-alkyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C_1-6 alkyl) and an optionally substituted haloalkyl; R¹⁷ can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_1-6 haloalkyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryl and an optionally substituted aryl(C_1-6 alkyl); and R¹⁸ can be hydrogen or an optionally substituted C_1-4-alkyl; or R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C_3-6 cycloalkyl.

[0106] When R¹⁷ is substituted, R¹⁷ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R¹⁷ can be an unsubstituted C_1-6-alkyl, such as those described herein. In some embodiments, R¹⁷ can be hydrogen. In other embodiments, R¹⁷ can be methyl. In some embodiments, R¹⁶ can be an optionally substituted C_1-6 alkyl. Examples of optionally substituted C_1-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In some embodiments, R¹⁶ can be methyl or isopropyl. In some embodiments, R¹⁶ can be ethyl or neopentyl. In other embodiments, R¹⁶ can be an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R¹⁶ can be an optionally substituted cyclohexyl. In still other embodiments, R¹⁶ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹⁶ can be an optionally substituted aryl(C_1-6 alkyl). In some embodiments, R¹⁶ can be an optionally substituted benzyl. In some embodiments, R¹⁶ can be an optionally substituted C_1-6 haloalkyl, for example, CF₃. In some embodiments, R¹⁸ can be hydrogen. In other embodiments, R¹⁸ 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, R¹⁸ can be methyl. In some embodiments, R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R¹⁷ and R¹⁸, the carbon to which R¹⁷ and R¹⁸ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁷ and R¹⁸ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R¹⁷ and R¹⁸ are attached may be a (S)-chiral center.

[0107] Examples of suitable

groups include the following:

[0108] In some embodiments, 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 aryl. In other embodiments, 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. In some embodiments, 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.

[0109] In some embodiments, R^5A can be

[0110]

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 —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O— heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^8A and R^9A can be hydrogen. In other embodiments, at least one of R^8A and R^9A can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, 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 —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^10A can be an unsubstituted —O—C_1-4 alkyl.

[0111] In some embodiments, R^5B can be

[0112]

R^8B and R^9B can be independently selected from hydrogen, an optionally substituted C_1-24 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 —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^8B and R^9B can be hydrogen. In other embodiments, at least one of R^8B and R^9B can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, R^10B can be hydrogen. In other embodiments, R^10B can be an optionally substituted C_1-24 alkyl. In some embodiments, R^10B can be an unsubstituted C_1-4 alkyl. In still other embodiments, R^10B can be an optionally substituted aryl. In yet still other embodiments, R^10B can be —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^10B can be an unsubstituted —O—C_1-4 alkyl. In some embodiments, R^5A can be

[0113]

[0114] In some embodiments, 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 —O—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^11A and R^12A can be hydrogen. In other embodiments, at least one of R^11A and R^12A can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, R^13A can be an optionally substituted C_1-24 alkyl. In some embodiments, R^13A can be an unsubstituted C_1-4 alkyl. In other embodiments, R^13A can be an optionally substituted aryl. In still other embodiments, R^13A can be an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^13A can be an unsubstituted —O—C_1-4 alkyl. In some embodiments, Z^1A can be O (oxygen). In other embodiments, Z^1A can be or S (sulfur).

[0115] In some embodiments, R^5B can be

wherein R^11B and R^12B 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 —O—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. In other embodiments, at least one of R^11B and R^12B can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, R^13B can be an optionally substituted C_1-24 alkyl. In some embodiments, R^13B can be an unsubstituted C_1-4 alkyl. In other embodiments, R^13B can be an optionally substituted aryl. In still other embodiments, R^13B can be an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^13B can be an unsubstituted —O—C_1-4 alkyl. In some embodiments, Z^1B can be O (oxygen). In other embodiments, Z^1B can be or S (sulfur). In some embodiments, R^5A can be

[0116]

[0117] In some embodiments, R^5A can be

In some embodiments, R^14A can be hydrogen. In other embodiments, R^14A can be an optionally substituted C_1-24 alkyl. In still other embodiments, R^14A can be an optionally substituted aryl. In some embodiments, R^14A can be a C_1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, p can be 1. In other embodiments, p can be 2.

[0118] In some embodiments, R^5B can be

In some embodiments, R^14B can be hydrogen. In other embodiments, R^14B can be an optionally substituted C_1-24 alkyl. In still other embodiments, R^14B can be an optionally substituted aryl. In some embodiments, R^14B can be a C_1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, q can be 1. In other embodiments, q can be 2. In some embodiments, R^5A can be

[0119]

[0120] In some embodiments, R^5A can be

In some embodiments, R^15A can be hydrogen. In other embodiments, R^15A can be an optionally substituted C_1-24 alkyl. In still other embodiments, R^15A can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R^15A can be an optionally substituted C_1-6 alkyl. In some embodiments, R^15A can be an unsubstituted C_1-6 alkyl. In some embodiments, s can be 3. In other embodiments, s can be 4. In still other embodiments, s can be 5.

[0121] In some embodiments, R^5B can be

In some embodiments, R^15B can be hydrogen. In other embodiments, R^15B can be an optionally substituted C_1-24 alkyl. In still other embodiments, R^15B can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R^15B can be an optionally substituted C_1-6 alkyl. In some embodiments, R^15B can be an unsubstituted C_1-6 alkyl. In some embodiments, t can be 3. In other embodiments, t can be 4. In still other embodiments, t can be 5. In some embodiments, R^5A can be

[0122]

[0123] In some embodiments, 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. In other embodiments, R^5A and R^5B can be both a pivaloyloxymethoxy (POM) group, and form a bis(pivaloyloxymethoxy) (bis(POM)) prodrug. In still other embodiments, R^5A and R^5B can be both a S-acylthioethyl (SATE)-O— group and form a SATE ester prodrug. In some embodiments, R^5A and R^5B can be the same. In other embodiments, R^5A and R^5B can be different.

[0124] In some embodiments, both - - - - - - - - can be each a single bond; R⁴ can be absent; R³ can be oxygen (O); and R^p can be

wherein Z^p can be oxygen (O) or sulfur (S) and R^p1 can be selected from O⁻, OH, an —O-optionally substituted C_1-6 alkyl.

an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative. When both - - - - - - are each a single bond, Formula (I) can have the structure:

[0125] In some embodiments, R^p1 can be O⁻. In other embodiments, R^p1 can be OH. In other embodiments, R^p1 can be an —O-optionally substituted C_1-6 alkyl. For example, R^p1 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).

[0126] In some embodiments, R^p1 can be

wherein R^p1 and R^p3 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 —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^p1 and R^p3 can be hydrogen. In other embodiments, at least one of R^p1 and R^p3 can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, R^p4 can be an optionally substituted C_1-24 alkyl. In some embodiments, R^p4 can be an unsubstituted C_1-4 alkyl. In other embodiments, R^p4 can be an optionally substituted aryl. In still other embodiments, R^p4 can be an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^p4 can be an unsubstituted —O—C_1-4 alkyl.

[0127] In some embodiments, R^p1 can be

wherein R^p5 and R^p6 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl and an optionally substituted aryl; R^p7 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; and Z^p1 can be independently O (oxygen) or S (sulfur). In some embodiments, R^p5 and R^p6 can be hydrogen. In other embodiments, at least one of R^p5 and R^p6 can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, R^p7 can be an optionally substituted C_1-24 alkyl. In some embodiments, R^p7 can be an unsubstituted C_1-4 alkyl. In other embodiments, R^p7 can be an optionally substituted aryl. In still other embodiments, R^p7 can be an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^p7 can be an unsubstituted —O—C_1-4 alkyl. In some embodiments, Z^p1 can be O (oxygen). In other embodiments, Z^p1 can be or S (sulfur). In some embodiments, R^p1 can be isopropyloxycarbonyloxymethyloxy (POC) group. In some embodiments, R^p1 can be pivaloyloxymethyloxy (POM) group.

[0128] In some embodiments, R^p1 can be

In some embodiments, R^p8 can be hydrogen. In other embodiments, R^p8 can be an optionally substituted C_1-24 alkyl. In still other embodiments, R^p8 can be an optionally substituted aryl. In some embodiments, R^p8 can be a C_1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, r can be 1. In other embodiments, r can be 2.

[0129] In some embodiments, R^p1 can be

In some embodiments, R^p9 can be hydrogen. In other embodiments, R^p9 can be an optionally substituted C_1-24 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 C_1-6 alkyl. In some embodiments, R^p9 can be an unsubstituted C_1-6 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^p1 can be a S-acylthioethyl (SATE) group and form a SATE ester prodrug.

[0130] In some embodiments, R^p1 can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. For example, R^p1 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. In some embodiments, R^p1 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. In some embodiments, R^p1 can have the structure

wherein R^p10 can be selected from hydrogen, an optionally substituted C_1-6-alkyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C_1-6 alkyl) and an optionally substituted haloalkyl; R^p11 can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_1-6 haloalkyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryl and an optionally substituted aryl(C_1-6 alkyl); and R^p12 can be hydrogen or an optionally substituted C_1-4-alkyl; or R^p11 and R^p12 can be taken together to form an optionally substituted C_3-6 cycloalkyl.

[0131] When R^p11 is substituted, R^p11 can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^p11 can be an unsubstituted C_1-6-alkyl, such as those described herein. In some embodiments, R^p11 can be hydrogen. In other embodiments, R^p11 can be methyl. In some embodiments, R^p10 can be an optionally substituted C_1-6 alkyl. Examples of optionally substituted C_1-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R^p10 can be methyl or isopropyl. In some embodiments, R^p10 can be ethyl or neopentyl. In other embodiments, R^p10 can be an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R^p10 can be an optionally substituted cyclohexyl. In still other embodiments, R^p10 can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^p10 can be an optionally substituted aryl(C_1-6 alkyl). In some embodiments, R^p10 can be an optionally substituted benzyl. In some embodiments, R^p10 can be an optionally substituted C_1-6 haloalkyl, for example, CF₃. In some embodiments, R^p12 can be hydrogen. In other embodiments, R^p12 can be an optionally substituted C_1-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In some embodiments, R^p12 can be methyl. In some embodiments, R^p11 and R^p12 can be taken together to form an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^p11 and R^p12, the carbon to which R^p11 and R^p12 are attached may be a chiral center. In some embodiment, the carbon to which R^p11 and R^p12 are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^p11 and R^p12 are attached may be a (S)-chiral center.

[0132] Examples of suitable

groups include the following:

[0133] The nucleobase can vary. In some embodiments, B¹ can be uracil. In some embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In other embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In some embodiments, R^6A can be an optionally substituted C_1-6 alkyl. For example, 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). In other embodiments, R^6A can be an optionally substituted C_3-6 cycloalkyl, for example, optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0134] In some embodiments, B¹ can be guanine. In some embodiments, B¹ can be an optionally substituted

In other embodiments, B¹ can be an optionally substituted

wherein R^6B can be selected from hydrogen, an unsubstituted C_1-6 alkyl, an unsubstituted C_3-6 alkenyl, an unsubstituted C_3-6 alkynyl and an unsubstituted C_3-6 cycloalkyl. In some embodiments, B¹ can be unsubstituted

In some embodiments, R^6B can be an unsubstituted C_1-6 alkyl. For example, R^6B can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In some embodiments, R^6B can be an unsubstituted C_3-6 alkenyl. In other embodiments, R^6B can be an unsubstituted C_3-6 alkynyl. In still other embodiments, R^6B can be an unsubstituted C_3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0135] In some embodiments, B¹ can be an optionally substituted

wherein R^6C can be selected from hydrogen, an unsubstituted C_1-6 alkyl, an unsubstituted C_3-6 alkenyl, an unsubstituted C_3-6 alkynyl and an unsubstituted C_3-6 cycloalkyl. In some embodiments, B¹ can be unsubstituted

In some embodiments, R^6C can be hydrogen. In some embodiments, R^6C can be an unsubstituted C_1-6 alkyl. For example, 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). In some embodiments, R^6C can be an ethyl. In some embodiments, R^6C can be an unsubstituted C_3-6 alkenyl. In other embodiments, R^6C can be an unsubstituted C_3-6 alkynyl. In other embodiments, R^6C can be an unsubstituted C_3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0136] In some embodiments, B¹ can be adenine. In some embodiments, B¹ can be an optionally substituted

wherein X¹ can be N (nitrogen) or —CR^6J; R^6J can be selected from hydrogen, halogen, an optionally substituted C_1-6 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; R^6G can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A1 and —C(═O)OR^A2; R^6H can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A3 and —C(═O)OR^A4; R^A1, R^A2, R^A3 and R^A4 can be independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_6-10 aryl, heteroaryl, heterocyclyl, aryl(C_1-6 alkyl), heteroaryl(C_1-6 alkyl) and heterocyclyl(C_1-6 alkyl). In some embodiments, X¹ can be N (nitrogen). In other embodiments, X¹ can be —CR^6I, wherein CR^6I can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl and an optionally substituted C_2-6 alkynyl. In some embodiments, X¹ 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 NH₂. In some embodiments, R^6D can be NHR^6G, wherein R^6G can be an optionally substituted C_1-6 alkyl. In some embodiments, R^6E can be hydrogen. In other embodiments, R^6E can be halogen. In still other embodiments, R^6E can be NHR^6H, wherein R^6H can be an optionally substituted C_1-6 alkyl. In other embodiments, R^6D can be NHR^6G, wherein R^6G can be selected from an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A1 and —C(═O)OR^A2. In other embodiments, R^6E can be NHR^6H, wherein R^6H can be selected from an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A3 and —C(═O)OR^A4. In some embodiments, R^6D and R^6E can be the same. In other embodiments, R^6D and R^6E can be different.

