SUBSTITUTED NUCLEOTIDE ANALOGS

Abstract

Disclosed herein are phosphoroamidate nucleotide analogs, methods of synthesizing phosphoroamidate nucleotide analogs and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with the phosphoroamidate nucleotide analogs.

Description

BACKGROUND

Field

The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are phosphoroamidate 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 phosphoroamidate nucleotide analog, alone or in combination therapy with other agents.

DESCRIPTION

Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, have been the subject of widespread research for the treatment of viral infections and cancer. Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active 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.

SUMMARY

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

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a neoplastic disease that can include administering to a subject suffering from the neoplastic disease a therapeutically 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 neoplastic disease. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a neoplastic disease.

Some embodiments disclosed herein relate to methods of inhibiting the growth of a tumor that can include administering to a subject having a tumor a therapeutically 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 inhibiting the growth of a tumor. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt of thereof, that can be used for inhibiting the growth of a tumor.

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically 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 viral infection. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a viral infection.

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the 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 viral infection that can include contacting a cell infected with the 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, that can be used for ameliorating and/or treating a viral infection by contacting a cell infected with the virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include contacting a cell infected with the 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 virus that can include contacting a cell infected with the 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 compound described herein, that can be used for inhibiting replication of a virus by contacting a cell infected with the virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a parasitic disease that can include administering to a subject suffering from the parasitic disease a therapeutically 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 parasitic disease. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a parasitic disease.

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), its mono-, di-, and/or tri-phosphate, or a pharmaceutically acceptable salt of the foregoing), 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 (BB), or a pharmaceutically acceptable salt thereof, a compound of Formula (CC), or a pharmaceutically acceptable salt thereof and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), its mono-, di-, and/or tri-phosphate, or a pharmaceutically acceptable salt of the foregoing), 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 (BB), or a pharmaceutically acceptable salt thereof, a compound of Formula (CC), or a pharmaceutically acceptable salt thereof and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), its mono-, di-, and/or tri-phosphate, or a pharmaceutically acceptable salt of the foregoing), 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 (BB), or a pharmaceutically acceptable salt thereof, a compound of Formula (CC), or a pharmaceutically acceptable salt thereof and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. In some embodiments, the agent can be a compound, or a pharmaceutically acceptable salt thereof, selected from Compound 1001-1014, 2001-2010, 3001-3008, 4001-4005, 5001-5002, 6000-6078, 8000-8012 or 9000, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or pharmaceutically acceptable salt thereof. In some embodiments, the method can further 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 (BB), or a pharmaceutically acceptable salt thereof, a compound of Formula (CC), or a pharmaceutically acceptable salt thereof and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is HCV.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows example HCV protease inhibitors.

FIG. 2 shows example nucleoside HCV polymerase inhibitors.

FIG. 3 shows example non-nucleoside HCV polymerase inhibitors.

FIG. 4 shows example NS5A inhibitors.

FIG. 5 shows example other antivirals.

FIGS. 6A-6I show example compounds of Formula (CC).

FIGS. 7A-7I show example compounds of Formula (I) and triphosphates thereof.

FIGS. 8A-8B show example compounds of Formula (BB).

FIG. 9 shows Formula (DD).

DETAILED DESCRIPTION

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.

As used herein, any “R” group(s) such as, without limitation, R¹, R², R^3a, R^3b, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R^1A, R^2A, R^3A, R^3B, R^4A, R^5A, R^6A, R^7A, R^8A and R″ represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R^1a and R^1b of an NR^1aR^1b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino and a di-substituted amino group, and protected derivatives thereof.

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, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a” to “b”, inclusive, carbon atoms. 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, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed.

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.

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.

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.

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.

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 group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. When composed of two or more rings, the rings may be joined together in a fused fashion. A cycloalkynyl group may be unsubstituted or substituted.

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.

As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. 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.

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, 3,4-methylenedioxyphenyl).

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 aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

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, and imidazolylalkyl, and their benzo-fused analogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3-thiazinan-4-yl)methyl.

“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.”

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or a cycloalkynyl is defined as above. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. An alkoxy may be substituted or unsubstituted.

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.

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.

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 and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in which R is an aryl, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.

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.

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.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

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.

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.

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

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_A)—” group wherein X is a halogen and R_A hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.

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

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

A “cyano” group refers to a “—CN” group.

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

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

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

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. A C-amido may be substituted or unsubstituted.

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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-amido may be substituted or unsubstituted.

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.

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.

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)).

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.

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).

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. 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. N-linked amino acids can be substituted or unsubstituted.

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, methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—, n-butyl-β—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—, neopentyl-O—C(═O)—, cyclopropyl-β—C(═O)—, cyclobutyl-O—C(═O)—, cyclopentyl-O—C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—, and benzyl-O—C(═O)—. N-linked amino acid ester derivatives can be substituted or unsubstituted.

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).

“Leaving group” as used herein refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates and halogens. Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.

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-toluensulfonic, 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.

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 of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. 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.

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.

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.

Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. For example all tautomers of phosphate groups are intended to be included. 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.

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).

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.

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.

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.

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

wherein: B¹ can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R¹ can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R² can be selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; R^3a and R^3b 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 aryl(C_1-6 alkyl), provided that at least one of R^3a and R^3b cannot be hydrogen; or R^3a and R^3b 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; R⁴ can be hydrogen; R⁵ can be selected from hydrogen, —OR⁹ and —OC(═O)R¹⁰; R⁶ can be selected from hydrogen, halogen, —OR¹¹ and —OC(═O)R¹²; or R⁵ and R⁶ can be both oxygen atoms and linked together by a carbonyl group; R⁷ can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl, —OR¹³ and —OC(═O)R¹⁴; R⁸ can be hydrogen or an optionally substituted C_1-6 alkyl; R⁹, R¹¹ and R¹³ can be independently selected from hydrogen and an optionally substituted C_1-6 alkyl; and R¹⁰, R¹² and R¹⁴ can be independently selected from an optionally substituted C_1-6 alkyl and an optionally substituted C_3-6 cycloalkyl.

In some embodiments, a compound of Formula (I) can have a structure selected from:

With respect to R², in some embodiments, R² can be an optionally substituted heteroaryl. In other embodiments, R² can be an optionally substituted heterocyclyl. In still other embodiments, R² can be an optionally substituted aryl. For example, R² can be an optionally substituted phenyl or an optionally substituted naphthyl. If R² is a substituted phenyl or a substituted naphthyl, the phenyl ring and the naphthyl ring(s) can be substituted one or more times. Suitable substituents that can be present on optionally substituted phenyl and an optionally substituted naphthyl include electron-donating groups and electron-withdrawing groups. In some embodiments, R² can be a para-substituted phenyl. In other embodiment, R² can be an unsubstituted phenyl or an unsubstituted naphthyl.

Various amino acids and amino acid ester derivatives can be used, including those described herein. In some embodiment, R¹ can be an optionally substituted N-linked α-amino acid. Suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional suitable amino acids include, but are not limited to, alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine. In other embodiments, R¹ can be an optionally substituted N-linked α-amino acid ester derivative. For example, R¹ can be an ester derivative 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 an embodiment, R¹ can be an ester derivative of alanine. In an embodiment, R¹ can be selected from alanine methyl ester, alanine ethyl ester, alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, when R¹ is an optionally substituted N-linked α-amino acid ester derivative, then R² can be an optionally substituted aryl. In some embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester derivative can be in the L-configuration. In other embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester derivative can be in the D-configuration.

In some embodiments, when R¹ is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, then R² can be selected from optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl. In some embodiments, when R¹ is an optionally substituted N-linked α-amino acid ester derivative, then R² can be an optionally substituted aryl. In other embodiments, when R¹ is an optionally substituted N-linked α-amino acid ester derivative, then R² can be an optionally substituted heteroaryl. In still other embodiments, when R¹ is an optionally substituted N-linked α-amino acid ester derivative, then R² can be an optionally substituted heterocyclyl.

In some embodiments, R¹ can have the structure

wherein R¹⁵ 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 C_1-6 haloalkyl; and R¹⁶ 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 R¹⁷ can be hydrogen or an optionally substituted C_1-4-alkyl; or R¹⁶ and R¹⁷ can be taken together to form an optionally substituted C_3-6 cycloalkyl.

When R¹ has the structure shown above, R¹⁶ can be an optionally substituted C_1-6-alkyl. Examples of suitable 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). When R¹⁶ is substituted, R¹⁶ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiment, R¹⁶ can be an unsubstituted C_1-6-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In an embodiment, R¹⁶ can be methyl.

As to R¹⁵, in some embodiments, R¹⁵ 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, R¹⁵ can be methyl or isopropyl. In some embodiments, R¹⁵ can be ethyl or neopentyl. In other embodiments, R¹⁵ 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 an embodiment, R¹⁵ can be an optionally substituted cyclohexyl. In still other embodiments, R¹⁵ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹⁵ can be an optionally substituted aryl(C_1-6 alkyl). In some embodiments, R¹⁵ can be an optionally substituted benzyl. In some embodiments, R¹⁵ can be an optionally substituted C_1-6 haloalkyl, for example, CF₃.

In some embodiments, R¹⁷ can be hydrogen. In other embodiments, R¹⁷ can be an optionally substituted C_1-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R¹⁷ can be methyl. In some embodiments, R¹⁶ and R¹⁷ 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 R¹⁶ and R¹⁷, the carbon to which R¹⁶ and R¹⁷ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁶ and R¹⁷ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R¹⁶ and R¹⁷ are attached may be a (S)-chiral center.

Examples of a suitable

groups include the following:

Depending upon the substituents attached to the phosphorus atom, the phosphorus atom can be a chiral center. In some embodiments, the phosphorus can be a (R)-stereocenter. In other embodiments, the phosphorus can be a (S)-stereocenter.

The substituents attached to the 5′-position of a compound of Formula (I) can vary. In some embodiments, R^3a and R^3b can be the same. In other embodiments, R^3a and R^3b can be different. In some embodiments, at least one of R^3a and R^3b cannot be hydrogen. In some embodiments, R^3a can be hydrogen. In some embodiments, R^3a can be an optionally substituted C_1-6 alkyl. Examples of suitable 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^3a can be an optionally substituted C_2-6 alkyl. In some embodiments, R^3a can be an optionally substituted C_2-6 alkenyl. In some embodiments, R^3a can be an optionally substituted C_2-6 alkynyl. In some embodiments, R^3a can be an optionally substituted C_1-6 haloalkyl. One example of a suitable optionally substituted C_1-6-haloalkyl is CF₃. In some embodiments, R^3a can be aryl(C_1-6 alkyl). One example of a suitable optionally substituted aryl(C_1-6 alkyl) is benzyl. In some embodiments, R^3b can be hydrogen. In some embodiments, R^3b can be an optionally substituted C_1-6 alkyl. In some embodiments, R^3b can be an optionally substituted C_2-6 alkyl. In some embodiments, R^3b can be an optionally substituted C_2-6 alkenyl. In some embodiments, R^3b can be an optionally substituted C_2-6 alkynyl. In some embodiments, R^3b can be an optionally substituted C_1-6 haloalkyl. In some embodiments, R^3b can be aryl(C_1-6 alkyl). In some embodiments, R^3a and R^3b 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. In some embodiments, R^3a and R^3b can be taken together to form an optionally substituted C_3-6 cycloalkyl.

In some embodiments, at least one of R^3a and R^3b can be an optionally substituted C_1-6-alkyl; and the other of R^3a and R^3b can be hydrogen. Examples of suitable 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 an embodiment, at least one of R^3a and R^3b can be methyl, and the other of R^3a and R^3b can be hydrogen. In some embodiments, at least one of R^3a and R^3b can be an optionally substituted C_2-6-alkyl; and the other of R^3a and R^3b can be hydrogen. In other embodiments, at least one of R^3a and R^3b can be an optionally substituted C_1-6-haloalkyl, and the other of R^3a and R^3b can be hydrogen. One example of a suitable optionally substituted C_1-6-haloalkyl is CF₃. When the substituents attached to the 5′-carbon make the 5′-carbon chiral, in some embodiments, the 5′-carbon can be a (R)-stereocenter. In other embodiments, the 5′-carbon can be an (S)-stereocenter.

The substituents attached to the 2′-carbon and the 3′-carbon can also vary. In some embodiments, R⁷ can be hydrogen. In other embodiments, R⁷ can be halogen. In still other embodiments, R⁷ can be —OR¹³. When R¹³ is hydrogen, R⁷ can be hydroxy. Alternatively, when R¹³ is an optionally substituted C_1-6 alkyl, R⁷ can be an optionally substituted C_1-6 alkoxy. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), and hexoxy (branched and straight-chained). In yet still other embodiments, R⁷ can be an optionally substituted C_1-6 alkyl. Examples of optionally substituted C_1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R⁷ can be —OC(═O)R¹⁴ in which R¹⁴ is an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl. Examples of suitable C_1-6 alkyl and C_3-6 cycloalkyl groups are described herein.