[0137] In some embodiments, B¹ can be cytosine. In some embodiments, B¹ can be an optionally substituted

wherein R^6F can be NHR^6I; R^6I can be selected hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A5 and —C(═O)OR^A6; and R^A5 and R^A6 are independently selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_6-10 aryl, heteroaryl, heterocyclyl, aryl(C_1-6 alkyl), heteroaryl(C_1-6 alkyl) and heterocyclyl(C_1-6 alkyl). In some embodiments, R^6F can be NH₂. In other embodiments, R^6F can be NHR^6I, wherein R^6I can be an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl or an optionally substituted C_3-6 cycloalkyl. In still other embodiments, R^6F can be NHR^6I, wherein R^6I can be —C(═O)R^A5 or —C(═O)OR^A6. When R^6I is —C(═O)R^A5 or —C(═O)OR^A6, R^A5 and R^A6 can be C_1-6 alkyl, C_2-6 alkenyl or C_2-6 alkynyl. R^A5 and R^A6 can also be C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_6-10 aryl or heteroaryl, heterocyclyl. Additionally, R^A5 and R^A6 can be aryl(C_1-6 alkyl), heteroaryl(C_1-6 alkyl) or heterocyclyl(C_1-6 alkyl).

[0138] In some embodiments, Z can be O (oxygen). In other embodiments, Z¹ can be S (sulfur).

[0139] In some embodiments, R² is not halo. In some embodiments, R² 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, R¹ is not an optionally substituted C_1-6 alkyl. For example, R¹ is not an unsubstituted C_1-6 alkyl, such as methyl. In some embodiments, B¹ is not an optionally substituted uracil, for example, a halo-substituted uracil. In some embodiment, when both are each - - - - - - - - absent; R^P is absent; R³ is OH or —OC(═O)R⁸; R² is F; and R¹ is methyl, ethyl or ethenyl; then R⁴ cannot be selected from H and

wherein R^5B is an —O-unsubstituted aryl; R^5A is

and Z¹ is oxygen. In some embodiments, R² is not halo (such as fluoro) when B¹ is uracil. In some embodiments, a compound of Formula (I) is not a compound in WO 2013/092481 (filed Dec. 17, 2012).

[0140] Example structures of a compound of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing. In some embodiments of this paragraph, R³ can be OH. In some embodiments of this paragraph, R^6C can be an unsubstituted C_1-6 alkyl, such as CH₂CH₃. In some embodiments of this paragraph, R^p1 can be —O-unsubstituted C_1-6 alkyl. In some embodiments, of this paragraph, R⁴ can be H. In other embodiments, of this paragraph, R⁴ can be a phosphoroamidate group. In still other embodiments, of this paragraph, R⁴ can be a phosphate group (such as a mono-, di- or tri-phosphate). In yet still other embodiments, of this paragraph, R⁴ can be a thiophosphoroamidate group. In some embodiments, of this paragraph, R⁴ can be thiophosphate group (such as an alpha-thiomono-, alpha-thiodi- or alpha-thiotri-phosphate). In some embodiments of this paragraph, R^p1 can be —O-ethyl, —O-isopropyl or —O-isobutyl.

[0141] Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0142] Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0143] Still further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0144] Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0145] Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0146] Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0147] Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

[0148] In some embodiments, a compound of Formula (I) cannot be selected from:

or a pharmaceutically acceptable salt of the foregoing.

[0149] As described herein, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have R⁴ being

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. By neutralizing the charge on the phosphate or thiophosphate, penetration of the cell membrane may be facilitated as a result of the increased lipophilicity of the compound. Once absorbed and taken inside the cell, the groups attached to the phosphorus can be easily removed by esterases, proteases and/or other enzymes. In some embodiments, 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.

[0150] In some embodiments, the phosphorylation of a thio-monophosphate of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can be stereoselective. For example, 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′-O-phosphorous atom. For example, one of the (R) and (S) configuration with respect to the 5′-O-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′-O-phosphorous atom. In some embodiments, 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′-O-phosphorous atom. In some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can result in formation of a compound that has the (S)-configuration at the 5′-O-phosphorous atom.

[0151] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can act as a chain terminator of HCV replication. For example, 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. For example, a compound of Formula (I) can contain a 2′-carbon modification wherein R¹ is a non-hydrogen group selected from an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl and an optionally substituted C_3-6 cycloalkyl.

[0152] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be more resistant to hydrolysis and/or more resistant to enzymatic transformations. For example, 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. In some embodiments, 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. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have a biological half-life of greater than 24 hours. In some embodiments, 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. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have more potent antiviral activity (for example, a lower EC₅₀ in an HCV replicon assay) as compared to the current standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, does not significantly inhibit mitochondrial function of the mitochondrial RNA polymerase. For example, 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 B¹.

[0153] Additionally, in some embodiments, 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. In some embodiments, 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. In some embodiments, a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can have improved oral bioavailability, improved aqueous stability and/or reduced risk of byproduct-related toxicity. In some embodiments, for comparison purposes, 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.

[0154] Compounds of Formula (I) and those described herein may be prepared in various ways. General synthetic routes to the compound of Formula (I), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown in Scheme 1 and 2, and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0155] 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.

[0156] One method for forming a compound of Formula (I) is shown in Scheme 1. In Scheme 1, R^1a, R^2a, R^3a and B^1a can be the same as R¹, R², R³ and B¹ as described herein for Formula (I). In some embodiments, 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. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnesium bromides. In other embodiments, an appropriate base can be used to form a compound of Formula (I). Examples of 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)).

[0157] When compounds of Formula (I) has Z¹ being sulfur, the sulfur can be added in various manners. In some embodiments, the sulfur can be part of the phosphorus containing precursor, for example,

Alternatively, 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-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage's reagent), 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

[0158] A phosphorus containing precursor can be coupled to the nucleoside, for example, a compound of Formula (A). Following the coupling of the phosphorus containing precursor, any leaving groups can be cleaved under suitable conditions, such as hydrolysis. In Scheme 2, R^1a, R^2a, R^3a and B^1a can be the same as R¹, R², R³ and B¹ 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. If desired, one or more bases can be used during the addition of each phosphorus-containing group. Examples of suitable bases are described herein.

[0159] As described herein, in some embodiments, R² and R³ can be each an oxygen atom, wherein the oxygen atoms are linked together by a carbonyl groups. The —O—C(═O)—O— group can be formed using methods known to those skilled in the art. For example, a compound of Formula (I), wherein R² and R³ are both hydroxy groups, can be treated with 1,1′-carbonyldiimidazole (CDI).

[0160] In some embodiments, R² and/or R³ can be —OC(═O)R¹² and —OC(═O)R⁸, respectively. The —OC(═O)R¹² and —OC(═O)R⁸ groups can be formed at the 2′- and 3′-positions using various methods known to those skilled in the art. As an example, a compound of Formula (I), wherein R² and R³ 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). If desired, a catalyst can be used to facilitate the reaction. An example of suitable catalyst is 4-dimethylaminopyridine (DMAP). Alternatively, the —OC(═O)R¹² and —OC(═O)R⁸ groups can be formed at the 2′- and 3′-positions by reacting an alkyl acid (e.g. acetic acid and propionic acid) in the presences of a carbodiimide or a coupling reagent. Examples of carbodiimides include, but are not limited to, N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).

[0161] To reduce the formation of side products, one or more the groups attached to the pentose ring can be protected with one or more suitable protecting groups. As an example, if R² and/or R³ is/are hydroxy group(s), the hydroxy group(s) can be protected with suitable protecting groups, such as triarylmethyl and/or silyl groups. Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy) trityl (TBTr), 4,4′,4″-tris(4,5-dichlorophthalimido) trityl (CPTr), 4,4′,4″-tris (levulinyloxy) trityl (TLTr), p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl, p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl, 9-(4-octadecyloxyphenyl) xanthen-9-yl, 1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl, 4,4′,4″-tris-(tert-butylphenyl) methyl (TTTr) and 4,4′-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups are described herein and include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. Alternatively, R² and/or R³ 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-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal and 1-(4-methoxyphenyl)ethylidene ketal.

[0162] Some embodiments described herein relates to 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. In some embodiments, 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). In other embodiments, the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, 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. In some embodiments, the pharmaceutical composition includes a 1:1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0163] The term “pharmaceutical 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.

[0164] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.

[0165] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0166] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, 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.

[0167] As used herein, 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.

[0168] The pharmaceutical 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.

[0169] The pharmaceutical 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.

[0170] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0171] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

[0172] The 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.

[0173] 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.

[0174] 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.

[0175] 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).

[0176] 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).

[0177] In some embodiments, the compound can be a compound of Formula (I), or a pharmaceutical acceptable salt thereof, wherein R⁴ is hydrogen. In other embodiments, 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. In still other embodiments, 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. In yet still other embodiments, 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. In some embodiments, 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. In some embodiments, 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].

[0178] HCV is an enveloped positive strand RNA virus in the Flaviviridae family. There are various nonstructural proteins of HCV, such as NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is believed to be an RNA-dependent RNA polymerase involved in the replication of HCV RNA.

[0179] 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).

[0180] 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). Also contemplated is a method for reducing or eliminating further virus-caused liver damage in a subject having an HCV infection by 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). In some embodiments, this method can include slowing or halting the progression of liver disease. In other embodiments, the course of the disease can be reversed, and stasis or improvement in liver function is contemplated. In some embodiments, 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.)

[0181] 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 11) main genotypes of HCV, although others have classified the genotypes as 6 main genotypes. Each of these genotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, 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. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can be effective to treat all 11 genotypes of HCV. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can be effective to treat 3 or more, 5 or more, 7 or more, or 9 or more genotypes of HCV. In some embodiments, 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).

[0182] Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Examples of 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. Similarly, 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.

[0183] In some embodiments, 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. In some embodiments, 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. For example, wherein the HCV viral load is 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). In some embodiments, 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. In some embodiments, 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. For example, 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).

[0184] In some embodiments, 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). In some embodiments, 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. In some embodiments, 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.

[0185] In some embodiments, 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.

[0186] In some embodiments, 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. Methods of measuring serum 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. 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. In general, 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. In some embodiments, 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.

[0187] Subjects who are clinically diagnosed with HCV infection include “naïve” 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).

[0188] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a treatment failure subject suffering from HCV. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a non-responder subject suffering from HCV. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a relapsed subject suffering from HCV.

[0189] After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, 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. In some embodiments, 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). In some embodiments, 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).

[0190] In some embodiments, 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. For example, 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. In some embodiments, 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.

[0191] Some subjects being treated for HCV experience a viral load rebound. The term “viral load rebound” as used herein 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. In some embodiments, 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.