In some embodiments, R⁴ can be hydrogen. In some embodiments, R⁵ can be hydrogen. In other embodiments, R⁵ can be —OR⁹, wherein R⁹ can be hydrogen. In yet still other embodiments, R⁵ can be —OR⁹, wherein R⁹ can be an optionally substituted C_1-6 alkyl. A non-limiting list of examples of R⁵ being —OR⁹, wherein R⁹ can be an optionally substituted C_1-6 alkyl are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched). In some embodiments, R⁵ can be —OC(═O)R¹⁰, wherein R¹⁰ can be selected from an optionally substituted C_1-6 alkyl and an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_1-6 alkyls and optionally substituted C_3-6 cycloalkyls are described herein.

In some embodiments, R⁶ can be hydrogen. In some embodiments, R⁶ can be halogen. In still other embodiments, R⁶ can be —OR¹¹. In an embodiment, when R¹¹ is hydrogen, R⁶ can be a hydroxy group. In yet still other embodiments, when R¹¹ is an optionally substituted C_1-6 alkyl, R⁶ can be an optionally substituted C_1-6 alkoxy. Suitable optionally substituted C_1-6 alkoxy groups are described herein. In some embodiments, R⁶ can be —OC(═O)R¹², wherein R¹² can be an optionally substituted C_1-6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In other embodiments, R⁶ can be —OC(═O)R¹², wherein R¹² can be an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_1-6 alkyls and optionally substituted C_3-6 cycloalkyls are described herein.

In some embodiments, R⁵ and R⁶ can both be hydroxy. In still other embodiments, R⁵ and R⁶ can both be both oxygen atoms and linked together by a carbonyl group, for example, —O—C(═O)—O—. In some embodiments, at least one of R⁶ and R⁷ can be a halogen. In some embodiments, R⁶ and R⁷ can both be a halogen. In other embodiments, R⁶ can be a halogen and R⁷ can be an optionally substituted C_1-6 alkyl, such as those described herein. In other embodiments, R⁶ can be hydrogen and R⁷ can be a halogen. In some embodiments, R⁵ can be —OC(═O)R¹⁰ and R⁶ can be —OC(═O)R¹². In some embodiments, R⁶ can be hydrogen and R⁷ can be hydroxy. Those skilled in the art understand that when a hydrogen atom is removed from an oxygen atom, the oxygen atoms can have a negative charge. For example, when R⁵ and/or R⁶ is a hydroxy group and the hydrogen is removed, the oxygen atom to which to hydrogen atom was associated with can be O⁻. In some embodiments, R^3a, R^3b, R⁴ and R⁸ can be hydrogen in any of the embodiments described in this paragraph. In some embodiments, B¹ can be an optionally substituted adenine, an optionally substituted guanine, and optionally substituted thymine, optionally substituted cytosine, or an optionally substituted uracil in any of the embodiments described in this paragraph.

In some embodiments, R⁸ can be hydrogen. In other embodiments, R⁸ can be an optionally substituted C_1-6 alkyl. For example, R⁸ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).

Various optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more of the amine and/or amino groups may be protected with a suitable protecting group. For example, an amino group may be protected by transforming the amine and/or amino group to an amide or a carbamate. In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can have one of the following structures:

wherein: R^A2 can be selected from hydrogen, halogen and NHR^J2, wherein R^J2 can be selected from hydrogen, —C(═O)R^K2 and —C(═O)OR^L2; R^B2 can be halogen or NHR^W2, wherein R^W2 is selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_3-8 cycloalkyl, —C(═O)R^M2 and —C(═O)OR^N2; R^C2 can be hydrogen or NHR^O2, wherein R^O2 can be selected from hydrogen, —C(═O)R^P2 and —C(═O)OR^Q2; R^D2 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^E2 can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-8 cycloalkyl, —C(═O)R^R2 and —C(═O)OR^S2; R^F2 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; Y² can be N (nitrogen) or CR^I2, wherein R^I2 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^G2 can be an optionally substituted C_1-6 alkyl; R^H2 can be hydrogen or NHR^T2, wherein R^T2 can be independently selected from hydrogen, —C(═O)R^U2 and —C(═O)OR^V2, and R^K2, R^L2, R^M2, R^N2, R^P2, R^Q2 R^R2, R^S2, R^U2 and R^V2 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_3-6 cycloalkynyl, C_6-10 aryl, heteroaryl, heteroalicyclyl, aryl(C_1-6 alkyl), heteroaryl(C_1-6 alkyl) and heteroalicyclyl(C_1-6 alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the definition of “substituted.”

In some embodiments, can be selected from adenine, guanine, thymine, cytosine and uracil. In some embodiments, B¹ can be

In other embodiments, B¹ can be

In still other embodiments, B¹ can be

In yet still other embodiments, B¹ can be

In some embodiments, B¹ can be

In other embodiments, B¹ can be

In some embodiments, R^B2 can be NH₂. In some embodiments, R^B2 can be NHR^W2, R^W2 can be —C(═O)R^M2, and R^M2 can be C_1-6 alkyl. In yet still other embodiments, B¹ can be

In some embodiments, B¹ can be

In some embodiments, a compound of Formula (I) cannot have a structure selected from:

In some embodiments, when R² is a substituted or unsubstituted phenyl, then R¹ cannot be

In other embodiments, when R² is a substituted or unsubstituted phenyl, then R¹ cannot be

In still other embodiments, when R² is a substituted or unsubstituted phenyl and R¹ is

then at least one of R⁵ and R⁶ cannot be hydroxy. In some embodiments, when R¹ is

R² is phenyl, one of R^3a and R^3b are methyl and the other of R^3a and R^3b is hydrogen, then B¹ cannot be adenosine, cytosine, or uracil. In some embodiments, when R¹ is

R² is phenyl, one of R^3a and R^3b are methyl and the other of R^3a and R^3b is hydrogen, then R⁶ cannot be OH. In some embodiments, when R¹ is

R² is phenyl, one of R^3a and R^3b are methyl and the other of R^3a and R^3b is hydrogen, then at least one of R⁵, R⁶ and R⁷ is halogen. In some embodiments, when R¹ is

R² is phenyl, one of R^3a and R^3b are methyl and the other of R^3a and R^3b is hydrogen, and B¹ is cytosine, then R⁷ cannot be hydroxy.

In some embodiments, R^3a cannot be hydrogen. In some embodiments, R^3b cannot be hydrogen. In some embodiments, R^3a cannot be an optionally substituted C_1-6 alkyl. In some embodiments, R^3b cannot be an optionally substituted C_1-6 alkyl. In some embodiments, R^3a cannot be methyl. In some embodiments, R^3b cannot be methyl. In other embodiments, R^3a cannot be an optionally substituted C_1-6-haloalkyl. In other embodiments, R^3b cannot be an optionally substituted C_1-6-haloalkyl.

In other embodiments, at least one of R⁵ and R⁶ cannot be hydroxy. For example, R⁵ cannot be hydroxy, R⁶ cannot be hydroxy, or both of R⁵ and R⁶ cannot be hydroxy. In some embodiments, R⁵ cannot be hydrogen. In some embodiments, R⁵ cannot be halogen. In still other embodiments, R⁵ cannot be —OR⁹. In some embodiments, R⁶ cannot be hydrogen. In some embodiments, R⁶ cannot be halogen. In still other embodiments, R⁶ cannot be —OR¹¹. In some embodiments, R⁷ cannot be hydrogen. In other embodiments, R⁷ cannot be halogen. In still other embodiments, R⁷ cannot be —OR¹³. In some embodiments, R⁷ cannot be hydroxy.

In some embodiments, B¹ cannot be

In some embodiments, B¹ cannot be

In some embodiments, B¹ cannot be

In some embodiments, B¹ cannot be

In some embodiments, B¹ cannot be

In some embodiments, B¹ cannot be adenine. In still other embodiments, B¹ cannot be thymine. In yet still other embodiments, B¹ cannot be uracil. In some embodiments, B¹ cannot be cytosine. In other embodiments, B¹ cannot be guanine. In other embodiments, B¹ cannot be hypoxanthine.

Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: B¹ can be an optionally substituted heterocyclic base as described in paragraph [0106]; R¹ can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R² can be an optionally substituted aryl; R^3a and R^3b) can be independently hydrogen or an optionally substituted C_1-6 alkyl, provided that at least one of R^3a and R^3b) cannot be hydrogen; R⁴ can be hydrogen; R⁵ can be selected from hydrogen, —OR⁹ and —OC(═O)R¹⁰; R⁶ can be selected from hydrogen, halogen, —OR¹¹ and —OC(═O)R¹²; or R⁵ and R⁶ can be both oxygen atoms and linked together by a carbonyl group; R⁷ can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl, and —OR¹³; R⁸ can be hydrogen; R⁹, R¹¹ and R¹³ can be independently hydrogen or an optionally substituted C_1-6 alkyl; and R¹⁰ and R¹² can be independently an optionally substituted C_1-6 alkyl.

Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: B¹ can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group selected from

R¹ can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R² can be an optionally substituted aryl; R^3a and R^3b) can be independently hydrogen or an optionally substituted C_1-6 alkyl, provided that at least one of R^3a and R^3b) cannot be hydrogen; R⁴ can be hydrogen; R⁵ can be selected from hydrogen, —OR⁹ and —OC(═O)R¹⁰; R⁶ can be selected from hydrogen, halogen, —OR¹¹ and —OC(═O)R¹²; or R⁵ and R⁶ can be both oxygen atoms and linked together by a carbonyl group; R⁷ can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl, and —OR¹³; R⁸ can be hydrogen; R⁹, R¹¹ and R¹³ can be independently hydrogen or an optionally substituted C_1-6 alkyl; and R¹⁹ and R¹² can be independently an optionally substituted C_1-6 alkyl.

In some embodiments, Formula (I) can be a compound of Formula (Iα), wherein: B¹ can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group selected from uridine, thymidine, guanine, adenine and

wherein R^A2 can be hydrogen, R^B2 can be NHR^W2, R^W2 can be —C(═O)OR^N2, R^N2 can be C_1-6 alkyl, and Y² can be N; R¹ can be an optionally substituted N-linked amino acid ester derivative selected from alanine methyl ester, alanine ethyl ester, alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester and alanine benzyl ester; R² can be selected from an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted pyridyl, an optionally substituted quinolyl; R^3a and R^3b can be selected from hydrogen and an optionally substituted C_1-6 alkyl, provided that at least one of R^3a and R^3b cannot be hydrogen; R⁴ can be hydrogen; R⁵ can be selected from hydrogen, —OR⁹ and —OC(═O)R¹⁹; R⁶ can be selected from hydrogen, halogen, —OR¹¹ and —OC(═O)R¹²; or R⁵ and R⁶ can be both oxygen atoms and linked together by a carbonyl group; R⁷ can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl and —OR¹³; R⁸ can be hydrogen; R⁹, R¹¹ and R¹³ can be independently selected from hydrogen and an optionally substituted C_1-6 alkyl; and R¹⁹ and R¹² can be an optionally substituted C_1-6 alkyl.

In some embodiments, a compound of Formula (I) can be a single diastereomer. In other embodiments, a compound of Formula (I) can be a mixture of diastereomers. In some embodiments, a compound of Formula (I) can be a 1:1 mixture of two diastereomers. In some embodiments, a compound of Formula (I) can be diasteriometrically enriched (for example, one diastereomer can be present at a concentration of >55%, ≧75%, ≧80%, ≧90%, ≧95%, ≧98%, or ≧99% as compared to the total concentration of the other diastereomers).