[0192] The standard of care for treating HCV has been associated with several side effects (adverse events). In some embodiments, 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. Examples of side effects include, but are not limited to fever, malaise, tachycardia, chills, headache, arthralgias, myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritability, confusion, depression, severe depression, suicidal ideation, anemia, low white blood cell counts, and thinning of hair. In some embodiments, a 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).

[0193] 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
			Percentage of
Percentage of	Percentage of	Percentage of	viral load	Number of	Severity of
non-responders	relapsers	resistance	rebound	side effects	side effects
10% less	10% less	10% less	10% less	10% less	10% less
25% less	25% less	25% less	25% less	25% less	25% less
40% less	40% less	40% less	40% less	40% less	40% less
50% less	50% less	50% less	50% less	50% less	50% less
60% less	60% less	60% less	60% less	60% less	60% less
70% less	70% less	70% less	70% less	70% less	70% less
80% less	80% less	80% less	80% less	80% less	80% less
90% less	90% less	90% less	90% less	90% less	90% less
about 10%	about 10%	about 10%	about 10%	about 10%	about 10%
to about	to about	to about	to about	to about	to about
30% less	30% less	30% less	30% less	30% less	30% less
about 20%	about 20%	about 20%	about 20%	about 20%	about 20%
to about	to about	to about	to about	to about	to about
50% less	50% less	50% less	50% less	50% less	50% less
about 30%	about 30%	about 30%	about 30%	about 30%	about 30%
to about	to about	to about	to about	to about	to about
70% less	70% less	70% less	70% less	70% less	70% less
about 20%	about 20%	about 20%	about 20%	about 20%	about 20%
to about	to about	to about	to about	to about	to about
80% less	80% less	80% less	80% less	80% less	80% less

[0194] As used herein, 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.

[0195] As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.

[0196] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, 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.

[0197] As will be readily apparent to one skilled in the art, 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.

[0198] 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. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some embodiments, a 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. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one time per day. For example, 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. In some embodiments, 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.

[0199] In instances where 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. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀ values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0200] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, 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.

[0201] 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). 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.

[0202] It should be noted that 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.

[0203] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, 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. Alternatively, 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.

[0204] In some embodiments, 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. In some embodiments, 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.

[0205] In some embodiments, 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. For example, for the treatment of HCV, 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.

[0206] In some embodiments, 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. For example, for the treatment of HCV, 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.

[0207] In some embodiments, 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. Examples of 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.

[0208] In some embodiments, 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. A non-limiting list of example 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. Additional 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, INX-8014, INX-8018, A-848837, A-837093, BILB-1941, VCH-916, VCH-716, GSK-71185, GSK-625433, XTL-2125 and those disclosed in PCT Publication No. WO 2012/142085, which is hereby incorporated by reference for the limited purpose of its disclosure of HCV protease inhibitors, HCV polymerase inhibitors and NS5A inhibitors. A non-limiting list of example HCV protease inhibitors includes the compounds numbered 1001-1016 in FIG. 1.

[0209] In some embodiments, 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. In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-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 FIG. 2. Examples of suitable 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 FIG. 3. Further 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.

[0210] In some embodiments, 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. Examples of 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 FIG. 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.

[0211] In some embodiments, 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. Examples of 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 FIG. 5.

[0212] In some embodiments, 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 Jun. 27, 2013, the contents of which are incorporated by reference in its entirety):

wherein: B^AA1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^AA1 can be selected from O⁻, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^AA2 be absent or selected from hydrogen, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and

wherein R^AA6, R^AA7 and R^AA8 can be independently absent or hydrogen, and n^AA can be 0 or 1; provided that when R^AA1 is O⁻ or OH, then R^AA2 is absent, hydrogen or

R^AA3 can be selected from hydrogen, halogen, —OR^AA9 and —OC(═O)R^AA10; R^AA4 can be selected from halogen, —OR^AA11 and —OC(═O)R^AA12; or R^AA3 and R^AA4 can be both an oxygen atom which are linked together by a carbonyl group; R^AA5 can be selected from an optionally substituted C_2-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl and an optionally substituted C_3-6 cycloalkyl; or R^AA4 and R^AA5 can form —(C_1-6 alkyl)-O— or —O—(C_1-6 alkyl)-; R^AA9 and R^AA11 can be independently hydrogen or an optionally substituted C_1-6 alkyl; and R^AA10 and R^AA12 can be independently an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl. A non-limiting list of examples of compounds of Formula (AA) includes the compounds numbered 7000-7027 in FIG. 7.

[0213] In some embodiments, 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 Jun. 28, 2012, the contents of which are incorporated by reference in their entireties):

wherein B^BB1 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^BB10); R^BB2 and R^BB3 can be independently selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted C_1-6 haloalkyl and an optionally substituted aryl(C_1-6 alkyl); or R^BB2 and R^BB3 can be taken together to form a group selected from an optionally substituted C_3-6 cycloalkyl, an optionally substituted C_3-6 cycloalkenyl, an optionally substituted C_3-6 aryl and an optionally substituted C_3-6 heteroaryl; R^BB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl and an optionally substituted allenyl; R^BB5 can be hydrogen or an optionally substituted C_1-6 alkyl; R^BB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C_1-6 alkyl, —OR^BB11 and —OC(═O)R^BB12; R^BB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^BB13 and —OC(═)R^BB14; R^BB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^BB15 and —OC(═O)R^BB16; 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(C_1-6alkyl), an optionally substituted heteroaryl(C_1-6alkyl) and an optionally substituted heterocyclyl(C_1-6alkyl); R^BB10 can be selected from hydrogen, 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(C_1-6alkyl), an optionally substituted heteroaryl(C_1-6alkyl) and an optionally substituted heterocyclyl(C_1-6alkyl); R^BB11, R^BB13 and R^BB15 can be independently hydrogen or an optionally substituted C_1-6 alkyl; and R^BB12, R^BB14 and R^BB16 can be independently an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl. In some embodiments, at least one of R^BB2 and R^BB3 is not hydrogen. A non-limiting list of example compounds of Formula (BB) includes the compound numbered 8000-8016 in FIG. 8.

[0214] In some embodiments, 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 Mar. 22, 2012, the contents of which are incorporated by reference in its entirety):

wherein 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^CC19, R^CC20 and R^CC21 can be independently absent or hydrogen, and n^CC can be 0 or 1; provided that when R^CC1 is O⁻ or OH, then R^CC2 is

R^CC3a and R^CC3b can be independently selected from hydrogen, deuterium, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted C_1-6 haloalkyl and aryl(C_1-6 alkyl); or R^CC3a and R^CC3b can be taken together to form an optionally substituted C_3-6 cycloalkyl; R^CC4 can be selected from hydrogen, azido, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl and an optionally substituted C_2-6 alkynyl; R^CC5 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^CC10 and —OC(═O)R^CC11; R^CC6 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^CC12 and —OC(═O)R^CC13; R^CC7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^CC14 and —OC(═O)R^CC15; or R^CC6 and R^CC7 can be both oxygen atoms and linked together by a carbonyl group; R^CC8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^CC16 and —OC(═O)R^CC17; R^CC9 can be selected from hydrogen, azido, cyano, an optionally substituted C_1-6 alkyl and —OR^CC18; R^CC10; R^CC12; R^CC14; R^CC16 and R^CC18 can be independently selected from hydrogen and an optionally substituted C_1-6 alkyl; and R^CC11, R^CC13; R^CC15 and R^CC17 can be independently selected from an optionally substituted C_1-6 alkyl and an optionally substituted C_3-6 cycloalkyl. In some embodiments, when R^CC3a, R^CC3b; R^CC4; R^CC5; R^CC7; R^CC8 and R^CC9 are all hydrogen, then R^CC6 is not azido. In some embodiments, R^CC2 cannot be

when R^CC3a is hydrogen, R^CC3b is hydrogen, R^CC4 is H, R^CC5 is OH or H, R^CC6 is hydrogen, OH, or —OC(═O)CH₃, R^CC7 is hydrogen, OH, OCH₃ or —OC(═O)CH₃, R^CC8 is hydrogen, OH or OCH₃, R^CC9 is H and B^CC1 is an optionally substituted adenine, an optionally substituted guanine, an optionally substituted uracil or an optionally substituted hypoxanthine. In some embodiments, R^CC2 cannot be

A non-limiting list of examples of compounds of Formula (CC) includes the compounds numbered 6000-6078 in FIG. 6.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] In some embodiments, 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. In some embodiments, 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. For example, 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. If there are at least two additional agents, 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.

[0220] 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. For example, when performing a conventional standard of care therapy using art-recognized dosing amounts and dosing schedules, 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.

[0221] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to all additional agents. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of at least one additional agent. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of all additional agents.

[0222] In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in an additive effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a synergistic effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a strongly synergistic effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) is not antagonistic.

[0223] As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e. as a single compound). As used herein, 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. As used herein, the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.

[0224] 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 FIGS. 1-8 (including pharmaceutically acceptable salts thereof) may be a reduction in the required amount(s) of one or more compounds of FIGS. 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 FIGS. 1-8 (including pharmaceutically acceptable salts thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound in FIGS. 1-8 (including a pharmaceutically acceptable salt thereof), can be less compared to the amount of the compound in FIGS. 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 FIGS. 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.

[0225] 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 FIGS. 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 FIGS. 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 FIGS. 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 FIGS. 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 FIGS. 1-8 (including pharmaceutically acceptable salts thereof); greater percentage of subjects achieving a sustained viral response compared to when a compound is administered as monotherapy and/or a decrease in treatment time to achieve a sustained viral response compared to when a compound is administered as monotherapy.

[0226] 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 FIGS. 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. For example, 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. For example, 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). Thus, the combination designated as 1001:9004 in Table A represents the combination of Telaprevir (compound 1001, as shown in FIG. 1) and

(compound 9004, as shown in FIG. 9), 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). 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. In some embodiments 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.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:9000	1001:9001	1001:9002	1001:9003	1001:9004	1001:9005
1002:9000	1002:9001	1002:9002	1002:9003	1002:9004	1002:9005
1003:9000	1003:9001	1003:9002	1003:9003	1003:9004	1003:9005
1004:9000	1004:9001	1004:9002	1004:9003	1004:9004	1004:9005
1005:9000	1005:9001	1005:9002	1005:9003	1005:9004	1005:9005
1006:9000	1006:9001	1006:9002	1006:9003	1006:9004	1006:9005
1007:9000	1007:9001	1007:9002	1007:9003	1007:9004	1007:9005
1008:9000	1008:9001	1008:9002	1008:9003	1008:9004	1008:9005
1009:9000	1009:9001	1009:9002	1009:9003	1009:9004	1009:9005
1010:9000	1010:9001	1010:9002	1010:9003	1010:9004	1010:9005
1011:9000	1011:9001	1011:9002	1011:9003	1011:9004	1011:9005
1012:9000	1012:9001	1012:9002	1012:9003	1012:9004	1012:9005
1013:9000	1013:9001	1013:9002	1013:9003	1013:9004	1013:9005
1014:9000	1014:9001	1014:9002	1014:9003	1014:9004	1014:9005
1015:9000	1015:9001	1015:9002	1015:9003	1015:9004	1015:9005
1016:9000	1016:9001	1016:9002	1016:9003	1016:9004	1016:9005
2001:9000	2001:9001	2001:9002	2001:9003	2001:9004	2001:9005
2002:9000	2002:9001	2002:9002	2002:9003	2002:9004	2002:9005
2003:9000	2003:9001	2003:9002	2003:9003	2003:9004	2003:9005
2004:9000	2004:9001	2004:9002	2004:9003	2004:9004	2004:9005
2005:9000	2005:9001	2005:9002	2005:9003	2005:9004	2005:9005
2006:9000	2006:9001	2006:9002	2006:9003	2006:9004	2006:9005
2007:9000	2007:9001	2007:9002	2007:9003	2007:9004	2007:9005
2008:9000	2008:9001	2008:9002	2008:9003	2008:9004	2008:9005
2009:9000	2009:9001	2009:9002	2009:9003	2009:9004	2009:9005
2010:9000	2010:9001	2010:9002	2010:9003	2010:9004	2010:9005
2011:9000	2011:9001	2011:9002	2011:9003	2011:9004	2011:9005
2012:9000	2012:9001	2012:9002	2012:9003	2012:9004	2012:9005
1001:9006	1001:9007	1001:9008	1001:9009	1001:9010	1001:9011
1002:9006	1002:9007	1002:9008	1002:9009	1002:9010	1002:9011
1003:9006	1003:9007	1003:9008	1003:9009	1003:9010	1003:9011
1004:9006	1004:9007	1004:9008	1004:9009	1004:9010	1004:9011
1005:9006	1005:9007	1005:9008	1005:9009	1005:9010	1005:9011
1006:9006	1006:9007	1006:9008	1006:9009	1006:9010	1006:9011
1007:9006	1007:9007	1007:9008	1007:9009	1007:9010	1007:9011
1008:9006	1008:9007	1008:9008	1008:9009	1008:9010	1008:9011
1009:9006	1009:9007	1009:9008	1009:9009	1009:9010	1009:9011
1010:9006	1010:9007	1010:9008	1010:9009	1010:9010	1010:9011
1011:9006	1011:9007	1011:9008	1011:9009	1011:9010	1011:9011
1012:9006	1012:9007	1012:9008	1012:9009	1012:9010	1012:9011
1013:9006	1013:9007	1013:9008	1013:9009	1013:9010	1013:9011
1014:9006	1014:9007	1014:9008	1014:9009	1014:9010	1014:9011
1015:9006	1015:9007	1015:9008	1015:9009	1015:9010	1015:9011
1016:9006	1016:9007	1016:9008	1016:9009	1016:9010	1016:9011
2001:9006	2001:9007	2001:9008	2001:9009	2001:9010	2001:9011
2002:9006	2002:9007	2002:9008	2002:9009	2002:9010	2002:9011
2003:9006	2003:9007	2003:9008	2003:9009	2003:9010	2003:9011
2004:9006	2004:9007	2004:9008	2004:9009	2004:9010	2004:9011
2005:9006	2005:9007	2005:9008	2005:9009	2005:9010	2005:9011
2006:9006	2006:9007	2006:9008	2006:9009	2006:9010	2006:9011
2007:9006	2007:9007	2007:9008	2007:9009	2007:9010	2007:9011
2008:9006	2008:9007	2008:9008	2008:9009	2008:9010	2008:9011
2009:9006	2009:9007	2009:9008	2009:9009	2009:9010	2009:9011
2010:9006	2010:9007	2010:9008	2010:9009	2010:9010	2010:9011
2011:9006	2011:9007	2011:9008	2011:9009	2011:9010	2011:9011
2012:9006	2012:9007	2012:9008	2012:9009	2012:9010	2012:9011
1001:9012	1001:9013	1001:9014	1001:9015	1001:9016	1001:9017
1002:9012	1002:9013	1002:9014	1002:9015	1002:9016	1002:9017
1003:9012	1003:9013	1003:9014	1003:9015	1003:9016	1003:9017
1004:9012	1004:9013	1004:9014	1004:9015	1004:9016	1004:9017
1005:9012	1005:9013	1005:9014	1005:9015	1005:9016	1005:9017
1006:9012	1006:9013	1006:9014	1006:9015	1006:9016	1006:9017
1007:9012	1007:9013	1007:9014	1007:9015	1007:9016	1007:9017
1008:9012	1008:9013	1008:9014	1008:9015	1008:9016	1008:9017
1009:9012	1009:9013	1009:9014	1009:9015	1009:9016	1009:9017
1010:9012	1010:9013	1010:9014	1010:9015	1010:9016	1010:9017
1011:9012	1011:9013	1011:9014	1011:9015	1011:9016	1011:9017
1012:9012	1012:9013	1012:9014	1012:9015	1012:9016	1012:9017
1013:9012	1013:9013	1013:9014	1013:9015	1013:9016	1013:9017
1014:9012	1014:9013	1014:9014	1014:9015	1014:9016	1014:9017
1015:9012	1015:9013	1015:9014	1015:9015	1015:9016	1015:9017
1016:9012	1016:9013	1016:9014	1016:9015	1016:9016	1016:9017
2001:9012	2001:9013	2001:9014	2001:9015	2001:9016	2001:9017
2002:9012	2002:9013	2002:9014	2002:9015	2002:9016	2002:9017
2003:9012	2003:9013	2003:9014	2003:9015	2003:9016	2003:9017
2004:9012	2004:9013	2004:9014	2004:9015	2004:9016	2004:9017
2005:9012	2005:9013	2005:9014	2005:9015	2005:9016	2005:9017
2006:9012	2006:9013	2006:9014	2006:9015	2006:9016	2006:9017
2007:9012	2007:9013	2007:9014	2007:9015	2007:9016	2007:9017
2008:9012	2008:9013	2008:9014	2008:9015	2008:9016	2008:9017
2009:9012	2009:9013	2009:9014	2009:9015	2009:9016	2009:9017
2010:9012	2010:9013	2010:9014	2010:9015	2010:9016	2010:9017
2011:9012	2011:9013	2011:9014	2011:9015	2011:9016	2011:9017
2012:9012	2012:9013	2012:9014	2012:9015	2012:9016	2012:9017
1001:9018	1001:9019	1001:9020	1001:9021	1001:9022	1001:9023
1002:9018	1002:9019	1002:9020	1002:9021	1002:9022	1002:9023
1003:9018	1003:9019	1003:9020	1003:9021	1003:9022	1003:9023
1004:9018	1004:9019	1004:9020	1004:9021	1004:9022	1004:9023
1005:9018	1005:9019	1005:9020	1005:9021	1005:9022	1005:9023
1006:9018	1006:9019	1006:9020	1006:9021	1006:9022	1006:9023
1007:9018	1007:9019	1007:9020	1007:9021	1007:9022	1007:9023
1008:9018	1008:9019	1008:9020	1008:9021	1008:9022	1008:9023
1009:9018	1009:9019	1009:9020	1009:9021	1009:9022	1009:9023
1010:9018	1010:9019	1010:9020	1010:9021	1010:9022	1010:9023
1011:9018	1011:9019	1011:9020	1011:9021	1011:9022	1011:9023
1012:9018	1012:9019	1012:9020	1012:9021	1012:9022	1012:9023
1013:9018	1013:9019	1013:9020	1013:9021	1013:9022	1013:9023
1014:9018	1014:9019	1014:9020	1014:9021	1014:9022	1014:9023
1015:9018	1015:9019	1015:9020	1015:9021	1015:9022	1015:9023
1016:9018	1016:9019	1016:9020	1016:9021	1016:9022	1016:9023
2001:9018	2001:9019	2001:9020	2001:9021	2001:9022	2001:9023
2002:9018	2002:9019	2002:9020	2002:9021	2002:9022	2002:9023
2003:9018	2003:9019	2003:9020	2003:9021	2003:9022	2003:9023
2004:9018	2004:9019	2004:9020	2004:9021	2004:9022	2004:9023
2005:9018	2005:9019	2005:9020	2005:9021	2005:9022	2005:9023
2006:9018	2006:9019	2006:9020	2006:9021	2006:9022	2006:9023
2007:9018	2007:9019	2007:9020	2007:9021	2007:9022	2007:9023
2008:9018	2008:9019	2008:9020	2008:9021	2008:9022	2008:9023
2009:9018	2009:9019	2009:9020	2009:9021	2009:9022	2009:9023
2010:9018	2010:9019	2010:9020	2010:9021	2010:9022	2010:9023
2011:9018	2011:9019	2011:9020	2011:9021	2011:9022	2011:9023
2012:9018	2012:9019	2012:9020	2012:9021	2012:9022	2012:9023
1001:9024	1001:9025	1001:9026	1001:9027	1001:9028	1001:9029
1002:9024	1002:9025	1002:9026	1002:9027	1002:9028	1002:9029
1003:9024	1003:9025	1003:9026	1003:9027	1003:9028	1003:9029
1004:9024	1004:9025	1004:9026	1004:9027	1004:9028	1004:9029
1005:9024	1005:9025	1005:9026	1005:9027	1005:9028	1005:9029
1006:9024	1006:9025	1006:9026	1006:9027	1006:9028	1006:9029
1007:9024	1007:9025	1007:9026	1007:9027	1007:9028	1007:9029
1008:9024	1008:9025	1008:9026	1008:9027	1008:9028	1008:9029
1009:9024	1009:9025	1009:9026	1009:9027	1009:9028	1009:9029
1010:9024	1010:9025	1010:9026	1010:9027	1010:9028	1010:9029
1011:9024	1011:9025	1011:9026	1011:9027	1011:9028	1011:9029
1012:9024	1012:9025	1012:9026	1012:9027	1012:9028	1012:9029
1013:9024	1013:9025	1013:9026	1013:9027	1013:9028	1013:9029
1014:9024	1014:9025	1014:9026	1014:9027	1014:9028	1014:9029
1015:9024	1015:9025	1015:9026	1015:9027	1015:9028	1015:9029
1016:9024	1016:9025	1016:9026	1016:9027	1016:9028	1016:9029
2001:9024	2001:9025	2001:9026	2001:9027	2001:9028	2001:9029
2002:9024	2002:9025	2002:9026	2002:9027	2002:9028	2002:9029
2003:9024	2003:9025	2003:9026	2003:9027	2003:9028	2003:9029
2004:9024	2004:9025	2004:9026	2004:9027	2004:9028	2004:9029
2005:9024	2005:9025	2005:9026	2005:9027	2005:9028	2005:9029
2006:9024	2006:9025	2006:9026	2006:9027	2006:9028	2006:9029
2007:9024	2007:9025	2007:9026	2007:9027	2007:9028	2007:9029
2008:9024	2008:9025	2008:9026	2008:9027	2008:9028	2008:9029
2009:9024	2009:9025	2009:9026	2009:9027	2009:9028	2009:9029
2010:9024	2010:9025	2010:9026	2010:9027	2010:9028	2010:9029
2011:9024	2011:9025	2011:9026	2011:9027	2011:9028	2011:9029
2012:9024	2012:9025	2012:9026	2012:9027	2012:9028	2012:9029
1001:9030	1001:9031	1001:9032	1001:9033	1001:9034	1001:9035
1002:9030	1002:9031	1002:9032	1002:9033	1002:9034	1002:9035
1003:9030	1003:9031	1003:9032	1003:9033	1003:9034	1003:9035
1004:9030	1004:9031	1004:9032	1004:9033	1004:9034	1004:9035
1005:9030	1005:9031	1005:9032	1005:9033	1005:9034	1005:9035
1006:9030	1006:9031	1006:9032	1006:9033	1006:9034	1006:9035
1007:9030	1007:9031	1007:9032	1007:9033	1007:9034	1007:9035
1008:9030	1008:9031	1008:9032	1008:9033	1008:9034	1008:9035
1009:9030	1009:9031	1009:9032	1009:9033	1009:9034	1009:9035
1010:9030	1010:9031	1010:9032	1010:9033	1010:9034	1010:9035
1011:9030	1011:9031	1011:9032	1011:9033	1011:9034	1011:9035
1012:9030	1012:9031	1012:9032	1012:9033	1012:9034	1012:9035
1013:9030	1013:9031	1013:9032	1013:9033	1013:9034	1013:9035
1014:9030	1014:9031	1014:9032	1014:9033	1014:9034	1014:9035
1015:9030	1015:9031	1015:9032	1015:9033	1015:9034	1015:9035
1016:9030	1016:9031	1016:9032	1016:9033	1016:9034	1016:9035
2001:9030	2001:9031	2001:9032	2001:9033	2001:9034	2001:9035
2002:9030	2002:9031	2002:9032	2002:9033	2002:9034	2002:9035
2003:9030	2003:9031	2003:9032	2003:9033	2003:9034	2003:9035
2004:9030	2004:9031	2004:9032	2004:9033	2004:9034	2004:9035
2005:9030	2005:9031	2005:9032	2005:9033	2005:9034	2005:9035
2006:9030	2006:9031	2006:9032	2006:9033	2006:9034	2006:9035