Some embodiments of R¹ and R² of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are provided in Table 1. Tables 2-4 provide the structures of the variables bb01-bb12, aa01-aa11 and es01-es14, respectively. For example, the first entry in Table 1 is “bb01,aa01,es01,” which corresponds to a compound of Formula (I), wherein R²

and R¹ is

TABLE 1
R2, R1, Rα	R2, R1, Rα	R2, R1, Rα	R2, R1, Rα	R2, R1, Rα
bb01, aa01, es01	bb03, aa01, es01	bb05, aa01, es01	bb07, aa01, es01	bb09, aa01, es01
bb01, aa01, es02	bb03, aa01, es02	bb05, aa01, es02	bb07, aa01, es02	bb09, aa01, es02
bb01, aa01, es03	bb03, aa01, es03	bb05, aa01, es03	bb07, aa01, es03	bb09, aa01, es03
bb01, aa01, es04	bb03, aa01, es04	bb05, aa01, es04	bb07, aa01, es04	bb09, aa01, es04
bb01, aa01, es05	bb03, aa01, es05	bb05, aa01, es05	bb07, aa01, es05	bb09, aa01, es05
bb01, aa01, es06	bb03, aa01, es06	bb05, aa01, es06	bb07, aa01, es06	bb09, aa01, es06
bb01, aa01, es07	bb03, aa01, es07	bb05, aa01, es07	bb07, aa01, es07	bb09, aa01, es07
bb01, aa01, es08	bb03, aa01, es08	bb05, aa01, es08	bb07, aa01, es08	bb09, aa01, es08
bb01, aa01, es09	bb03, aa01, es09	bb05, aa01, es09	bb07, aa01, es09	bb09, aa01, es09
bb01, aa01, es10	bb03, aa01, es10	bb05, aa01, es10	bb07, aa01, es10	bb09, aa01, es10
bb01, aa01, es11	bb03, aa01, es11	bb05, aa01, es11	bb07, aa01, es11	bb09, aa01, es11
bb01, aa01, es12	bb03, aa01, es12	bb05, aa01, es12	bb07, aa01, es12	bb09, aa01, es12
bb01, aa02, es01	bb03, aa02, es01	bb05, aa02, es01	bb07, aa02, es01	bb09, aa02, es01
bb01, aa02, es02	bb03, aa02, es02	bb05, aa02, es02	bb07, aa02, es02	bb09, aa02, es02
bb01, aa02, es03	bb03, aa02, es03	bb05, aa02, es03	bb07, aa02, es03	bb09, aa02, es03
bb01, aa02, es04	bb03, aa02, es04	bb05, aa02, es04	bb07, aa02, es04	bb09, aa02, es04
bb01, aa02, es05	bb03, aa02, es05	bb05, aa02, es05	bb07, aa02, es05	bb09, aa02, es05
bb01, aa02, es06	bb03, aa02, es06	bb05, aa02, es06	bb07, aa02, es06	bb09, aa02, es06
bb01, aa02, es07	bb03, aa02, es07	bb05, aa02, es07	bb07, aa02, es07	bb09, aa02, es07
bb01, aa02, es08	bb03, aa02, es08	bb05, aa02, es08	bb07, aa02, es08	bb09, aa02, es08
bb01, aa02, es09	bb03, aa02, es09	bb05, aa02, es09	bb07, aa02, es09	bb09, aa02, es09
bb01, aa02, es10	bb03, aa02, es10	bb05, aa02, es10	bb07, aa02, es10	bb09, aa02, es10
bb01, aa02, es11	bb03, aa02, es11	bb05, aa02, es11	bb07, aa02, es11	bb09, aa02, es11
bb01, aa02, es12	bb03, aa02, es12	bb05, aa02, es12	bb07, aa02, es12	bb09, aa02, es12
bb01, aa03, es01	bb03, aa03, es01	bb05, aa03, es01	bb07, aa03, es01	bb09, aa03, es01
bb01, aa03, es02	bb03, aa03, es02	bb05, aa03, es02	bb07, aa03, es02	bb09, aa03, es02
bb01, aa03, es03	bb03, aa03, es03	bb05, aa03, es03	bb07, aa03, es03	bb09, aa03, es03
bb01, aa03, es04	bb03, aa03, es04	bb05, aa03, es04	bb07, aa03, es04	bb09, aa03, es04
bb01, aa03, es05	bb03, aa03, es05	bb05, aa03, es05	bb07, aa03, es05	bb09, aa03, es05
bb01, aa03, es06	bb03, aa03, es06	bb05, aa03, es06	bb07, aa03, es06	bb09, aa03, es06
bb01, aa03, es07	bb03, aa03, es07	bb05, aa03, es07	bb07, aa03, es07	bb09, aa03, es07
bb01, aa03, es08	bb03, aa03, es08	bb05, aa03, es08	bb07, aa03, es08	bb09, aa03, es08
bb01, aa03, es09	bb03, aa03, es09	bb05, aa03, es09	bb07, aa03, es09	bb09, aa03, es09
bb01, aa03, es10	bb03, aa03, es10	bb05, aa03, es10	bb07, aa03, es10	bb09, aa03, es10
bb01, aa03, es11	bb03, aa03, es11	bb05, aa03, es11	bb07, aa03, es11	bb09, aa03, es11
bb01, aa03, es12	bb03, aa03, es12	bb05, aa03, es12	bb07, aa03, es12	bb09, aa03, es12
bb01, aa04, es01	bb03, aa04, es01	bb05, aa04, es01	bb07, aa04, es01	bb09, aa04, es01
bb01, aa04, es02	bb03, aa04, es02	bb05, aa04, es02	bb07, aa04, es02	bb09, aa04, es02
bb01, aa04, es03	bb03, aa04, es03	bb05, aa04, es03	bb07, aa04, es03	bb09, aa04, es03
bb01, aa04, es04	bb03, aa04, es04	bb05, aa04, es04	bb07, aa04, es04	bb09, aa04, es04
bb01, aa04, es05	bb03, aa04, es05	bb05, aa04, es05	bb07, aa04, es05	bb09, aa04, es05
bb01, aa04, es06	bb03, aa04, es06	bb05, aa04, es06	bb07, aa04, es06	bb09, aa04, es06
bb01, aa04, es07	bb03, aa04, es07	bb05, aa04, es07	bb07, aa04, es07	bb09, aa04, es07
bb01, aa04, es08	bb03, aa04, es08	bb05, aa04, es08	bb07, aa04, es08	bb09, aa04, es08
bb01, aa04, es09	bb03, aa04, es09	bb05, aa04, es09	bb07, aa04, es09	bb09, aa04, es09
bb01, aa04, es10	bb03, aa04, es10	bb05, aa04, es10	bb07, aa04, es10	bb09, aa04, es10
bb01, aa04, es11	bb03, aa04, es11	bb05, aa04, es11	bb07, aa04, es11	bb09, aa04, es11
bb01, aa04, es12	bb03, aa04, es12	bb05, aa04, es12	bb07, aa04, es12	bb09, aa04, es12
bb01, aa05, es01	bb03, aa05, es01	bb05, aa05, es01	bb07, aa05, es01	bb09, aa05, es01
bb01, aa05, es02	bb03, aa05, es02	bb05, aa05, es02	bb07, aa05, es02	bb09, aa05, es02
bb01, aa05, es03	bb03, aa05, es03	bb05, aa05, es03	bb07, aa05, es03	bb09, aa05, es03
bb01, aa05, es04	bb03, aa05, es04	bb05, aa05, es04	bb07, aa05, es04	bb09, aa05, es04
bb01, aa05, es05	bb03, aa05, es05	bb05, aa05, es05	bb07, aa05, es05	bb09, aa05, es05
bb01, aa05, es06	bb03, aa05, es06	bb05, aa05, es06	bb07, aa05, es06	bb09, aa05, es06
bb01, aa05, es07	bb03, aa05, es07	bb05, aa05, es07	bb07, aa05, es07	bb09, aa05, es07
bb01, aa05, es08	bb03, aa05, es08	bb05, aa05, es08	bb07, aa05, es08	bb09, aa05, es08
bb01, aa05, es09	bb03, aa05, es09	bb05, aa05, es09	bb07, aa05, es09	bb09, aa05, es09
bb01, aa05, es10	bb03, aa05, es10	bb05, aa05, es10	bb07, aa05, es10	bb09, aa05, es10
bb01, aa05, es11	bb03, aa05, es11	bb05, aa05, es11	bb07, aa05, es11	bb09, aa05, es11
bb01, aa05, es12	bb03, aa05, es12	bb05, aa05, es12	bb07, aa05, es12	bb09, aa05, es12
bb01, aa06, es01	bb03, aa06, es01	bb05, aa06, es01	bb07, aa06, es01	bb09, aa06, es01
bb01, aa06, es02	bb03, aa06, es02	bb05, aa06, es02	bb07, aa06, es02	bb09, aa06, es02
bb01, aa06, es03	bb03, aa06, es03	bb05, aa06, es03	bb07, aa06, es03	bb09, aa06, es03
bb01, aa06, es04	bb03, aa06, es04	bb05, aa06, es04	bb07, aa06, es04	bb09, aa06, es04
bb01, aa06, es05	bb03, aa06, es05	bb05, aa06, es05	bb07, aa06, es05	bb09, aa06, es05
bb01, aa06, es06	bb03, aa06, es06	bb05, aa06, es06	bb07, aa06, es06	bb09, aa06, es06
bb01, aa06, es07	bb03, aa06, es07	bb05, aa06, es07	bb07, aa06, es07	bb09, aa06, es07
bb01, aa06, es08	bb03, aa06, es08	bb05, aa06, es08	bb07, aa06, es08	bb09, aa06, es08
bb01, aa06, es09	bb03, aa06, es09	bb05, aa06, es09	bb07, aa06, es09	bb09, aa06, es09
bb01, aa06, es10	bb03, aa06, es10	bb05, aa06, es10	bb07, aa06, es10	bb09, aa06, es10
bb01, aa06, es11	bb03, aa06, es11	bb05, aa06, es11	bb07, aa06, es11	bb09, aa06, es11
bb01, aa06, es12	bb03, aa06, es12	bb05, aa06, es12	bb07, aa06, es12	bb09, aa06, es12
bb01, aa07, es01	bb03, aa07, es01	bb05, aa07, es01	bb07, aa07, es01	bb09, aa07, es01
bb01, aa07, es02	bb03, aa07, es02	bb05, aa07, es02	bb07, aa07, es02	bb09, aa07, es02
bb01, aa07, es03	bb03, aa07, es03	bb05, aa07, es03	bb07, aa07, es03	bb09, aa07, es03
bb01, aa07, es04	bb03, aa07, es04	bb05, aa07, es04	bb07, aa07, es04	bb09, aa07, es04
bb01, aa07, es05	bb03, aa07, es05	bb05, aa07, es05	bb07, aa07, es05	bb09, aa07, es05
bb01, aa07, es06	bb03, aa07, es06	bb05, aa07, es06	bb07, aa07, es06	bb09, aa07, es06
bb01, aa07, es07	bb03, aa07, es07	bb05, aa07, es07	bb07, aa07, es07	bb09, aa07, es07
bb01, aa07, es08	bb03, aa07, es08	bb05, aa07, es08	bb07, aa07, es08	bb09, aa07, es08
bb01, aa07, es09	bb03, aa07, es09	bb05, aa07, es09	bb07, aa07, es09	bb09, aa07, es09
bb01, aa07, es10	bb03, aa07, es10	bb05, aa07, es10	bb07, aa07, es10	bb09, aa07, es10
bb01, aa07, es11	bb03, aa07, es11	bb05, aa07, es11	bb07, aa07, es11	bb09, aa07, es11
bb01, aa07, es12	bb03, aa07, es12	bb05, aa07, es12	bb07, aa07, es12	bb09, aa07, es12
bb01, aa08, es01	bb03, aa08, es01	bb05, aa08, es01	bb07, aa08, es01	bb09, aa08, es01
bb01, aa08, es02	bb03, aa08, es02	bb05, aa08, es02	bb07, aa08, es02	bb09, aa08, es02
bb01, aa08, es03	bb03, aa08, es03	bb05, aa08, es03	bb07, aa08, es03	bb09, aa08, es03
bb01, aa08, es04	bb03, aa08, es04	bb05, aa08, es04	bb07, aa08, es04	bb09, aa08, es04
bb01, aa08, es05	bb03, aa08, es05	bb05, aa08, es05	bb07, aa08, es05	bb09, aa08, es05
bb01, aa08, es06	bb03, aa08, es06	bb05, aa08, es06	bb07, aa08, es06	bb09, aa08, es06
bb01, aa08, es07	bb03, aa08, es07	bb05, aa08, es07	bb07, aa08, es07	bb09, aa08, es07
bb01, aa08, es08	bb03, aa08, es08	bb05, aa08, es08	bb07, aa08, es08	bb09, aa08, es08
bb01, aa08, es09	bb03, aa08, es09	bb05, aa08, es09	bb07, aa08, es09	bb09, aa08, es09
bb01, aa08, es10	bb03, aa08, es10	bb05, aa08, es10	bb07, aa08, es10	bb09, aa08, es10
bb01, aa08, es11	bb03, aa08, es11	bb05, aa08, es11	bb07, aa08, es11	bb09, aa08, es11
bb01, aa08, es12	bb03, aa08, es12	bb05, aa08, es12	bb07, aa08, es12	bb09, aa08, es12
bb01, aa09, es01	bb03, aa09, es01	bb05, aa09, es01	bb07, aa09, es01	bb09, aa09, es01
bb01, aa09, es02	bb03, aa09, es02	bb05, aa09, es02	bb07, aa09, es02	bb09, aa09, es02
bb01, aa09, es03	bb03, aa09, es03	bb05, aa09, es03	bb07, aa09, es03	bb09, aa09, es03
bb01, aa09, es04	bb03, aa09, es04	bb05, aa09, es04	bb07, aa09, es04	bb09, aa09, es04
bb01, aa09, es05	bb03, aa09, es05	bb05, aa09, es05	bb07, aa09, es05	bb09, aa09, es05
bb01, aa09, es06	bb03, aa09, es06	bb05, aa09, es06	bb07, aa09, es06	bb09, aa09, es06
bb01, aa09, es07	bb03, aa09, es07	bb05, aa09, es07	bb07, aa09, es07	bb09, aa09, es07
bb01, aa09, es08	bb03, aa09, es08	bb05, aa09, es08	bb07, aa09, es08	bb09, aa09, es08
bb01, aa09, es09	bb03, aa09, es09	bb05, aa09, es09	bb07, aa09, es09	bb09, aa09, es09
bb01, aa09, es10	bb03, aa09, es10	bb05, aa09, es10	bb07, aa09, es10	bb09, aa09, es10
bb01, aa09, es11	bb03, aa09, es11	bb05, aa09, es11	bb07, aa09, es11	bb09, aa09, es11
bb01, aa09, es12	bb03, aa09, es12	bb05, aa09, es12	bb07, aa09, es12	bb09, aa09, es12
bb01, aa10, es01	bb03, aa10, es01	bb05, aa10, es01	bb07, aa10, es01	bb09, aa10, es01
bb01, aa10, es02	bb03, aa10, es02	bb05, aa10, es02	bb07, aa10, es02	bb09, aa10, es02
bb01, aa10, es03	bb03, aa10, es03	bb05, aa10, es03	bb07, aa10, es03	bb09, aa10, es03
bb01, aa10, es04	bb03, aa10, es04	bb05, aa10, es04	bb07, aa10, es04	bb09, aa10, es04
bb01, aa10, es05	bb03, aa10, es05	bb05, aa10, es05	bb07, aa10, es05	bb09, aa10, es05
bb01, aa10, es06	bb03, aa10, es06	bb05, aa10, es06	bb07, aa10, es06	bb09, aa10, es06
bb01, aa10, es07	bb03, aa10, es07	bb05, aa10, es07	bb07, aa10, es07	bb09, aa10, es07
bb01, aa10, es08	bb03, aa10, es08	bb05, aa10, es08	bb07, aa10, es08	bb09, aa10, es08
bb01, aa10, es09	bb03, aa10, es09	bb05, aa10, es09	bb07, aa10, es09	bb09, aa10, es09
bb01, aa10, es10	bb03, aa10, es10	bb05, aa10, es10	bb07, aa10, es10	bb09, aa10, es10
bb01, aa10, es11	bb03, aa10, es11	bb05, aa10, es11	bb07, aa10, es11	bb09, aa10, es11
bb01, aa10, es12	bb03, aa10, es12	bb05, aa10, es12	bb07, aa10, es12	bb09, aa10, es12
bb02, aa01, es01	bb04, aa01, es01	bb06, aa01, es01	bb08, aa01, es01	bb10, aa01, es01
bb02, aa01, es02	bb04, aa01, es02	bb06, aa01, es02	bb08, aa01, es02	bb10, aa01, es02
bb02, aa01, es03	bb04, aa01, es03	bb06, aa01, es03	bb08, aa01, es03	bb10, aa01, es03
bb02, aa01, es04	bb04, aa01, es04	bb06, aa01, es04	bb08, aa01, es04	bb10, aa01, es04
bb02, aa01, es05	bb04, aa01, es05	bb06, aa01, es05	bb08, aa01, es05	bb10, aa01, es05
bb02, aa01, es06	bb04, aa01, es06	bb06, aa01, es06	bb08, aa01, es06	bb10, aa01, es06
bb02, aa01, es07	bb04, aa01, es07	bb06, aa01, es07	bb08, aa01, es07	bb10, aa01, es07
bb02, aa01, es08	bb04, aa01, es08	bb06, aa01, es08	bb08, aa01, es08	bb10, aa01, es08
bb02, aa01, es09	bb04, aa01, es09	bb06, aa01, es09	bb08, aa01, es09	bb10, aa01, es09
bb02, aa01, es10	bb04, aa01, es10	bb06, aa01, es10	bb08, aa01, es10	bb10, aa01, es10
bb02, aa01, es11	bb04, aa01, es11	bb06, aa01, es11	bb08, aa01, es11	bb10, aa01, es11
bb02, aa01, es12	bb04, aa01, es12	bb06, aa01, es12	bb08, aa01, es12	bb10, aa01, es12
bb02, aa02, es01	bb04, aa02, es01	bb06, aa02, es01	bb08, aa02, es01	bb10, aa02, es01
bb02, aa02, es02	bb04, aa02, es02	bb06, aa02, es02	bb08, aa02, es02	bb10, aa02, es02
bb02, aa02, es03	bb04, aa02, es03	bb06, aa02, es03	bb08, aa02, es03	bb10, aa02, es03
bb02, aa02, es04	bb04, aa02, es04	bb06, aa02, es04	bb08, aa02, es04	bb10, aa02, es04
bb02, aa02, es05	bb04, aa02, es05	bb06, aa02, es05	bb08, aa02, es05	bb10, aa02, es05
bb02, aa02, es06	bb04, aa02, es06	bb06, aa02, es06	bb08, aa02, es06	bb10, aa02, es06
bb02, aa02, es07	bb04, aa02, es07	bb06, aa02, es07	bb08, aa02, es07	bb10, aa02, es07
bb02, aa02, es08	bb04, aa02, es08	bb06, aa02, es08	bb08, aa02, es08	bb10, aa02, es08
bb02, aa02, es09	bb04, aa02, es09	bb06, aa02, es09	bb08, aa02, es09	bb10, aa02, es09
bb02, aa02, es10	bb04, aa02, es10	bb06, aa02, es10	bb08, aa02, es10	bb10, aa02, es10
bb02, aa02, es11	bb04, aa02, es11	bb06, aa02, es11	bb08, aa02, es11	bb10, aa02, es11
bb02, aa02, es12	bb04, aa02, es12	bb06, aa02, es12	bb08, aa02, es12	bb10, aa02, es12
bb02, aa03, es01	bb04, aa03, es01	bb06, aa03, es01	bb08, aa03, es01	bb10, aa03, es01
bb02, aa03, es02	bb04, aa03, es02	bb06, aa03, es02	bb08, aa03, es02	bb10, aa03, es02
bb02, aa03, es03	bb04, aa03, es03	bb06, aa03, es03	bb08, aa03, es03	bb10, aa03, es03
bb02, aa03, es04	bb04, aa03, es04	bb06, aa03, es04	bb08, aa03, es04	bb10, aa03, es04
bb02, aa03, es05	bb04, aa03, es05	bb06, aa03, es05	bb08, aa03, es05	bb10, aa03, es05
bb02, aa03, es06	bb04, aa03, es06	bb06, aa03, es06	bb08, aa03, es06	bb10, aa03, es06
bb02, aa03, es07	bb04, aa03, es07	bb06, aa03, es07	bb08, aa03, es07	bb10, aa03, es07
bb02, aa03, es08	bb04, aa03, es08	bb06, aa03, es08	bb08, aa03, es08	bb10, aa03, es08
bb02, aa03, es09	bb04, aa03, es09	bb06, aa03, es09	bb08, aa03, es09	bb10, aa03, es09
bb02, aa03, es10	bb04, aa03, es10	bb06, aa03, es10	bb08, aa03, es10	bb10, aa03, es10
bb02, aa03, es11	bb04, aa03, es11	bb06, aa03, es11	bb08, aa03, es11	bb10, aa03, es11
bb02, aa03, es12	bb04, aa03, es12	bb06, aa03, es12	bb08, aa03, es12	bb10, aa03, es12
bb02, aa04, es01	bb04, aa04, es01	bb06, aa04, es01	bb08, aa04, es01	bb10, aa04, es01
bb02, aa04, es02	bb04, aa04, es02	bb06, aa04, es02	bb08, aa04, es02	bb10, aa04, es02
bb02, aa04, es03	bb04, aa04, es03	bb06, aa04, es03	bb08, aa04, es03	bb10, aa04, es03
bb02, aa04, es04	bb04, aa04, es04	bb06, aa04, es04	bb08, aa04, es04	bb10, aa04, es04
bb02, aa04, es05	bb04, aa04, es05	bb06, aa04, es05	bb08, aa04, es05	bb10, aa04, es05
bb02, aa04, es06	bb04, aa04, es06	bb06, aa04, es06	bb08, aa04, es06	bb10, aa04, es06
bb02, aa04, es07	bb04, aa04, es07	bb06, aa04, es07	bb08, aa04, es07	bb10, aa04, es07
bb02, aa04, es08	bb04, aa04, es08	bb06, aa04, es08	bb08, aa04, es08	bb10, aa04, es08
bb02, aa04, es09	bb04, aa04, es09	bb06, aa04, es09	bb08, aa04, es09	bb10, aa04, es09
bb02, aa04, es10	bb04, aa04, es10	bb06, aa04, es10	bb08, aa04, es10	bb10, aa04, es10
bb02, aa04, es11	bb04, aa04, es11	bb06, aa04, es11	bb08, aa04, es11	bb10, aa04, es11
bb02, aa04, es12	bb04, aa04, es12	bb06, aa04, es12	bb08, aa04, es12	bb10, aa04, es12
bb02, aa05, es01	bb04, aa05, es01	bb06, aa05, es01	bb08, aa05, es01	bb10, aa05, es01
bb02, aa05, es02	bb04, aa05, es02	bb06, aa05, es02	bb08, aa05, es02	bb10, aa05, es02
bb02, aa05, es03	bb04, aa05, es03	bb06, aa05, es03	bb08, aa05, es03	bb10, aa05, es03
bb02, aa05, es04	bb04, aa05, es04	bb06, aa05, es04	bb08, aa05, es04	bb10, aa05, es04
bb02, aa05, es05	bb04, aa05, es05	bb06, aa05, es05	bb08, aa05, es05	bb10, aa05, es05
bb02, aa05, es06	bb04, aa05, es06	bb06, aa05, es06	bb08, aa05, es06	bb10, aa05, es06
bb02, aa05, es07	bb04, aa05, es07	bb06, aa05, es07	bb08, aa05, es07	bb10, aa05, es07
bb02, aa05, es08	bb04, aa05, es08	bb06, aa05, es08	bb08, aa05, es08	bb10, aa05, es08
bb02, aa05, es09	bb04, aa05, es09	bb06, aa05, es09	bb08, aa05, es09	bb10, aa05, es09
bb02, aa05, es10	bb04, aa05, es10	bb06, aa05, es10	bb08, aa05, es10	bb10, aa05, es10
bb02, aa05, es11	bb04, aa05, es11	bb06, aa05, es11	bb08, aa05, es11	bb10, aa05, es11
bb02, aa05, es12	bb04, aa05, es12	bb06, aa05, es12	bb08, aa05, es12	bb10, aa05, es12
bb02, aa06, es01	bb04, aa06, es01	bb06, aa06, es01	bb08, aa06, es01	bb10, aa06, es01
bb02, aa06, es02	bb04, aa06, es02	bb06, aa06, es02	bb08, aa06, es02	bb10, aa06, es02
bb02, aa06, es03	bb04, aa06, es03	bb06, aa06, es03	bb08, aa06, es03	bb10, aa06, es03
bb02, aa06, es04	bb04, aa06, es04	bb06, aa06, es04	bb08, aa06, es04	bb10, aa06, es04
bb02, aa06, es05	bb04, aa06, es05	bb06, aa06, es05	bb08, aa06, es05	bb10, aa06, es05
bb02, aa06, es06	bb04, aa06, es06	bb06, aa06, es06	bb08, aa06, es06	bb10, aa06, es06
bb02, aa06, es07	bb04, aa06, es07	bb06, aa06, es07	bb08, aa06, es07	bb10, aa06, es07
bb02, aa06, es08	bb04, aa06, es08	bb06, aa06, es08	bb08, aa06, es08	bb10, aa06, es08
bb02, aa06, es09	bb04, aa06, es09	bb06, aa06, es09	bb08, aa06, es09	bb10, aa06, es09
bb02, aa06, es10	bb04, aa06, es10	bb06, aa06, es10	bb08, aa06, es10	bb10, aa06, es10
bb02, aa06, es11	bb04, aa06, es11	bb06, aa06, es11	bb08, aa06, es11	bb10, aa06, es11
bb02, aa06, es12	bb04, aa06, es12	bb06, aa06, es12	bb08, aa06, es12	bb10, aa06, es12
bb02, aa07, es01	bb04, aa07, es01	bb06, aa07, es01	bb08, aa07, es01	bb10, aa07, es01
bb02, aa07, es02	bb04, aa07, es02	bb06, aa07, es02	bb08, aa07, es02	bb10, aa07, es02
bb02, aa07, es03	bb04, aa07, es03	bb06, aa07, es03	bb08, aa07, es03	bb10, aa07, es03
bb02, aa07, es04	bb04, aa07, es04	bb06, aa07, es04	bb08, aa07, es04	bb10, aa07, es04
bb02, aa07, es05	bb04, aa07, es05	bb06, aa07, es05	bb08, aa07, es05	bb10, aa07, es05
bb02, aa07, es06	bb04, aa07, es06	bb06, aa07, es06	bb08, aa07, es06	bb10, aa07, es06
bb02, aa07, es07	bb04, aa07, es07	bb06, aa07, es07	bb08, aa07, es07	bb10, aa07, es07
bb02, aa07, es08	bb04, aa07, es08	bb06, aa07, es08	bb08, aa07, es08	bb10, aa07, es08
bb02, aa07, es09	bb04, aa07, es09	bb06, aa07, es09	bb08, aa07, es09	bb10, aa07, es09
bb02, aa07, es10	bb04, aa07, es10	bb06, aa07, es10	bb08, aa07, es10	bb10, aa07, es10
bb02, aa07, es11	bb04, aa07, es11	bb06, aa07, es11	bb08, aa07, es11	bb10, aa07, es11
bb02, aa07, es12	bb04, aa07, es12	bb06, aa07, es12	bb08, aa07, es12	bb10, aa07, es12
bb02, aa08, es01	bb04, aa08, es01	bb06, aa08, es01	bb08, aa08, es01	bb10, aa08, es01
bb02, aa08, es02	bb04, aa08, es02	bb06, aa08, es02	bb08, aa08, es02	bb10, aa08, es02
bb02, aa08, es03	bb04, aa08, es03	bb06, aa08, es03	bb08, aa08, es03	bb10, aa08, es03
bb02, aa08, es04	bb04, aa08, es04	bb06, aa08, es04	bb08, aa08, es04	bb10, aa08, es04
bb02, aa08, es05	bb04, aa08, es05	bb06, aa08, es05	bb08, aa08, es05	bb10, aa08, es05
bb02, aa08, es06	bb04, aa08, es06	bb06, aa08, es06	bb08, aa08, es06	bb10, aa08, es06
bb02, aa08, es07	bb04, aa08, es07	bb06, aa08, es07	bb08, aa08, es07	bb10, aa08, es07
bb02, aa08, es08	bb04, aa08, es08	bb06, aa08, es08	bb08, aa08, es08	bb10, aa08, es08
bb02, aa08, es09	bb04, aa08, es09	bb06, aa08, es09	bb08, aa08, es09	bb10, aa08, es09
bb02, aa08, es10	bb04, aa08, es10	bb06, aa08, es10	bb08, aa08, es10	bb10, aa08, es10
bb02, aa08, es11	bb04, aa08, es11	bb06, aa08, es11	bb08, aa08, es11	bb10, aa08, es11
bb02, aa08, es12	bb04, aa08, es12	bb06, aa08, es12	bb08, aa08, es12	bb10, aa08, es12
bb02, aa09, es01	bb04, aa09, es01	bb06, aa09, es01	bb08, aa09, es01	bb10, aa09, es01
bb02, aa09, es02	bb04, aa09, es02	bb06, aa09, es02	bb08, aa09, es02	bb10, aa09, es02
bb02, aa09, es03	bb04, aa09, es03	bb06, aa09, es03	bb08, aa09, es03	bb10, aa09, es03
bb02, aa09, es04	bb04, aa09, es04	bb06, aa09, es04	bb08, aa09, es04	bb10, aa09, es04
bb02, aa09, es05	bb04, aa09, es05	bb06, aa09, es05	bb08, aa09, es05	bb10, aa09, es05
bb02, aa09, es06	bb04, aa09, es06	bb06, aa09, es06	bb08, aa09, es06	bb10, aa09, es06
bb02, aa09, es07	bb04, aa09, es07	bb06, aa09, es07	bb08, aa09, es07	bb10, aa09, es07
bb02, aa09, es08	bb04, aa09, es08	bb06, aa09, es08	bb08, aa09, es08	bb10, aa09, es08
bb02, aa09, es09	bb04, aa09, es09	bb06, aa09, es09	bb08, aa09, es09	bb10, aa09, es09
bb02, aa09, es10	bb04, aa09, es10	bb06, aa09, es10	bb08, aa09, es10	bb10, aa09, es10
bb02, aa09, es11	bb04, aa09, es11	bb06, aa09, es11	bb08, aa09, es11	bb10, aa09, es11
bb02, aa09, es12	bb04, aa09, es12	bb06, aa09, es12	bb08, aa09, es12	bb10, aa09, es12
bb02, aa10, es01	bb04, aa10, es01	bb06, aa10, es01	bb08, aa10, es01	bb10, aa10, es01
bb02, aa10, es02	bb04, aa10, es02	bb06, aa10, es02	bb08, aa10, es02	bb10, aa10, es02
bb02, aa10, es03	bb04, aa10, es03	bb06, aa10, es03	bb08, aa10, es03	bb10, aa10, es03
bb02, aa10, es04	bb04, aa10, es04	bb06, aa10, es04	bb08, aa10, es04	bb10, aa10, es04
bb02, aa10, es05	bb04, aa10, es05	bb06, aa10, es05	bb08, aa10, es05	bb10, aa10, es05
bb02, aa10, es06	bb04, aa10, es06	bb06, aa10, es06	bb08, aa10, es06	bb10, aa10, es06
bb02, aa10, es07	bb04, aa10, es07	bb06, aa10, es07	bb08, aa10, es07	bb10, aa10, es07
bb02, aa10, es08	bb04, aa10, es08	bb06, aa10, es08	bb08, aa10, es08	bb10, aa10, es08
bb02, aa10, es09	bb04, aa10, es09	bb06, aa10, es09	bb08, aa10, es09	bb10, aa10, es09
bb02, aa10, es10	bb04, aa10, es10	bb06, aa10, es10	bb08, aa10, es10	bb10, aa10, es10
bb02, aa10, es11	bb04, aa10, es11	bb06, aa10, es11	bb08, aa10, es11	bb10, aa10, es11
bb02, aa10, es12	bb04, aa10, es12	bb06, aa10, es12	bb08, aa10, es12	bb10, aa10, es12