2007:9030	2007:9031	2007:9032	2007:9033	2007:9034	2007:9035
2008:9030	2008:9031	2008:9032	2008:9033	2008:9034	2008:9035
2009:9030	2009:9031	2009:9032	2009:9033	2009:9034	2009:9035
2010:9030	2010:9031	2010:9032	2010:9033	2010:9034	2010:9035
2011:9030	2011:9031	2011:9032	2011:9033	2011:9034	2011:9035
2012:9030	2012:9031	2012:9032	2012:9033	2012:9034	2012:9035
1001:9036	1001:9037	1001:9038	1001:9039	1001:9040	1001:9041
1002:9036	1002:9037	1002:9038	1002:9039	1002:9040	1002:9041
1003:9036	1003:9037	1003:9038	1003:9039	1003:9040	1003:9041
1004:9036	1004:9037	1004:9038	1004:9039	1004:9040	1004:9041
1005:9036	1005:9037	1005:9038	1005:9039	1005:9040	1005:9041
1006:9036	1006:9037	1006:9038	1006:9039	1006:9040	1006:9041
1007:9036	1007:9037	1007:9038	1007:9039	1007:9040	1007:9041
1008:9036	1008:9037	1008:9038	1008:9039	1008:9040	1008:9041
1009:9036	1009:9037	1009:9038	1009:9039	1009:9040	1009:9041
1010:9036	1010:9037	1010:9038	1010:9039	1010:9040	1010:9041
1011:9036	1011:9037	1011:9038	1011:9039	1011:9040	1011:9041
1012:9036	1012:9037	1012:9038	1012:9039	1012:9040	1012:9041
1013:9036	1013:9037	1013:9038	1013:9039	1013:9040	1013:9041
1014:9036	1014:9037	1014:9038	1014:9039	1014:9040	1014:9041
1015:9036	1015:9037	1015:9038	1015:9039	1015:9040	1015:9041
1016:9036	1016:9037	1016:9038	1016:9039	1016:9040	1016:9041
2001:9036	2001:9037	2001:9038	2001:9039	2001:9040	2001:9041
2002:9036	2002:9037	2002:9038	2002:9039	2002:9040	2002:9041
2003:9036	2003:9037	2003:9038	2003:9039	2003:9040	2003:9041
2004:9036	2004:9037	2004:9038	2004:9039	2004:9040	2004:9041
2005:9036	2005:9037	2005:9038	2005:9039	2005:9040	2005:9041
2006:9036	2006:9037	2006:9038	2006:9039	2006:9040	2006:9041
2007:9036	2007:9037	2007:9038	2007:9039	2007:9040	2007:9041
2008:9036	2008:9037	2008:9038	2008:9039	2008:9040	2008:9041
2009:9036	2009:9037	2009:9038	2009:9039	2009:9040	2009:9041
2010:9036	2010:9037	2010:9038	2010:9039	2010:9040	2010:9041
2011:9036	2011:9037	2011:9038	2011:9039	2011:9040	2011:9041
2012:9036	2012:9037	2012:9038	2012:9039	2012:9040	2012:9041
1001:9042	1001:9043	1001:9044	1001:9045	1001:9046	1001:9047
1002:9042	1002:9043	1002:9044	1002:9045	1002:9046	1002:9047
1003:9042	1003:9043	1003:9044	1003:9045	1003:9046	1003:9047
1004:9042	1004:9043	1004:9044	1004:9045	1004:9046	1004:9047
1005:9042	1005:9043	1005:9044	1005:9045	1005:9046	1005:9047
1006:9042	1006:9043	1006:9044	1006:9045	1006:9046	1006:9047
1007:9042	1007:9043	1007:9044	1007:9045	1007:9046	1007:9047
1008:9042	1008:9043	1008:9044	1008:9045	1008:9046	1008:9047
1009:9042	1009:9043	1009:9044	1009:9045	1009:9046	1009:9047
1010:9042	1010:9043	1010:9044	1010:9045	1010:9046	1010:9047
1011:9042	1011:9043	1011:9044	1011:9045	1011:9046	1011:9047
1012:9042	1012:9043	1012:9044	1012:9045	1012:9046	1012:9047
1013:9042	1013:9043	1013:9044	1013:9045	1013:9046	1013:9047
1014:9042	1014:9043	1014:9044	1014:9045	1014:9046	1014:9047
1015:9042	1015:9043	1015:9044	1015:9045	1015:9046	1015:9047
1016:9042	1016:9043	1016:9044	1016:9045	1016:9046	1016:9047
2001:9042	2001:9043	2001:9044	2001:9045	2001:9046	2001:9047
2002:9042	2002:9043	2002:9044	2002:9045	2002:9046	2002:9047
2003:9042	2003:9043	2003:9044	2003:9045	2003:9046	2003:9047
2004:9042	2004:9043	2004:9044	2004:9045	2004:9046	2004:9047
2005:9042	2005:9043	2005:9044	2005:9045	2005:9046	2005:9047
2006:9042	2006:9043	2006:9044	2006:9045	2006:9046	2006:9047
2007:9042	2007:9043	2007:9044	2007:9045	2007:9046	2007:9047
2008:9042	2008:9043	2008:9044	2008:9045	2008:9046	2008:9047
2009:9042	2009:9043	2009:9044	2009:9045	2009:9046	2009:9047
2010:9042	2010:9043	2010:9044	2010:9045	2010:9046	2010:9047
2011:9042	2011:9043	2011:9044	2011:9045	2011:9046	2011:9047
2012:9042	2012:9043	2012:9044	2012:9045	2012:9046	2012:9047
1001:9048	1001:9049	1001:9050	1001:9051	1001:9052	1001:9053
1002:9048	1002:9049	1002:9050	1002:9051	1002:9052	1002:9053
1003:9048	1003:9049	1003:9050	1003:9051	1003:9052	1003:9053
1004:9048	1004:9049	1004:9050	1004:9051	1004:9052	1004:9053
1005:9048	1005:9049	1005:9050	1005:9051	1005:9052	1005:9053
1006:9048	1006:9049	1006:9050	1006:9051	1006:9052	1006:9053
1007:9048	1007:9049	1007:9050	1007:9051	1007:9052	1007:9053
1008:9048	1008:9049	1008:9050	1008:9051	1008:9052	1008:9053
1009:9048	1009:9049	1009:9050	1009:9051	1009:9052	1009:9053
1010:9048	1010:9049	1010:9050	1010:9051	1010:9052	1010:9053
1011:9048	1011:9049	1011:9050	1011:9051	1011:9052	1011:9053
1012:9048	1012:9049	1012:9050	1012:9051	1012:9052	1012:9053
1013:9048	1013:9049	1013:9050	1013:9051	1013:9052	1013:9053
1014:9048	1014:9049	1014:9050	1014:9051	1014:9052	1014:9053
1015:9048	1015:9049	1015:9050	1015:9051	1015:9052	1015:9053
1016:9048	1016:9049	1016:9050	1016:9051	1016:9052	1016:9053
2001:9048	2001:9049	2001:9050	2001:9051	2001:9052	2001:9053
2002:9048	2002:9049	2002:9050	2002:9051	2002:9052	2002:9053
2003:9048	2003:9049	2003:9050	2003:9051	2003:9052	2003:9053
2004:9048	2004:9049	2004:9050	2004:9051	2004:9052	2004:9053
2005:9048	2005:9049	2005:9050	2005:9051	2005:9052	2005:9053
2006:9048	2006:9049	2006:9050	2006:9051	2006:9052	2006:9053
2007:9048	2007:9049	2007:9050	2007:9051	2007:9052	2007:9053
2008:9048	2008:9049	2008:9050	2008:9051	2008:9052	2008:9053
2009:9048	2009:9049	2009:9050	2009:9051	2009:9052	2009:9053
2010:9048	2010:9049	2010:9050	2010:9051	2010:9052	2010:9053
2011:9048	2011:9049	2011:9050	2011:9051	2011:9052	2011:9053
2012:9048	2012:9049	2012:9050	2012:9051	2012:9052	2012:9053
1001:9054	1001:9055	1001:9056	1001:9057	1001:9058	1001:9059
1002:9054	1002:9055	1002:9056	1002:9057	1002:9058	1002:9059
1003:9054	1003:9055	1003:9056	1003:9057	1003:9058	1003:9059
1004:9054	1004:9055	1004:9056	1004:9057	1004:9058	1004:9059
1005:9054	1005:9055	1005:9056	1005:9057	1005:9058	1005:9059
1006:9054	1006:9055	1006:9056	1006:9057	1006:9058	1006:9059
1007:9054	1007:9055	1007:9056	1007:9057	1007:9058	1007:9059
1008:9054	1008:9055	1008:9056	1008:9057	1008:9058	1008:9059
1009:9054	1009:9055	1009:9056	1009:9057	1009:9058	1009:9059
1010:9054	1010:9055	1010:9056	1010:9057	1010:9058	1010:9059
1011:9054	1011:9055	1011:9056	1011:9057	1011:9058	1011:9059
1012:9054	1012:9055	1012:9056	1012:9057	1012:9058	1012:9059
1013:9054	1013:9055	1013:9056	1013:9057	1013:9058	1013:9059
1014:9054	1014:9055	1014:9056	1014:9057	1014:9058	1014:9059
1015:9054	1015:9055	1015:9056	1015:9057	1015:9058	1015:9059
1016:9054	1016:9055	1016:9056	1016:9057	1016:9058	1016:9059
2001:9054	2001:9055	2001:9056	2001:9057	2001:9058	2001:9059
2002:9054	2002:9055	2002:9056	2002:9057	2002:9058	2002:9059
2003:9054	2003:9055	2003:9056	2003:9057	2003:9058	2003:9059
2004:9054	2004:9055	2004:9056	2004:9057	2004:9058	2004:9059
2005:9054	2005:9055	2005:9056	2005:9057	2005:9058	2005:9059
2006:9054	2006:9055	2006:9056	2006:9057	2006:9058	2006:9059
2007:9054	2007:9055	2007:9056	2007:9057	2007:9058	2007:9059
2008:9054	2008:9055	2008:9056	2008:9057	2008:9058	2008:9059
2009:9054	2009:9055	2009:9056	2009:9057	2009:9058	2009:9059
2010:9054	2010:9055	2010:9056	2010:9057	2010:9058	2010:9059
2011:9054	2011:9055	2011:9056	2011:9057	2011:9058	2011:9059
2012:9054	2012:9055	2012:9056	2012:9057	2012:9058	2012:9059
1001:9060	1001:9061	1001:9062	1001:9063	1001:9064	1001:9065
1002:9060	1002:9061	1002:9062	1002:9063	1002:9064	1002:9065
1003:9060	1003:9061	1003:9062	1003:9063	1003:9064	1003:9065
1004:9060	1004:9061	1004:9062	1004:9063	1004:9064	1004:9065
1005:9060	1005:9061	1005:9062	1005:9063	1005:9064	1005:9065
1006:9060	1006:9061	1006:9062	1006:9063	1006:9064	1006:9065
1007:9060	1007:9061	1007:9062	1007:9063	1007:9064	1007:9065
1008:9060	1008:9061	1008:9062	1008:9063	1008:9064	1008:9065
1009:9060	1009:9061	1009:9062	1009:9063	1009:9064	1009:9065
1010:9060	1010:9061	1010:9062	1010:9063	1010:9064	1010:9065
1011:9060	1011:9061	1011:9062	1011:9063	1011:9064	1011:9065
1012:9060	1012:9061	1012:9062	1012:9063	1012:9064	1012:9065
1013:9060	1013:9061	1013:9062	1013:9063	1013:9064	1013:9065
1014:9060	1014:9061	1014:9062	1014:9063	1014:9064	1014:9065
1015:9060	1015:9061	1015:9062	1015:9063	1015:9064	1015:9065
1016:9060	1016:9061	1016:9062	1016:9063	1016:9064	1016:9065
2001:9060	2001:9061	2001:9062	2001:9063	2001:9064	2001:9065
2002:9060	2002:9061	2002:9062	2002:9063	2002:9064	2002:9065
2003:9060	2003:9061	2003:9062	2003:9063	2003:9064	2003:9065
2004:9060	2004:9061	2004:9062	2004:9063	2004:9064	2004:9065
2005:9060	2005:9061	2005:9062	2005:9063	2005:9064	2005:9065
2006:9060	2006:9061	2006:9062	2006:9063	2006:9064	2006:9065
2007:9060	2007:9061	2007:9062	2007:9063	2007:9064	2007:9065
2008:9060	2008:9061	2008:9062	2008:9063	2008:9064	2008:9065
2009:9060	2009:9061	2009:9062	2009:9063	2009:9064	2009:9065
2010:9060	2010:9061	2010:9062	2010:9063	2010:9064	2010:9065
2011:9060	2011:9061	2011:9062	2011:9063	2011:9064	2011:9065
2012:9060	2012:9061	2012:9062	2012:9063	2012:9064	2012:9065
1001:9066	1001:9067	1001:9068	1001:9069	1001:9070	1001:9071
1002:9066	1002:9067	1002:9068	1002:9069	1002:9070	1002:9071
1003:9066	1003:9067	1003:9068	1003:9069	1003:9070	1003:9071
1004:9066	1004:9067	1004:9068	1004:9069	1004:9070	1004:9071
1005:9066	1005:9067	1005:9068	1005:9069	1005:9070	1005:9071
1006:9066	1006:9067	1006:9068	1006:9069	1006:9070	1006:9071
1007:9066	1007:9067	1007:9068	1007:9069	1007:9070	1007:9071
1008:9066	1008:9067	1008:9068	1008:9069	1008:9070	1008:9071
1009:9066	1009:9067	1009:9068	1009:9069	1009:9070	1009:9071
1010:9066	1010:9067	1010:9068	1010:9069	1010:9070	1010:9071
1011:9066	1011:9067	1011:9068	1011:9069	1011:9070	1011:9071
1012:9066	1012:9067	1012:9068	1012:9069	1012:9070	1012:9071
1013:9066	1013:9067	1013:9068	1013:9069	1013:9070	1013:9071
1014:9066	1014:9067	1014:9068	1014:9069	1014:9070	1014:9071
1015:9066	1015:9067	1015:9068	1015:9069	1015:9070	1015:9071
1016:9066	1016:9067	1016:9068	1016:9069	1016:9070	1016:9071
2001:9066	2001:9067	2001:9068	2001:9069	2001:9070	2001:9071
2002:9066	2002:9067	2002:9068	2002:9069	2002:9070	2002:9071
2003:9066	2003:9067	2003:9068	2003:9069	2003:9070	2003:9071
2004:9066	2004:9067	2004:9068	2004:9069	2004:9070	2004:9071