TABLE 2
bb01
bb02
bb03
bb04
bb05
bb06
bb07
bb08
bb09
bb10

TABLE 3
aa01
aa02
aa03
aa04
aa05
aa06
aa07
aa08
aa09
aa10

TABLE 4
es01 Rα = methyl	es02 Rα = ethyl	es03 Rα = isopropyl
es04 Rα = propyl	es05 Rα = cyclohexyl	es06 Rα = cyclopentyl
es07 Rα = cyclobutyl	es08 Rα = cyclopropyl	es09 Rα = benzyl
es11 Rα = neopentyl	es10 Rα = t-butyl	es12 Rα = hydrogen

In some embodiments, one of R^3a and R^3b is methyl and the other of R^1a and R^3b is hydrogen, and R⁴ and R⁸ can be both hydrogens in any of the embodiments described in Table 1. In some embodiments, at least one of R⁵ and R⁶ can be OH in any of the embodiments described in Table 1. In some embodiments, R⁷ can be hydrogen, halogen or C_1-6 alkyl in any of the embodiments described in Table 1. In some embodiments, B¹ can be adenine, guanine, uracil, thymine or cystine in any of the embodiments described in Table 1. In some embodiments, R^3a, R^3b, R⁴, R⁵, R⁶, R⁷, R⁸ and B¹ can be the groups provided with respect to Formula (Iα) in any of the embodiments described in Table 1.

Examples of compounds of Formula (I) include, but are not limited to the following:

Additional examples of compounds of Formula (I) are shown below.

Additional examples of compounds of Formula (I) include, but are not limited to the following:

Additional examples of compounds of Formula (I) include, but are not limited to the following:

In some embodiments, neutralizing the charge on the phosphate group of a nucleoside monophosphate, or nucleotide, may facilitate the penetration of the cell membrane by oral administration of a compound of Formula (I) (including a compound of Formula (Iα)) by making the compound more lipophilic compared to a nucleotide having a comparable structure with one or more charges present on the phosphate. Once absorbed and taken inside the cell, the groups attached to the phosphate can be easily removed by esterases, proteases or other enzymes. In some embodiments, the groups attached to the phosphate can be removed by simple hydrolysis. Inside the cell, the monophosphate thus released may then be metabolized by cellular enzymes to the diphosphate or the active triphosphate.

In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can act as a chain terminator of HCV replication. For example, incorporation of a compound of Formula (I) containing a moiety at the 2′-carbon position can terminate further elongation of the RNA chain of HCV. For example, a compound of Formula (I) can contain a 2′-carbon modification when R⁷ is a non-hydrogen group selected from halogen or an optionally substituted C_1-6 alkyl.

In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can have increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), 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 cirrohis 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 in the range of about 28 hours to about 36 hours. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have more potent antiviral activity (for example, a lower IC₅₀ in an HCV replicon assay) as compared to the current standard of care.

Synthesis

Compounds of Formula (I) (including compounds of Formula (Iα)), 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 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.

One method for forming a compound of Formula (I) is shown in Scheme 1. In Scheme 1, R^3A, R^3B, R^5A, R^6A, R^7A, R^8A and B^1A can be the same as R^3a, R^3b, R⁴, R⁵, R⁶, R⁷, R⁸ and B¹ as described herein for Formula (I); and R¹ and R² can be the same as described herein for Formula (I). As shown in Scheme 1, a compound of Formula (A) can be reacted with a phosphorochloridate of formula R²O—P(═O)(R¹)—Cl to form a compound of Formula (I).

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 R^5A and/or R^6A 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. Alternatively, R^5A and/or R^6A 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.

If desired, any —NH and/or NH₂ groups present on the B^1A can also be protected with one or more suitable protecting groups. Examples of suitable protecting groups include triarylmethyl groups and silyl groups. Examples of silyl groups include, but are not limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.

Suitable phosphorochloridates can be commercially obtained or prepared by a synthetic method described herein. An example of a general structure of a phosphorochloridate is shown in Scheme 1. In some embodiments, the phosphorochloridate can be coupled to a compound of Formula (A). In some embodiments, to facilitate the coupling, a Grignard reagent can be used. 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, the phosphorochloridate can be added to a compound of Formula (A) using a base. Suitable bases are known to those skilled in the art. Examples of 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 imidzoles (e.g., N-methylimidazole)).

When at least one of R^3a and R^3b is an optionally substituted C_1-6 alkyl or an optionally substituted C_1-6 haloalkyl, the optionally substituted C_1-6 alkyl or the optionally substituted C_1-6 haloalkyl can be added to the 5′-position using methods known to those skilled in the art. In some embodiments, the hydroxy attached to the 5′-carbon can be oxidized to an aldehyde. Suitable oxidation conditions include, but are not limited to, DMSO in combination with an activating agent (usually an acylating agent or an acid) and an amine base, Moffatt oxidation, Swern oxidation and Corey-Kim oxidation, and suitable oxidizing agents include, but are not limited to, Dess-Martin periodinane, TPAP/NMO (tetrapropylammonium perruthenate/N-methylmorpholine N-oxide), Swern oxidation reagent, PCC (pyridinium chlorochromate), and/or PDC (pyridinium dichromate), sodium periodate, Collin's reagent, ceric ammonium nitrate CAN, Na₂Cr₂O₇ in water, Ag₂CO₃ on celite, hot HNO₃ in aqueous glyme, O₂-pyridine CuCl, Pb(OAc)₄-pyridine and benzoyl peroxide-NiBr₂. The resulting aldehyde compound can be reacted with a Grignard reagent, an organolithium reagent or trialkylaluminum (e.g. trimethylaluminum) to form a compound of Formula (A) where at least one of R^3A and R^3B is an optionally substituted C_1-6 alkyl or an optionally substituted C_1-6 haloalkyl. Optionally, the alkylating reagents can be in the presence of a Lewis acid. Suitable Lewis acids are known to those skilled in the art.

The chirality of the 5′-carbon of compounds of Formulae (A) and/or (I) can be inverted using methods known to the skilled in the art. For example, the oxygen attached to the 5′-carbon can be oxidized, for example to an aldehyde, for a compound of Formula (A), or ketone, for a compound of Formula (I), using a suitable oxidizing agent. The aldehyde and/or ketone can then be reduced using a suitable reducing agent. Examples of suitable reducing agents include, but are not limited to, NaH, LiH, NaBH₄, LiAlH₄ and CaH₂. Suitable oxidizing and reducing agents are known to those skilled in the art. Examples of suitable oxidizing agents and conditions are described herein.

As described herein, in some embodiments, R⁵ and R⁶ can be both oxygen atoms 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 R⁵ and R⁶ are both hydroxy groups, can be treated with 1,1′-carbonyldiimidazole (CDI).

In some embodiments, R⁵ and/or R⁶ can be —OC(═O)R¹⁰ and —OC(═O)R¹², respectively. The —OC(═O)R¹⁰ and —OC(═O)R¹² 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 R⁵ and R⁶ 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)R¹⁰ and —OC(═O)R¹² 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).

As described herein, B^1A can include a carbamate and/or an amide. Those skilled in the art know methods for forming a carbamate and/or an amide on B^1A. In some embodiments, the carbamate can be formed using 1,1′-carbonyldiimidazole and an alcohol.

B^1A can be added to the pentose ring using various methods known to those skilled in the art. In some embodiments, a compound of Formula (B) can be reacted with a nitrogenous base. In some embodiments, R^3A, R^3B, R^4A, R^5A, R^6A, R^7A, R^8A and B^1A of a compound of Formula (B) can be the same as disclosed herein, with respect to R^3a, R^3b, R⁴, R⁵, R⁶, R⁷, R⁸ and B¹; and PG¹ can be an appropriate protecting group. In some embodiments, PG¹ can be p-nitrobenzyl group. In some embodiments, any hydroxy groups attached to the pentose ring can be protected with one or more suitable protecting groups. In some embodiments, any hydroxy groups attached to the pentose ring can be protected with benzoyl groups. Examples of nitrogenous bases include an optionally substituted heterocyclic bases described herein, wherein the nitrogen atom (—N) connected to the pentose ring is —NH. If desired, any —NH and/or NH₂ groups present on the nitrogenous base can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. In some embodiments, the nitrogenous base can be added via a coupling reaction in the presence of a Lewis acid or TMSOTf (trimethylsilyl trifluoromethanesulfonate). Suitable Lewis acids are known to those skilled in the art.

During the synthesis of any of the compounds described herein, if desired, any hydroxy groups attached to the pentose ring, and any —NH and/or NH₂ groups present on the B^1A can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. Those skilled in the art will appreciate that groups attached to the pentose ring and any —NH and/or NH₂ groups present on the B^1A can be protected with various protecting groups, and any protecting groups present can be exchanged for other protecting groups. The selection and exchange of the protecting groups is within the skill of those of ordinary skill in the art. Any protecting group(s) can be removed by methods known in the art, for example, with an acid (e.g., a mineral or an organic acid), a base or a fluoride source.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceutical composition, that can include a therapeutically effective amount of one or more compounds described herein (e.g., a compound of Formulae (I) or (Iα)), 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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Methods of Use

One embodiment disclosed herein relates to a method of treating and/or ameliorating a disease or condition that can include administering to a subject a therapeutically effective amount of one or more compounds described herein, such as a compound of Formula (I) (including compounds of Formula (Iα)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein.

Some embodiments disclosed herein relate to a method of ameliorating or treating a neoplastic disease that can include administering to a subject suffering from a neoplastic disease a therapeutically effective amount of one or more compounds described herein (e.g., a compound of Formulae (I) and/or (Iα), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein. In an embodiment, the neoplastic disease can be cancer. In some embodiments, the neoplastic disease can be a tumor such as a solid tumor. In an embodiment, the neoplastic disease can be leukemia. Exemplary leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and juvenile myelomonocytic leukemia (JMML).

Some embodiments disclosed herein relate to a method of inhibiting the growth of a tumor that can include administering to a subject having a tumor a therapeutically effective amount of one or more compounds described herein (for example, a compound of Formulae (I) and/or (Iα)), or a pharmaceutical composition that includes one or more compounds described herein.

Other embodiments disclosed herein relates to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from a viral infection a therapeutically effective amount of one or more compounds described herein (for example, a compound of Formulae (I) and/or (Iα)), or a pharmaceutical composition that includes one or more compounds described herein. In an embodiment, the viral infection can be caused by a virus selected from an adenovirus, an Alphaviridae, an Arbovirus, an Astrovirus, a Bunyaviridae, a Coronaviridae, a Filoviridae, a Flaviviridae, a Hepadnaviridae, a Herpesviridae, an Alphaherpesvirinae, a Betaherpesvirinae, a Gammaherpesvirinae, a Norwalk Virus, an Astroviridae, a Caliciviridae, an Orthomyxoviridae, a Paramyxoviridae, a Paramyxoviruses, a Rubulavirus, a Morbillivirus, a Papovaviridae, a Parvoviridae, a Picornaviridae, an Aphthoviridae, a Cardioviridae, an Enteroviridae, a Coxsackie virus, a Polio Virus, a Rhinoviridae, a Phycodnaviridae, a Poxyiridae, a Reoviridae, a Rotavirus, a Retroviridae, an A-Type Retrovirus, an Immunodeficiency Virus, a Leukemia Viruses, an Avian Sarcoma Viruses, a Rhabdoviruses, a Rubiviridae, a Togaviridae an Arenaviridae and/or a Bornaviridae. In some embodiments, the viral infection can be a hepatitis C viral (HCV) infection. In other embodiments, the viral infection can be influenza. In still other embodiments, the viral infection can be HIV.

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the 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 viral infection that can include contacting a cell infected with the 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 viral infection by contacting a cell infected with the virus with an effective amount of said compound(s). In some embodiments, the compound can be a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of a compound of Formulae (I) and/or (Iα), or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the virus can be a HCV virus.

Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include contacting a cell infected with the 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 virus that can include contacting a cell infected with the 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 virus by contacting a cell infected with the virus with an effective amount of said compound(s). In some embodiments, the compound can be a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of a compound of Formulae (I) and/or (Iα), or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the virus can be a HCV virus.

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.

Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity can include contacting a cell (for example, a cell infected with HCV) with an effective amount of a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof. Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity can include administering a cell (for example, a cell infected with HCV) with an effective amount of a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can inhibit an RNA dependent RNA polymerase. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can inhibit a HCV polymerase (for example, NS5B polymerase).

Some embodiments described herein relate to a method of treating HCV infection in a subject suffering from a HCV infection that can include administering to the subject an effective amount of a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof. Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrohis, 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 Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof). One cause of the liver fibrosis, liver cirrohis, and/or liver cancer can be 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 Formulae (I) and/or (Iα), 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 Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof). In one embodiment, this method comprises slowing or halting the progression of liver disease. In another embodiment, the course of the disease is reversed, and stasis or improvement in liver function is contemplated.

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 Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formulae (I) and/or (Iα), 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 Formulae (I) and/or (Iα), 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 Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof) can be effective to treat 3 or more, 5 or more, 7 or more of 9 more genotypes of HCV. In some embodiments, a compound of Formula (I) and/or (Iα), or a pharmaceutical acceptable salt thereof is more effective against a larger number of HCV genotypes than the standard of care. In some embodiments, a compound of Formula (I) and/or (Iα), or a pharmaceutical acceptable salt thereof, is more effective against a particular HCV genotype than the standard of care (such as genotype 1, 2, 3, 4, 5 and/or 6).

Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Example 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 Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof) can reduce the incidence of liver cancer in HCV patients.

In some embodiments, an effective amount of a compound of Formulae (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral titers to undetectable levels, for example, to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum. In some embodiments, an effective amount of a compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral load compared to the viral load before administration of the compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof. For example, wherein the viral load is measure before administration of the compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion). In some embodiments, an effective amount of a compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, can be an amount that is effective to reduce viral load to lower than about 100 genome copies/mL serum. In some embodiments, an effective amount of a compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a reduction in viral titer in the serum of the subject in the range of about 1.5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5-log reduction compared to the viral load before administration of the compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof. For example, the viral load can be measured before administration of the compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion).

In some embodiments, a compound of Formula (I) and/or (Iα), 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 HCV 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) and/or (Iα), or a pharmaceutically acceptable salt thereof, can result in a reduction of the replication of HCV relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, can result in a reduction of HCV replication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of HCV replication compared to the reduction of HCV 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.

In some embodiments, an effective amount of a compound of Formula (I) and/or (Iα), 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 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the subject's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.

In some embodiments, a therapeutically effective amount of a compound of Formula (I) and/or (Iα), 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 a markers includes measuring the levels of serum alanine aminotransferase (ALT), asparatate aminotransferacse (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) using known methods. 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) and/or (Iα) is an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with what is considered a normal level.

Subjects who are clinically diagnosed with HCV infection include “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).

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.

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. In some embodiments, development of resistant HCV strains is delayed when patients are 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.

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 or ribavirin.

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.

The standard of care for treating HCV has been associated with several side effects (adverse events). In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), 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 apetite, 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.

Table 5 provides some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 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 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 5
Percent-			Percent-
age of	Percent-	Percent-	age of	Number	Severity
non-	age of	age of	viral load	of side	of side
responders	relapsers	resistance	rebound	effects	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

Yet still other embodiments disclosed herein relates to a method of ameliorating or treating a parasitic disease that can include administering to a subject suffering from a parasitic disease a therapeutically effective amount of one or more compounds described herein (for example, a compound of Formula (I) and/or (Iα)), or a pharmaceutical composition that includes one or more compounds described herein. In an embodiment, the parasite disease can be Chagas' disease.

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.

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.

The term “therapeutically effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically 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 a therapeutically effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically 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.

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.

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) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can less compared to the total time of the treatment regime with the standard of care.

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.

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.

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.

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.

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.

Combination Therapies

In some embodiments, the compounds disclosed herein, such as a compound of Formula (I) (including compounds of Formula (Iα)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, 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 (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), compounds of Formula (DD) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (DD), 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 and D.

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, or Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin. As another example, a compound disclosed herein can be used in combination with oseltamivir (TAMIFLU®) or zanamivin (RELENZA®) for treating an influenza infection.

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.

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.

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. A non-limiting list of example HCV protease inhibitors includes the compounds numbered 1001-1014 in FIG. 1.

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 2001-2010 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 3001-3008 in FIG. 3.

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. A non-limiting list of example 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 4001-4005 in FIG. 4.

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 and/or combinations thereof. A non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5002 in FIG. 5.

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. Provisional Application No. 61/426,471, filed Dec. 22, 2010, the contents of which are incorporated by reference in its entirety):

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(═O)RBB¹⁴; 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 8000-8012 in FIGS. 8A-8B.

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. Provisional Application Nos. 61/385,363, filed Sep. 22, 2010, and 61/426,461, filed Dec. 22, 2010, 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. A non-limiting list of examples of compounds of Formula (CC) includes the compounds numbered 6000-6078 in FIGS. 6A-6I.