2005:9066	2005:9067	2005:9068	2005:9069	2005:9070	2005:9071
2006:9066	2006:9067	2006:9068	2006:9069	2006:9070	2006:9071
2007:9066	2007:9067	2007:9068	2007:9069	2007:9070	2007:9071
2008:9066	2008:9067	2008:9068	2008:9069	2008:9070	2008:9071
2009:9066	2009:9067	2009:9068	2009:9069	2009:9070	2009:9071
2010:9066	2010:9067	2010:9068	2010:9069	2010:9070	2010:9071
2011:9066	2011:9067	2011:9068	2011:9069	2011:9070	2011:9071
2012:9066	2012:9067	2012:9068	2012:9069	2012:9070	2012:9071
1001:9072	1001:9073	1001:9074	1001:9075	1001:9076	1001:9077
1002:9072	1002:9073	1002:9074	1002:9075	1002:9076	1002:9077
1003:9072	1003:9073	1003:9074	1003:9075	1003:9076	1003:9077
1004:9072	1004:9073	1004:9074	1004:9075	1004:9076	1004:9077
1005:9072	1005:9073	1005:9074	1005:9075	1005:9076	1005:9077
1006:9072	1006:9073	1006:9074	1006:9075	1006:9076	1006:9077
1007:9072	1007:9073	1007:9074	1007:9075	1007:9076	1007:9077
1008:9072	1008:9073	1008:9074	1008:9075	1008:9076	1008:9077
1009:9072	1009:9073	1009:9074	1009:9075	1009:9076	1009:9077
1010:9072	1010:9073	1010:9074	1010:9075	1010:9076	1010:9077
1011:9072	1011:9073	1011:9074	1011:9075	1011:9076	1011:9077
1012:9072	1012:9073	1012:9074	1012:9075	1012:9076	1012:9077
1013:9072	1013:9073	1013:9074	1013:9075	1013:9076	1013:9077
1014:9072	1014:9073	1014:9074	1014:9075	1014:9076	1014:9077
1015:9072	1015:9073	1015:9074	1015:9075	1015:9076	1015:9077
1016:9072	1016:9073	1016:9074	1016:9075	1016:9076	1016:9077
2001:9072	2001:9073	2001:9074	2001:9075	2001:9076	2001:9077
2002:9072	2002:9073	2002:9074	2002:9075	2002:9076	2002:9077
2003:9072	2003:9073	2003:9074	2003:9075	2003:9076	2003:9077
2004:9072	2004:9073	2004:9074	2004:9075	2004:9076	2004:9077
2005:9072	2005:9073	2005:9074	2005:9075	2005:9076	2005:9077
2006:9072	2006:9073	2006:9074	2006:9075	2006:9076	2006:9077
2007:9072	2007:9073	2007:9074	2007:9075	2007:9076	2007:9077
2008:9072	2008:9073	2008:9074	2008:9075	2008:9076	2008:9077
2009:9072	2009:9073	2009:9074	2009:9075	2009:9076	2009:9077
2010:9072	2010:9073	2010:9074	2010:9075	2010:9076	2010:9077
2011:9072	2011:9073	2011:9074	2011:9075	2011:9076	2011:9077
2012:9072	2012:9073	2012:9074	2012:9075	2012:9076	2012:9077
1001:9078	1001:9079	1001:9080	1001:9081	1001:9082	1001:9083
1002:9078	1002:9079	1002:9080	1002:9081	1002:9082	1002:9083
1003:9078	1003:9079	1003:9080	1003:9081	1003:9082	1003:9083
1004:9078	1004:9079	1004:9080	1004:9081	1004:9082	1004:9083
1005:9078	1005:9079	1005:9080	1005:9081	1005:9082	1005:9083
1006:9078	1006:9079	1006:9080	1006:9081	1006:9082	1006:9083
1007:9078	1007:9079	1007:9080	1007:9081	1007:9082	1007:9083
1008:9078	1008:9079	1008:9080	1008:9081	1008:9082	1008:9083
1009:9078	1009:9079	1009:9080	1009:9081	1009:9082	1009:9083
1010:9078	1010:9079	1010:9080	1010:9081	1010:9082	1010:9083
1011:9078	1011:9079	1011:9080	1011:9081	1011:9082	1011:9083
1012:9078	1012:9079	1012:9080	1012:9081	1012:9082	1012:9083
1013:9078	1013:9079	1013:9080	1013:9081	1013:9082	1013:9083
1014:9078	1014:9079	1014:9080	1014:9081	1014:9082	1014:9083
1015:9078	1015:9079	1015:9080	1015:9081	1015:9082	1015:9083
1016:9078	1016:9079	1016:9080	1016:9081	1016:9082	1016:9083
2001:9078	2001:9079	2001:9080	2001:9081	2001:9082	2001:9083
2002:9078	2002:9079	2002:9080	2002:9081	2002:9082	2002:9083
2003:9078	2003:9079	2003:9080	2003:9081	2003:9082	2003:9083
2004:9078	2004:9079	2004:9080	2004:9081	2004:9082	2004:9083
2005:9078	2005:9079	2005:9080	2005:9081	2005:9082	2005:9083
2006:9078	2006:9079	2006:9080	2006:9081	2006:9082	2006:9083
2007:9078	2007:9079	2007:9080	2007:9081	2007:9082	2007:9083
2008:9078	2008:9079	2008:9080	2008:9081	2008:9082	2008:9083
2009:9078	2009:9079	2009:9080	2009:9081	2009:9082	2009:9083
2010:9078	2010:9079	2010:9080	2010:9081	2010:9082	2010:9083
2011:9078	2011:9079	2011:9080	2011:9081	2011:9082	2011:9083
2012:9078	2012:9079	2012:9080	2012:9081	2012:9082	2012:9083
1001:9084	1001:9085	1001:9086	1001:9087	1001:9088	1001:9089
1002:9084	1002:9085	1002:9086	1002:9087	1002:9088	1002:9089
1003:9084	1003:9085	1003:9086	1003:9087	1003:9088	1003:9089
1004:9084	1004:9085	1004:9086	1004:9087	1004:9088	1004:9089
1005:9084	1005:9085	1005:9086	1005:9087	1005:9088	1005:9089
1006:9084	1006:9085	1006:9086	1006:9087	1006:9088	1006:9089
1007:9084	1007:9085	1007:9086	1007:9087	1007:9088	1007:9089
1008:9084	1008:9085	1008:9086	1008:9087	1008:9088	1008:9089
1009:9084	1009:9085	1009:9086	1009:9087	1009:9088	1009:9089
1010:9084	1010:9085	1010:9086	1010:9087	1010:9088	1010:9089
1011:9084	1011:9085	1011:9086	1011:9087	1011:9088	1011:9089
1012:9084	1012:9085	1012:9086	1012:9087	1012:9088	1012:9089
1013:9084	1013:9085	1013:9086	1013:9087	1013:9088	1013:9089
1014:9084	1014:9085	1014:9086	1014:9087	1014:9088	1014:9089
1015:9084	1015:9085	1015:9086	1015:9087	1015:9088	1015:9089
1016:9084	1016:9085	1016:9086	1016:9087	1016:9088	1016:9089
2001:9084	2001:9085	2001:9086	2001:9087	2001:9088	2001:9089
2002:9084	2002:9085	2002:9086	2002:9087	2002:9088	2002:9089
2003:9084	2003:9085	2003:9086	2003:9087	2003:9088	2003:9089
2004:9084	2004:9085	2004:9086	2004:9087	2004:9088	2004:9089
2005:9084	2005:9085	2005:9086	2005:9087	2005:9088	2005:9089
2006:9084	2006:9085	2006:9086	2006:9087	2006:9088	2006:9089
2007:9084	2007:9085	2007:9086	2007:9087	2007:9088	2007:9089
2008:9084	2008:9085	2008:9086	2008:9087	2008:9088	2008:9089
2009:9084	2009:9085	2009:9086	2009:9087	2009:9088	2009:9089
2010:9084	2010:9085	2010:9086	2010:9087	2010:9088	2010:9089
2011:9084	2011:9085	2011:9086	2011:9087	2011:9088	2011:9089
2012:9084	2012:9085	2012:9086	2012:9087	2012:9088	2012:9089
1001:9090	1001:9091	1001:9092	1001:9093	1001:9094	1001:9095
1002:9090	1002:9091	1002:9092	1002:9093	1002:9094	1002:9095
1003:9090	1003:9091	1003:9092	1003:9093	1003:9094	1003:9095
1004:9090	1004:9091	1004:9092	1004:9093	1004:9094	1004:9095
1005:9090	1005:9091	1005:9092	1005:9093	1005:9094	1005:9095
1006:9090	1006:9091	1006:9092	1006:9093	1006:9094	1006:9095
1007:9090	1007:9091	1007:9092	1007:9093	1007:9094	1007:9095
1008:9090	1008:9091	1008:9092	1008:9093	1008:9094	1008:9095
1009:9090	1009:9091	1009:9092	1009:9093	1009:9094	1009:9095
1010:9090	1010:9091	1010:9092	1010:9093	1010:9094	1010:9095
1011:9090	1011:9091	1011:9092	1011:9093	1011:9094	1011:9095
1012:9090	1012:9091	1012:9092	1012:9093	1012:9094	1012:9095
1013:9090	1013:9091	1013:9092	1013:9093	1013:9094	1013:9095
1014:9090	1014:9091	1014:9092	1014:9093	1014:9094	1014:9095
1015:9090	1015:9091	1015:9092	1015:9093	1015:9094	1015:9095
1016:9090	1016:9091	1016:9092	1016:9093	1016:9094	1016:9095
2001:9090	2001:9091	2001:9092	2001:9093	2001:9094	2001:9095
2002:9090	2002:9091	2002:9092	2002:9093	2002:9094	2002:9095
2003:9090	2003:9091	2003:9092	2003:9093	2003:9094	2003:9095
2004:9090	2004:9091	2004:9092	2004:9093	2004:9094	2004:9095
2005:9090	2005:9091	2005:9092	2005:9093	2005:9094	2005:9095
2006:9090	2006:9091	2006:9092	2006:9093	2006:9094	2006:9095
2007:9090	2007:9091	2007:9092	2007:9093	2007:9094	2007:9095
2008:9090	2008:9091	2008:9092	2008:9093	2008:9094	2008:9095
2009:9090	2009:9091	2009:9092	2009:9093	2009:9094	2009:9095
2010:9090	2010:9091	2010:9092	2010:9093	2010:9094	2010:9095
2011:9090	2011:9091	2011:9092	2011:9093	2011:9094	2011:9095
2012:9090	2012:9091	2012:9092	2012:9093	2012:9094	2012:9095
1001:9096	1001:9097	1001:9098	1001:9099	1001:9100	1001:9101
1002:9096	1002:9097	1002:9098	1002:9099	1002:9100	1002:9101
1003:9096	1003:9097	1003:9098	1003:9099	1003:9100	1003:9101
1004:9096	1004:9097	1004:9098	1004:9099	1004:9100	1004:9101
1005:9096	1005:9097	1005:9098	1005:9099	1005:9100	1005:9101
1006:9096	1006:9097	1006:9098	1006:9099	1006:9100	1006:9101
1007:9096	1007:9097	1007:9098	1007:9099	1007:9100	1007:9101
1008:9096	1008:9097	1008:9098	1008:9099	1008:9100	1008:9101
1009:9096	1009:9097	1009:9098	1009:9099	1009:9100	1009:9101
1010:9096	1010:9097	1010:9098	1010:9099	1010:9100	1010:9101
1011:9096	1011:9097	1011:9098	1011:9099	1011:9100	1011:9101
1012:9096	1012:9097	1012:9098	1012:9099	1012:9100	1012:9101
1013:9096	1013:9097	1013:9098	1013:9099	1013:9100	1013:9101
1014:9096	1014:9097	1014:9098	1014:9099	1014:9100	1014:9101
1015:9096	1015:9097	1015:9098	1015:9099	1015:9100	1015:9101
1016:9096	1016:9097	1016:9098	1016:9099	1016:9100	1016:9101
2001:9096	2001:9097	2001:9098	2001:9099	2001:9100	2001:9101
2002:9096	2002:9097	2002:9098	2002:9099	2002:9100	2002:9101
2003:9096	2003:9097	2003:9098	2003:9099	2003:9100	2003:9101
2004:9096	2004:9097	2004:9098	2004:9099	2004:9100	2004:9101
2005:9096	2005:9097	2005:9098	2005:9099	2005:9100	2005:9101
2006:9096	2006:9097	2006:9098	2006:9099	2006:9100	2006:9101
2007:9096	2007:9097	2007:9098	2007:9099	2007:9100	2007:9101
2008:9096	2008:9097	2008:9098	2008:9099	2008:9100	2008:9101
2009:9096	2009:9097	2009:9098	2009:9099	2009:9100	2009:9101
2010:9096	2010:9097	2010:9098	2010:9099	2010:9100	2010:9101
2011:9096	2011:9097	2011:9098	2011:9099	2011:9100	2011:9101
2012:9096	2012:9097	2012:9098	2012:9099	2012:9100	2012:9101
1001:9102	1001:9103	1001:9104	1001:9105	—	—
1002:9102	1002:9103	1002:9104	1002:9105
1003:9102	1003:9103	1003:9104	1003:9105
1004:9102	1004:9103	1004:9104	1004:9105
1005:9102	1005:9103	1005:9104	1005:9105
1006:9102	1006:9103	1006:9104	1006:9105
1007:9102	1007:9103	1007:9104	1007:9105
1008:9102	1008:9103	1008:9104	1008:9105
1009:9102	1009:9103	1009:9104	1009:9105
1010:9102	1010:9103	1010:9104	1010:9105
1011:9102	1011:9103	1011:9104	1011:9105
1012:9102	1012:9103	1012:9104	1012:9105
1013:9102	1013:9103	1013:9104	1013:9105
1014:9102	1014:9103	1014:9104	1014:9105
1015:9102	1015:9103	1015:9104	1015:9105
1016:9102	1016:9103	1016:9104	1016:9105
2001:9102	2001:9103	2001:9104	2001:9105
2002:9102	2002:9103	2002:9104	2002:9105
2003:9102	2003:9103	2003:9104	2003:9105
2004:9102	2004:9103	2004:9104	2004:9105
2005:9102	2005:9103	2005:9104	2005:9105
2006:9102	2006:9103	2006:9104	2006:9105
2007:9102	2007:9103	2007:9104	2007:9105
2008:9102	2008:9103	2008:9104	2008:9105
2009:9102	2009:9103	2009:9104	2009:9105
2010:9102	2010:9103	2010:9104	2010:9105
2011:9102	2011:9103	2011:9104	2011:9105
2012:9102	2012:9103	2012:9104	2012:9105

TABLE B
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
3001:9000	3001:9001	3001:9002	3001:9003	3001:9004	3001:9005
3002:9000	3002:9001	3002:9002	3002:9003	3002:9004	3002:9005
3003:9000	3003:9001	3003:9002	3003:9003	3003:9004	3003:9005
3004:9000	3004:9001	3004:9002	3004:9003	3004:9004	3004:9005
3005:9000	3005:9001	3005:9002	3005:9003	3005:9004	3005:9005
3006:9000	3006:9001	3006:9002	3006:9003	3006:9004	3006:9005
3007:9000	3007:9001	3007:9002	3007:9003	3007:9004	3007:9005
3008:9000	3008:9001	3008:9002	3008:9003	3008:9004	3008:9005
3009:9000	3009:9001	3009:9002	3009:9003	3009:9004	3009:9005
3010:9000	3010:9001	3010:9002	3010:9003	3010:9004	3010:9005
3011:9000	3011:9001	3011:9002	3011:9003	3011:9004	3011:9005
3012:9000	3012:9001	3012:9002	3012:9003	3012:9004	3012:9005
3013:9000	3013:9001	3013:9002	3013:9003	3013:9004	3013:9005
3014:9000	3014:9001	3014:9002	3014:9003	3014:9004	3014:9005
4001:9000	4001:9001	4001:9002	4001:9003	4001:9004	4001:9005
4002:9000	4002:9001	4002:9002	4002:9003	4002:9004	4002:9005
4003:9000	4003:9001	4003:9002	4003:9003	4003:9004	4003:9005
4004:9000	4004:9001	4004:9002	4004:9003	4004:9004	4004:9005
4005:9000	4005:9001	4005:9002	4005:9003	4005:9004	4005:9005
4006:9000	4006:9001	4006:9002	4006:9003	4006:9004	4006:9005
4007:9000	4007:9001	4007:9002	4007:9003	4007:9004	4007:9005
4008:9000	4008:9001	4008:9002	4008:9003	4008:9004	4008:9005
4009:9000	4009:9001	4009:9002	4009:9003	4009:9004	4009:9005
4010:9000	4010:9001	4010:9002	4010:9003	4010:9004	4010:9005
4011:9000	4011:9001	4011:9002	4011:9003	4011:9004	4011:9005
4012:9000	4012:9001	4012:9002	4012:9003	4012:9004	4012:9005
5001:9000	5001:9001	5001:9002	5001:9003	5001:9004	5001:9005
5002:9000	5002:9001	5002:9002	5002:9003	5002:9004	5002:9005
5003:9000	5003:9001	5003:9002	5003:9003	5003:9004	5003:9005
5004:9000	5004:9001	5004:9002	5004:9003	5004:9004	5004:9005
5005:9000	5005:9001	5005:9002	5005:9003	5005:9004	5005:9005
5006:9000	5006:9001	5006:9002	5006:9003	5006:9004	5006:9005
5007:9000	5007:9001	5007:9002	5007:9003	5007:9004	5007:9005
5008:9000	5008:9001	5008:9002	5008:9003	5008:9004	5008:9005
5009:9000	5009:9001	5009:9002	5009:9003	5009:9004	5009:9005
5010:9000	5010:9001	5010:9002	5010:9003	5010:9004	5010:9005
5011:9000	5011:9001	5011:9002	5011:9003	5011:9004	5011:9005
5012:9000	5012:9001	5012:9002	5012:9003	5012:9004	5012:9005
3001:9006	3001:9007	3001:9008	3001:9009	3001:9010	3001:9011
3002:9006	3002:9007	3002:9008	3002:9009	3002:9010	3002:9011
3003:9006	3003:9007	3003:9008	3003:9009	3003:9010	3003:9011
3004:9006	3004:9007	3004:9008	3004:9009	3004:9010	3004:9011
3005:9006	3005:9007	3005:9008	3005:9009	3005:9010	3005:9011
3006:9006	3006:9007	3006:9008	3006:9009	3006:9010	3006:9011
3007:9006	3007:9007	3007:9008	3007:9009	3007:9010	3007:9011
3008:9006	3008:9007	3008:9008	3008:9009	3008:9010	3008:9011
3009:9006	3009:9007	3009:9008	3009:9009	3009:9010	3009:9011
3010:9006	3010:9007	3010:9008	3010:9009	3010:9010	3010:9011
3011:9006	3011:9007	3011:9008	3011:9009	3011:9010	3011:9011
3012:9006	3012:9007	3012:9008	3012:9009	3012:9010	3012:9011
3013:9006	3013:9007	3013:9008	3013:9009	3013:9010	3013:9011
3014:9006	3014:9007	3014:9008	3014:9009	3014:9010	3014:9011
4001:9006	4001:9007	4001:9008	4001:9009	4001:9010	4001:9011
4002:9006	4002:9007	4002:9008	4002:9009	4002:9010	4002:9011
4003:9006	4003:9007	4003:9008	4003:9009	4003:9010	4003:9011
4004:9006	4004:9007	4004:9008	4004:9009	4004:9010	4004:9011
4005:9006	4005:9007	4005:9008	4005:9009	4005:9010	4005:9011
4006:9006	4006:9007	4006:9008	4006:9009	4006:9010	4006:9011
4007:9006	4007:9007	4007:9008	4007:9009	4007:9010	4007:9011
4008:9006	4008:9007	4008:9008	4008:9009	4008:9010	4008:9011
4009:9006	4009:9007	4009:9008	4009:9009	4009:9010	4009:9011
4010:9006	4010:9007	4010:9008	4010:9009	4010:9010	4010:9011
4011:9006	4011:9007	4011:9008	4011:9009	4011:9010	4011:9011
4012:9006	4012:9007	4012:9008	4012:9009	4012:9010	4012:9011
5001:9006	5001:9007	5001:9008	5001:9009	5001:9010	5001:9011
5002:9006	5002:9007	5002:9008	5002:9009	5002:9010	5002:9011
5003:9006	5003:9007	5003:9008	5003:9009	5003:9010	5003:9011
5004:9006	5004:9007	5004:9008	5004:9009	5004:9010	5004:9011
5005:9006	5005:9007	5005:9008	5005:9009	5005:9010	5005:9011
5006:9006	5006:9007	5006:9008	5006:9009	5006:9010	5006:9011
5007:9006	5007:9007	5007:9008	5007:9009	5007:9010	5007:9011
5008:9006	5008:9007	5008:9008	5008:9009	5008:9010	5008:9011
5009:9006	5009:9007	5009:9008	5009:9009	5009:9010	5009:9011
5010:9006	5010:9007	5010:9008	5010:9009	5010:9010	5010:9011
5011:9006	5011:9007	5011:9008	5011:9009	5011:9010	5011:9011
5012:9006	5012:9007	5012:9008	5012:9009	5012:9010	5012:9011
3001:9012	3001:9013	3001:9014	3001:9015	3001:9016	3001:9017
3002:9012	3002:9013	3002:9014	3002:9015	3002:9016	3002:9017
3003:9012	3003:9013	3003:9014	3003:9015	3003:9016	3003:9017
3004:9012	3004:9013	3004:9014	3004:9015	3004:9016	3004:9017
3005:9012	3005:9013	3005:9014	3005:9015	3005:9016	3005:9017
3006:9012	3006:9013	3006:9014	3006:9015	3006:9016	3006:9017
3007:9012	3007:9013	3007:9014	3007:9015	3007:9016	3007:9017
3008:9012	3008:9013	3008:9014	3008:9015	3008:9016	3008:9017
3009:9012	3009:9013	3009:9014	3009:9015	3009:9016	3009:9017
3010:9012	3010:9013	3010:9014	3010:9015	3010:9016	3010:9017
3011:9012	3011:9013	3011:9014	3011:9015	3011:9016	3011:9017
3012:9012	3012:9013	3012:9014	3012:9015	3012:9016	3012:9017
3013:9012	3013:9013	3013:9014	3013:9015	3013:9016	3013:9017
3014:9012	3014:9013	3014:9014	3014:9015	3014:9016	3014:9017
4001:9012	4001:9013	4001:9014	4001:9015	4001:9016	4001:9017
4002:9012	4002:9013	4002:9014	4002:9015	4002:9016	4002:9017
4003:9012	4003:9013	4003:9014	4003:9015	4003:9016	4003:9017
4004:9012	4004:9013	4004:9014	4004:9015	4004:9016	4004:9017
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3001:9084	3001:9085	3001:9086	3001:9087	3001:9088	3001:9089
3002:9084	3002:9085	3002:9086	3002:9087	3002:9088	3002:9089
3003:9084	3003:9085	3003:9086	3003:9087	3003:9088	3003:9089
3004:9084	3004:9085	3004:9086	3004:9087	3004:9088	3004:9089
3005:9084	3005:9085	3005:9086	3005:9087	3005:9088	3005:9089
3006:9084	3006:9085	3006:9086	3006:9087	3006:9088	3006:9089
3007:9084	3007:9085	3007:9086	3007:9087	3007:9088	3007:9089
3008:9084	3008:9085	3008:9086	3008:9087	3008:9088	3008:9089
3009:9084	3009:9085	3009:9086	3009:9087	3009:9088	3009:9089
3010:9084	3010:9085	3010:9086	3010:9087	3010:9088	3010:9089
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3014:9084	3014:9085	3014:9086	3014:9087	3014:9088	3014:9089
4001:9084	4001:9085	4001:9086	4001:9087	4001:9088	4001:9089
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4004:9084	4004:9085	4004:9086	4004:9087	4004:9088	4004:9089
4005:9084	4005:9085	4005:9086	4005:9087	4005:9088	4005:9089
4006:9084	4006:9085	4006:9086	4006:9087	4006:9088	4006:9089
4007:9084	4007:9085	4007:9086	4007:9087	4007:9088	4007:9089
4008:9084	4008:9085	4008:9086	4008:9087	4008:9088	4008:9089