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 (DD), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (DD), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2010-0249068, filed Mar. 19, 2010, the contents of which are incorporated by reference in its entirety):

wherein each can be independently a double or single bond; A^DD1 can be selected from C (carbon), O (oxygen) and S (sulfur); B^DD1 can be an optionally substituted heterocyclic base or a derivative thereof; D^DD1 can be selected from C═CH₂, CH₂, O (oxygen), S (sulfur), CHF, and CF₂; R^DD1 can be hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aralkyl, dialkylaminoalkylene, alkyl-C(═O)—, aryl-C(═O)—, alkoxyalkyl-C(═O)—, aryloxyalkyl-C(═O)—, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,

an —O-linked amino acid, diphosphate, triphosphate or derivatives thereof; R^DD2 and R^DD3 can be each 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 and an optionally substituted C_1-6 haloalkyl, provided that at least one of R^DD2 and R^DD3 cannot be hydrogen; or R^DD2 and R^DD3 are taken together to form a group selected from among C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_3-6 aryl, and a C_3-6 heteroaryl; R^DD4 and R^DD9 can be independently selected from hydrogen, halogen, —NH₂, —NHR^DDa1, NR^DDa1R^DDb1, —OR^DDa1, —SR^DDa1, —CN, —NC, —N₃, —NO₂, —N(R^DDc1)—NR^DDa1R^DDb1, —N(R^DDc1)—OR^DDa1, —S—SR^DDa1, —(C═O)R^DDa1, —C(═O)OR^DDa1, —C(═O)R^DDa1R^DDb1, —O—(C═O)OR^DDa1, —O—C(═O)OR^DDa1, —O—C(═O)NR^DDa1R^DDb1, —N(R^DDc1)—C(═O)NR^DDa1R^DDb1, —S(═O)R^DDa1, S(═O)₂R^DDa1, —O—S(═O)₂NR^DDa1R^DDb1, —N(R^DDc1)—S(═O)₂NR^DDa1R^DDb1, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; R^DD5, R^DD6 and R^DD7 can be independently absent or selected from hydrogen, halogen, —NH₂, —NHR^DDa1, NR^DDa1R^DDb1, —OR^DDa1, —SR^DDa1, —CN, —NC, —N₃, —NO₂, —N(R^DDc1)—NR^DDa1R^DDb1, —N(R^DDc1)—OR^DDa1, —S—SR^DDa1, —C(═O)R^DDa1, —C(═O)OR^DDa1, —C(═O)NR^DDa1R^DDb1, —O—(C═O)R^DDa1, —O—C(═O)OR^DDa1, —O—C(═O)NR^DDa1R^DDb1, —N(R^DDc1)—C(═O)NR^DDa1R^DDb1, —S(═O)R^DDa1, S(═O)₂R^DDa1, —O—S(═O)₂NR^DDa1R^DDb1, —N(R^DDc1)—S(═O)₂NR^DDa1R^DDb1, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; or R^DD6 and R^DD7 taken together form —O—C(═O)—O—; R^DD8 can be absent or selected from the group consisting of hydrogen, halogen, —NH₂, —NHR^DDa1, NR^DDa1R^DDb1, —OR^DDa1, —SR^DDa1, —CN, —NC, —N₃, —NO₂, —N(R^DDc1)—NR^DDa1R^DDb1, —N(R^DDc1)—OR^DDa1, —S—SR^DDa1, —C(═O)R^DDa1, —C(═O)OR^DDa1, —C(═O)NR^DDa1R^DDb1, —O—C(═O)OR^DDa1, —O—C(═O)NR^DDa1R^DDb1, —N(R^DDc1)—C(═O)NR^DDa1R^DDb1, —S(O)R^DDa1, S(═O)₂R^DDa1, —O—S(═O)₂NR^DDa1R^DDb1, —N(R^DDc1)—S(═O)₂NR^DDa1R^DDb1, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted haloalkyl, an optionally substituted hydroxyalkyl and an —O-linked amino acid, or when the bond to R^DD7 indicated by is a double bond, then R^DD7 is a C_2-6 alkylidene and R^DD8 is absent; R^DDa1, R^DDb1 and R^DDc1 can be each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and an optionally substituted heteroaryl(C_1-6 alkyl); R^DD10 can be selected from O⁻, —OH, an optionally substituted aryloxy or aryl-O—,

alkyl-C(═O)—O—CH₂—O—, alkyl-C(═O)—S—CH₂CH₂—O— and an —N-linked amino acid; R^DD11 can be selected from O⁻, —OH, an optionally substituted aryloxy or aryl-O—,

alkyl-C(═O)—O—CH₂—O—, alkyl-C(═O)—S—CH₂CH₂—O— and an —N-linked amino acid; each R^DD12 and each R^DD13 can be independently or an optionally substituted substituent selected from C_1-8 organylcarbonyl, C_1-8 alkoxycarbonyl and C_1-8 organylaminocarbonyl; each R^DD14 can be hydrogen or an optionally substituted C_1-6-alkyl; each m^DD can be independently 1 or 2, and if both R^DD10 and R^DD11 are

each R^DD12, each R^DD13, each R^DD14 and each m^DD can be the same or different. In some embodiments, R^DD8 can be halogen, —OR^DDa1, 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_1-6 haloalkyl.

Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a compound selected from a compound of Formula (I) (including a compound of Formula (Iα)), compound 7072, compound 7073, compound 7074, compound 7075, compound 7076 and compound 7077, a monophosphate of any of the foregoing, and a diphosphate of any of the foregoing, or a pharmaceutically acceptable salt the foregoing, 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 (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of a compound selected from a compound of Formula (I) (including a compound of Formula (Iα)), compound 7072, compound 7073, compound 7074, compound 7075, compound 7076 and compound 7077, a monophosphate of any of the foregoing, and a diphosphate of any of the foregoing, or a pharmaceutically acceptable salt the foregoing, 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 (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting viral replication of a virus that can include contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I) (including a compound of Formula (Iα)), compound 7072, compound 7073, compound 7074, compound 7075, compound 7076 and compound 7077, a monophosphate of any of the foregoing, and a diphosphate of any of the foregoing, or a pharmaceutically acceptable salt the foregoing, 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 (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a compound selected from a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt the foregoing, 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 (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of a compound selected from a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt the foregoing, 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 (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting viral replication of a virus that can include contacting a cell infected with the virus with an effective amount of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt the foregoing, 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 (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.

The dosing amount(s) and dosing schedule(s) when using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents are within the knowledge of those skilled in the art. 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.

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) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can be administered prior to all additional agents. In other embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), 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) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of all additional agents.

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. 1-6 and 8-9 (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. 1-6 and 8-9 (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. 1-6 and 8-9 (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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof) is not antagonistic.

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.

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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof) may be a reduction in the required amount(s) of one or more compounds of FIGS. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs 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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound in FIGS. 1-6 and 8-9 (including a pharmaceutically acceptable salt and prodrug thereof), can be less compared to the amount of the compound in FIGS. 1-6 and 8-9 (including a pharmaceutically acceptable salt and prodrug 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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs 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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs 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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs 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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or 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. 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof).

A non-limiting list of example combination of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, with one or more additional agent(s) are provided in Tables A, B, C and D. In addition, a compound selected from Compounds 7072-7077, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, can be used in combination with one or more additional agent(s), as provided in Tables A, B, C and D. Each numbered X and Y compound in Tables A, B, C and D has a corresponding name and/or structure provided in FIGS. 1 to 9. The numbered compounds in Tables A, B, C and D 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 and D 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 1001:7001 in Table A represents a combination of compound 1001 with compound 7001, including pharmaceutically acceptable salts of compound 1001 and/or 7001, and pharmaceutical compositions including compound 1001 and 7001 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 7001). Thus, the combination designated as 1001:7001 in Table A represents the combination of Telaprevir (compound 1001, as shown in FIG. 1) and