4009:9084	4009:9085	4009:9086	4009:9087	4009:9088	4009:9089
4010:9084	4010:9085	4010:9086	4010:9087	4010:9088	4010:9089
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5001:9084	5001:9085	5001:9086	5001:9087	5001:9088	5001:9089
5002:9084	5002:9085	5002:9086	5002:9087	5002:9088	5002:9089
5003:9084	5003:9085	5003:9086	5003:9087	5003:9088	5003:9089
5004:9084	5004:9085	5004:9086	5004:9087	5004:9088	5004:9089
5005:9084	5005:9085	5005:9086	5005:9087	5005:9088	5005:9089
5006:9084	5006:9085	5006:9086	5006:9087	5006:9088	5006:9089
5007:9084	5007:9085	5007:9086	5007:9087	5007:9088	5007:9089
5008:9084	5008:9085	5008:9086	5008:9087	5008:9088	5008:9089
5009:9084	5009:9085	5009:9086	5009:9087	5009:9088	5009:9089
5010:9084	5010:9085	5010:9086	5010:9087	5010:9088	5010:9089
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5012:9084	5012:9085	5012:9086	5012:9087	5012:9088	5012:9089
3001:9090	3001:9091	3001:9092	3001:9093	3001:9094	3001:9095
3002:9090	3002:9091	3002:9092	3002:9093	3002:9094	3002:9095
3003:9090	3003:9091	3003:9092	3003:9093	3003:9094	3003:9095
3004:9090	3004:9091	3004:9092	3004:9093	3004:9094	3004:9095
3005:9090	3005:9091	3005:9092	3005:9093	3005:9094	3005:9095
3006:9090	3006:9091	3006:9092	3006:9093	3006:9094	3006:9095
3007:9090	3007:9091	3007:9092	3007:9093	3007:9094	3007:9095
3008:9090	3008:9091	3008:9092	3008:9093	3008:9094	3008:9095
3009:9090	3009:9091	3009:9092	3009:9093	3009:9094	3009:9095
3010:9090	3010:9091	3010:9092	3010:9093	3010:9094	3010:9095
3011:9090	3011:9091	3011:9092	3011:9093	3011:9094	3011:9095
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3013:9090	3013:9091	3013:9092	3013:9093	3013:9094	3013:9095
3014:9090	3014:9091	3014:9092	3014:9093	3014:9094	3014:9095
4001:9090	4001:9091	4001:9092	4001:9093	4001:9094	4001:9095
4002:9090	4002:9091	4002:9092	4002:9093	4002:9094	4002:9095
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4004:9090	4004:9091	4004:9092	4004:9093	4004:9094	4004:9095
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4007:9090	4007:9091	4007:9092	4007:9093	4007:9094	4007:9095
4008:9090	4008:9091	4008:9092	4008:9093	4008:9094	4008:9095
4009:9090	4009:9091	4009:9092	4009:9093	4009:9094	4009:9095
4010:9090	4010:9091	4010:9092	4010:9093	4010:9094	4010:9095
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4012:9090	4012:9091	4012:9092	4012:9093	4012:9094	4012:9095
5001:9090	5001:9091	5001:9092	5001:9093	5001:9094	5001:9095
5002:9090	5002:9091	5002:9092	5002:9093	5002:9094	5002:9095
5003:9090	5003:9091	5003:9092	5003:9093	5003:9094	5003:9095
5004:9090	5004:9091	5004:9092	5004:9093	5004:9094	5004:9095
5005:9090	5005:9091	5005:9092	5005:9093	5005:9094	5005:9095
5006:9090	5006:9091	5006:9092	5006:9093	5006:9094	5006:9095
5007:9090	5007:9091	5007:9092	5007:9093	5007:9094	5007:9095
5008:9090	5008:9091	5008:9092	5008:9093	5008:9094	5008:9095
5009:9090	5009:9091	5009:9092	5009:9093	5009:9094	5009:9095
5010:9090	5010:9091	5010:9092	5010:9093	5010:9094	5010:9095
5011:9090	5011:9091	5011:9092	5011:9093	5011:9094	5011:9095
5012:9090	5012:9091	5012:9092	5012:9093	5012:9094	5012:9095
3001:9096	3001:9097	3001:9098	3001:9099	3001:9100	3001:9101
3002:9096	3002:9097	3002:9098	3002:9099	3002:9100	3002:9101
3003:9096	3003:9097	3003:9098	3003:9099	3003:9100	3003:9101
3004:9096	3004:9097	3004:9098	3004:9099	3004:9100	3004:9101
3005:9096	3005:9097	3005:9098	3005:9099	3005:9100	3005:9101
3006:9096	3006:9097	3006:9098	3006:9099	3006:9100	3006:9101
3007:9096	3007:9097	3007:9098	3007:9099	3007:9100	3007:9101
3008:9096	3008:9097	3008:9098	3008:9099	3008:9100	3008:9101
3009:9096	3009:9097	3009:9098	3009:9099	3009:9100	3009:9101
3010:9096	3010:9097	3010:9098	3010:9099	3010:9100	3010:9101
3011:9096	3011:9097	3011:9098	3011:9099	3011:9100	3011:9101
3012:9096	3012:9097	3012:9098	3012:9099	3012:9100	3012:9101
3013:9096	3013:9097	3013:9098	3013:9099	3013:9100	3013:9101
3014:9096	3014:9097	3014:9098	3014:9099	3014:9100	3014:9101
4001:9096	4001:9097	4001:9098	4001:9099	4001:9100	4001:9101
4002:9096	4002:9097	4002:9098	4002:9099	4002:9100	4002:9101
4003:9096	4003:9097	4003:9098	4003:9099	4003:9100	4003:9101
4004:9096	4004:9097	4004:9098	4004:9099	4004:9100	4004:9101
4005:9096	4005:9097	4005:9098	4005:9099	4005:9100	4005:9101
4006:9096	4006:9097	4006:9098	4006:9099	4006:9100	4006:9101
4007:9096	4007:9097	4007:9098	4007:9099	4007:9100	4007:9101
4008:9096	4008:9097	4008:9098	4008:9099	4008:9100	4008:9101
4009:9096	4009:9097	4009:9098	4009:9099	4009:9100	4009:9101
4010:9096	4010:9097	4010:9098	4010:9099	4010:9100	4010:9101
4011:9096	4011:9097	4011:9098	4011:9099	4011:9100	4011:9101
4012:9096	4012:9097	4012:9098	4012:9099	4012:9100	4012:9101
5001:9096	5001:9097	5001:9098	5001:9099	5001:9100	5001:9101
5002:9096	5002:9097	5002:9098	5002:9099	5002:9100	5002:9101
5003:9096	5003:9097	5003:9098	5003:9099	5003:9100	5003:9101
5004:9096	5004:9097	5004:9098	5004:9099	5004:9100	5004:9101
5005:9096	5005:9097	5005:9098	5005:9099	5005:9100	5005:9101
5006:9096	5006:9097	5006:9098	5006:9099	5006:9100	5006:9101
5007:9096	5007:9097	5007:9098	5007:9099	5007:9100	5007:9101
5008:9096	5008:9097	5008:9098	5008:9099	5008:9100	5008:9101
5009:9096	5009:9097	5009:9098	5009:9099	5009:9100	5009:9101
5010:9096	5010:9097	5010:9098	5010:9099	5010:9100	5010:9101
5011:9096	5011:9097	5011:9098	5011:9099	5011:9100	5011:9101
5012:9096	5012:9097	5012:9098	5012:9099	5012:9100	5012:9101
3001:9102	3001:9103	3001:9104	3001:9105	—	—
3002:9102	3002:9103	3002:9104	3002:9105
3003:9102	3003:9103	3003:9104	3003:9105
3004:9102	3004:9103	3004:9104	3004:9105
3005:9102	3005:9103	3005:9104	3005:9105
3006:9102	3006:9103	3006:9104	3006:9105
3007:9102	3007:9103	3007:9104	3007:9105
3008:9102	3008:9103	3008:9104	3008:9105
3009:9102	3009:9103	3009:9104	3009:9105
3010:9102	3010:9103	3010:9104	3010:9105
3011:9102	3011:9103	3011:9104	3011:9105
3012:9102	3012:9103	3012:9104	3012:9105
3013:9102	3013:9103	3013:9104	3013:9105
3014:9102	3014:9103	3014:9104	3014:9105
4001:9102	4001:9103	4001:9104	4001:9105
4002:9102	4002:9103	4002:9104	4002:9105
4003:9102	4003:9103	4003:9104	4003:9105
4004:9102	4004:9103	4004:9104	4004:9105
4005:9102	4005:9103	4005:9104	4005:9105
4006:9102	4006:9103	4006:9104	4006:9105
4007:9102	4007:9103	4007:9104	4007:9105
4008:9102	4008:9103	4008:9104	4008:9105
4009:9102	4009:9103	4009:9104	4009:9105
4010:9102	4010:9103	4010:9104	4010:9105
4011:9102	4011:9103	4011:9104	4011:9105
4012:9102	4012:9103	4012:9104	4012:9105
5001:9102	5001:9103	5001:9104	5001:9105
5002:9102	5002:9103	5002:9104	5002:9105
5003:9102	5003:9103	5003:9104	5003:9105
5004:9102	5004:9103	5004:9104	5004:9105
5005:9102	5005:9103	5005:9104	5005:9105
5006:9102	5006:9103	5006:9104	5006:9105
5007:9102	5007:9103	5007:9104	5007:9105
5008:9102	5008:9103	5008:9104	5008:9105
5009:9102	5009:9103	5009:9104	5009:9105
5010:9102	5010:9103	5010:9104	5010:9105
5011:9102	5011:9103	5011:9104	5011:9105
5012:9102	5012:9103	5012:9104	5012:9105