(compound 7001, as shown in FIG. 7A), including pharmaceutically acceptable salts of compound 1001 and/or 7001, and pharmaceutical compositions including compound 1001 and 7001 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 7001). Each of the combinations provided in Tables A, B, C and D can be used with one, two, three or more additional agents described herein. In some embodiments, embodiments described herein, the combination of agents can be used to treat, amerliorate 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	X:Y
1001:7000	1001:7001	1001:7002	1001:7003	1001:7004	1001:7005	1001:7006
1002:7000	1002:7001	1002:7002	1002:7003	1002:7004	1002:7005	1002:7006
1003:7000	1003:7001	1003:7002	1003:7003	1003:7004	1003:7005	1003:7006
1004:7000	1004:7001	1004:7002	1004:7003	1004:7004	1004:7005	1004:7006
1005:7000	1005:7001	1005:7002	1005:7003	1005:7004	1005:7005	1005:7006
1006:7000	1006:7001	1006:7002	1006:7003	1006:7004	1006:7005	1006:7006
1007:7000	1007:7001	1007:7002	1007:7003	1007:7004	1007:7005	1007:7006
1008:7000	1008:7001	1008:7002	1008:7003	1008:7004	1008:7005	1008:7006
1009:7000	1009:7001	1009:7002	1009:7003	1009:7004	1009:7005	1009:7006
1010:7000	1010:7001	1010:7002	1010:7003	1010:7004	1010:7005	1010:7006
1011:7000	1011:7001	1011:7002	1011:7003	1011:7004	1011:7005	1011:7006
1012:7000	1012:7001	1012:7002	1012:7003	1012:7004	1012:7005	1012:7006
1013:7000	1013:7001	1013:7002	1013:7003	1013:7004	1013:7005	1013:7006
1014:7000	1014:7001	1014:7002	1014:7003	1014:7004	1014:7005	1014:7006
2001:7000	2001:7001	2001:7002	2001:7003	2001:7004	2001:7005	2001:7006
2002:7000	2002:7001	2002:7002	2002:7003	2002:7004	2002:7005	2002:7006
2003:7000	2003:7001	2003:7002	2003:7003	2003:7004	2003:7005	2003:7006
2004:7000	2004:7001	2004:7002	2004:7003	2004:7004	2004:7005	2004:7006
2005:7000	2005:7001	2005:7002	2005:7003	2005:7004	2005:7005	2005:7006
2006:7000	2006:7001	2006:7002	2006:7003	2006:7004	2006:7005	2006:7006
2007:7000	2007:7001	2007:7002	2007:7003	2007:7004	2007:7005	2007:7006
2008:7000	2008:7001	2008:7002	2008:7003	2008:7004	2008:7005	2008:7006
2009:7000	2009:7001	2009:7002	2009:7003	2009:7004	2009:7005	2009:7006
2010:7000	2010:7001	2010:7002	2010:7003	2010:7004	2010:7005	2010:7006
3001:7000	3001:7001	3001:7002	3001:7003	3001:7004	3001:7005	3001:7006
3002:7000	3002:7001	3002:7002	3002:7003	3002:7004	3002:7005	3002:7006
3003:7000	3003:7001	3003:7002	3003:7003	3003:7004	3003:7005	3003:7006
3004:7000	3004:7001	3004:7002	3004:7003	3004:7004	3004:7005	3004:7006
3005:7000	3005:7001	3005:7002	3005:7003	3005:7004	3005:7005	3005:7006
3006:7000	3006:7001	3006:7002	3006:7003	3006:7004	3006:7005	3006:7006
3007:7000	3007:7001	3007:7002	3007:7003	3007:7004	3007:7005	3007:7006
3008:7000	3008:7001	3008:7002	3008:7003	3008:7004	3008:7005	3008:7006
4001:7000	4001:7001	4001:7002	4001:7003	4001:7004	4001:7005	4001:7006
4002:7000	4002:7001	4002:7002	4002:7003	4002:7004	4002:7005	4002:7006
4003:7000	4003:7001	4003:7002	4003:7003	4003:7004	4003:7005	4003:7006
4004:7000	4004:7001	4004:7002	4004:7003	4004:7004	4004:7005	4004:7006
4005:7000	4005:7001	4005:7002	4005:7003	4005:7004	4005:7005	4005:7006
5001:7000	5001:7001	5001:7002	5001:7003	5001:7004	5001:7005	5001:7006
5002:7000	5002:7001	5002:7002	5002:7003	5002:7004	5002:7005	5002:7006
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7007	1001:7008	1001:7009	1001:7010	1001:7011	1001:7012	1001:7013
1002:7007	1002:7008	1002:7009	1002:7010	1002:7011	1002:7012	1002:7013
1003:7007	1003:7008	1003:7009	1003:7010	1003:7011	1003:7012	1003:7013
1004:7007	1004:7008	1004:7009	1004:7010	1004:7011	1004:7012	1004:7013
1005:7007	1005:7008	1005:7009	1005:7010	1005:7011	1005:7012	1005:7013
1006:7007	1006:7008	1006:7009	1006:7010	1006:7011	1006:7012	1006:7013
1007:7007	1007:7008	1007:7009	1007:7010	1007:7011	1007:7012	1007:7013
1008:7007	1008:7008	1008:7009	1008:7010	1008:7011	1008:7012	1008:7013
1009:7007	1009:7008	1009:7009	1009:7010	1009:7011	1009:7012	1009:7013
1010:7007	1010:7008	1010:7009	1010:7010	1010:7011	1010:7012	1010:7013
1011:7007	1011:7008	1011:7009	1011:7010	1011:7011	1011:7012	1011:7013
1012:7007	1012:7008	1012:7009	1012:7010	1012:7011	1012:7012	1012:7013
1013:7007	1013:7008	1013:7009	1013:7010	1013:7011	1013:7012	1013:7013
1014:7007	1014:7008	1014:7009	1014:7010	1014:7011	1014:7012	1014:7013
2001:7007	2001:7008	2001:7009	2001:7010	2001:7011	2001:7012	2001:7013
2002:7007	2002:7008	2002:7009	2002:7010	2002:7011	2002:7012	2002:7013
2003:7007	2003:7008	2003:7009	2003:7010	2003:7011	2003:7012	2003:7013
2004:7007	2004:7008	2004:7009	2004:7010	2004:7011	2004:7012	2004:7013
2005:7007	2005:7008	2005:7009	2005:7010	2005:7011	2005:7012	2005:7013
2006:7007	2006:7008	2006:7009	2006:7010	2006:7011	2006:7012	2006:7013
2007:7007	2007:7008	2007:7009	2007:7010	2007:7011	2007:7012	2007:7013
2008:7007	2008:7008	2008:7009	2008:7010	2008:7011	2008:7012	2008:7013
2009:7007	2009:7008	2009:7009	2009:7010	2009:7011	2009:7012	2009:7013
2010:7007	2010:7008	2010:7009	2010:7010	2010:7011	2010:7012	2010:7013
3001:7007	3001:7008	3001:7009	3001:7010	3001:7011	3001:7012	3001:7013
3002:7007	3002:7008	3002:7009	3002:7010	3002:7011	3002:7012	3002:7013
3003:7007	3003:7008	3003:7009	3003:7010	3003:7011	3003:7012	3003:7013
3004:7007	3004:7008	3004:7009	3004:7010	3004:7011	3004:7012	3004:7013
3005:7007	3005:7008	3005:7009	3005:7010	3005:7011	3005:7012	3005:7013
3006:7007	3006:7008	3006:7009	3006:7010	3006:7011	3006:7012	3006:7013
3007:7007	3007:7008	3007:7009	3007:7010	3007:7011	3007:7012	3007:7013
3008:7007	3008:7008	3008:7009	3008:7010	3008:7011	3008:7012	3008:7013
4001:7007	4001:7008	4001:7009	4001:7010	4001:7011	4001:7012	4001:7013
4002:7007	4002:7008	4002:7009	4002:7010	4002:7011	4002:7012	4002:7013
4003:7007	4003:7008	4003:7009	4003:7010	4003:7011	4003:7012	4003:7013
4004:7007	4004:7008	4004:7009	4004:7010	4004:7011	4004:7012	4004:7013
4005:7007	4005:7008	4005:7009	4005:7010	4005:7011	4005:7012	4005:7013
5001:7007	5001:7008	5001:7009	5001:7010	5001:7011	5001:7012	5001:7013
5002:7007	5002:7008	5002:7009	5002:7010	5002:7011	5002:7012	5002:7013
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7014	1001:7015	1001:7016	1001:7017	1001:7018	1001:7019	1001:7020
1002:7014	1002:7015	1002:7016	1002:7017	1002:7018	1002:7019	1002:7020
1003:7014	1003:7015	1003:7016	1003:7017	1003:7018	1003:7019	1003:7020
1004:7014	1004:7015	1004:7016	1004:7017	1004:7018	1004:7019	1004:7020
1005:7014	1005:7015	1005:7016	1005:7017	1005:7018	1005:7019	1005:7020
1006:7014	1006:7015	1006:7016	1006:7017	1006:7018	1006:7019	1006:7020
1007:7014	1007:7015	1007:7016	1007:7017	1007:7018	1007:7019	1007:7020
1008:7014	1008:7015	1008:7016	1008:7017	1008:7018	1008:7019	1008:7020
1009:7014	1009:7015	1009:7016	1009:7017	1009:7018	1009:7019	1009:7020
1010:7014	1010:7015	1010:7016	1010:7017	1010:7018	1010:7019	1010:7020
1011:7014	1011:7015	1011:7016	1011:7017	1011:7018	1011:7019	1011:7020
1012:7014	1012:7015	1012:7016	1012:7017	1012:7018	1012:7019	1012:7020
1013:7014	1013:7015	1013:7016	1013:7017	1013:7018	1013:7019	1013:7020
1014:7014	1014:7015	1014:7016	1014:7017	1014:7018	1014:7019	1014:7020
2001:7014	2001:7015	2001:7016	2001:7017	2001:7018	2001:7019	2001:7020
2002:7014	2002:7015	2002:7016	2002:7017	2002:7018	2002:7019	2002:7020
2003:7014	2003:7015	2003:7016	2003:7017	2003:7018	2003:7019	2003:7020
2004:7014	2004:7015	2004:7016	2004:7017	2004:7018	2004:7019	2004:7020
2005:7014	2005:7015	2005:7016	2005:7017	2005:7018	2005:7019	2005:7020
2006:7014	2006:7015	2006:7016	2006:7017	2006:7018	2006:7019	2006:7020
2007:7014	2007:7015	2007:7016	2007:7017	2007:7018	2007:7019	2007:7020
2008:7014	2008:7015	2008:7016	2008:7017	2008:7018	2008:7019	2008:7020
2009:7014	2009:7015	2009:7016	2009:7017	2009:7018	2009:7019	2009:7020
2010:7014	2010:7015	2010:7016	2010:7017	2010:7018	2010:7019	2010:7020
3001:7014	3001:7015	3001:7016	3001:7017	3001:7018	3001:7019	3001:7020
3002:7014	3002:7015	3002:7016	3002:7017	3002:7018	3002:7019	3002:7020
3003:7014	3003:7015	3003:7016	3003:7017	3003:7018	3003:7019	3003:7020
3004:7014	3004:7015	3004:7016	3004:7017	3004:7018	3004:7019	3004:7020
3005:7014	3005:7015	3005:7016	3005:7017	3005:7018	3005:7019	3005:7020
3006:7014	3006:7015	3006:7016	3006:7017	3006:7018	3006:7019	3006:7020
3007:7014	3007:7015	3007:7016	3007:7017	3007:7018	3007:7019	3007:7020
3008:7014	3008:7015	3008:7016	3008:7017	3008:7018	3008:7019	3008:7020
4001:7014	4001:7015	4001:7016	4001:7017	4001:7018	4001:7019	4001:7020
4002:7014	4002:7015	4002:7016	4002:7017	4002:7018	4002:7019	4002:7020
4003:7014	4003:7015	4003:7016	4003:7017	4003:7018	4003:7019	4003:7020
4004:7014	4004:7015	4004:7016	4004:7017	4004:7018	4004:7019	4004:7020
4005:7014	4005:7015	4005:7016	4005:7017	4005:7018	4005:7019	4005:7020
5001:7014	5001:7015	5001:7016	5001:7017	5001:7018	5001:7019	5001:7020
5002:7014	5002:7015	5002:7016	5002:7017	5002:7018	5002:7019	5002:7020
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7021	1001:7022	1001:7023	1001:7024	1001:7025	1001:7026	1001:7027
1002:7021	1002:7022	1002:7023	1002:7024	1002:7025	1002:7026	1002:7027
1003:7021	1003:7022	1003:7023	1003:7024	1003:7025	1003:7026	1003:7027
1004:7021	1004:7022	1004:7023	1004:7024	1004:7025	1004:7026	1004:7027
1005:7021	1005:7022	1005:7023	1005:7024	1005:7025	1005:7026	1005:7027
1006:7021	1006:7022	1006:7023	1006:7024	1006:7025	1006:7026	1006:7027
1007:7021	1007:7022	1007:7023	1007:7024	1007:7025	1007:7026	1007:7027
1008:7021	1008:7022	1008:7023	1008:7024	1008:7025	1008:7026	1008:7027
1009:7021	1009:7022	1009:7023	1009:7024	1009:7025	1009:7026	1009:7027
1010:7021	1010:7022	1010:7023	1010:7024	1010:7025	1010:7026	1010:7027
1011:7021	1011:7022	1011:7023	1011:7024	1011:7025	1011:7026	1011:7027
1012:7021	1012:7022	1012:7023	1012:7024	1012:7025	1012:7026	1012:7027
1013:7021	1013:7022	1013:7023	1013:7024	1013:7025	1013:7026	1013:7027
1014:7021	1014:7022	1014:7023	1014:7024	1014:7025	1014:7026	1014:7027
2001:7021	2001:7022	2001:7023	2001:7024	2001:7025	2001:7026	2001:7027
2002:7021	2002:7022	2002:7023	2002:7024	2002:7025	2002:7026	2002:7027
2003:7021	2003:7022	2003:7023	2003:7024	2003:7025	2003:7026	2003:7027
2004:7021	2004:7022	2004:7023	2004:7024	2004:7025	2004:7026	2004:7027
2005:7021	2005:7022	2005:7023	2005:7024	2005:7025	2005:7026	2005:7027
2006:7021	2006:7022	2006:7023	2006:7024	2006:7025	2006:7026	2006:7027
2007:7021	2007:7022	2007:7023	2007:7024	2007:7025	2007:7026	2007:7027
2008:7021	2008:7022	2008:7023	2008:7024	2008:7025	2008:7026	2008:7027
2009:7021	2009:7022	2009:7023	2009:7024	2009:7025	2009:7026	2009:7027
2010:7021	2010:7022	2010:7023	2010:7024	2010:7025	2010:7026	2010:7027
3001:7021	3001:7022	3001:7023	3001:7024	3001:7025	3001:7026	3001:7027
3002:7021	3002:7022	3002:7023	3002:7024	3002:7025	3002:7026	3002:7027
3003:7021	3003:7022	3003:7023	3003:7024	3003:7025	3003:7026	3003:7027
3004:7021	3004:7022	3004:7023	3004:7024	3004:7025	3004:7026	3004:7027
3005:7021	3005:7022	3005:7023	3005:7024	3005:7025	3005:7026	3005:7027
3006:7021	3006:7022	3006:7023	3006:7024	3006:7025	3006:7026	3006:7027
3007:7021	3007:7022	3007:7023	3007:7024	3007:7025	3007:7026	3007:7027
3008:7021	3008:7022	3008:7023	3008:7024	3008:7025	3008:7026	3008:7027
4001:7021	4001:7022	4001:7023	4001:7024	4001:7025	4001:7026	4001:7027
4002:7021	4002:7022	4002:7023	4002:7024	4002:7025	4002:7026	4002:7027
4003:7021	4003:7022	4003:7023	4003:7024	4003:7025	4003:7026	4003:7027
4004:7021	4004:7022	4004:7023	4004:7024	4004:7025	4004:7026	4004:7027
4005:7021	4005:7022	4005:7023	4005:7024	4005:7025	4005:7026	4005:7027
5001:7021	5001:7022	5001:7023	5001:7024	5001:7025	5001:7026	5001:7027
5002:7021	5002:7022	5002:7023	5002:7024	5002:7025	5002:7026	5002:7027
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7028	1001:7029	1001:7030	1001:7031	1001:7032	1001:7033	1001:7034
1002:7028	1002:7029	1002:7030	1002:7031	1002:7032	1002:7033	1002:7034
1003:7028	1003:7029	1003:7030	1003:7031	1003:7032	1003:7033	1003:7034
1004:7028	1004:7029	1004:7030	1004:7031	1004:7032	1004:7033	1004:7034
1005:7028	1005:7029	1005:7030	1005:7031	1005:7032	1005:7033	1005:7034
1006:7028	1006:7029	1006:7030	1006:7031	1006:7032	1006:7033	1006:7034
1007:7028	1007:7029	1007:7030	1007:7031	1007:7032	1007:7033	1007:7034
1008:7028	1008:7029	1008:7030	1008:7031	1008:7032	1008:7033	1008:7034
1009:7028	1009:7029	1009:7030	1009:7031	1009:7032	1009:7033	1009:7034
1010:7028	1010:7029	1010:7030	1010:7031	1010:7032	1010:7033	1010:7034
1011:7028	1011:7029	1011:7030	1011:7031	1011:7032	1011:7033	1011:7034
1012:7028	1012:7029	1012:7030	1012:7031	1012:7032	1012:7033	1012:7034
1013:7028	1013:7029	1013:7030	1013:7031	1013:7032	1013:7033	1013:7034
1014:7028	1014:7029	1014:7030	1014:7031	1014:7032	1014:7033	1014:7034
2001:7028	2001:7029	2001:7030	2001:7031	2001:7032	2001:7033	2001:7034
2002:7028	2002:7029	2002:7030	2002:7031	2002:7032	2002:7033	2002:7034
2003:7028	2003:7029	2003:7030	2003:7031	2003:7032	2003:7033	2003:7034
2004:7028	2004:7029	2004:7030	2004:7031	2004:7032	2004:7033	2004:7034
2005:7028	2005:7029	2005:7030	2005:7031	2005:7032	2005:7033	2005:7034
2006:7028	2006:7029	2006:7030	2006:7031	2006:7032	2006:7033	2006:7034
2007:7028	2007:7029	2007:7030	2007:7031	2007:7032	2007:7033	2007:7034
2008:7028	2008:7029	2008:7030	2008:7031	2008:7032	2008:7033	2008:7034
2009:7028	2009:7029	2009:7030	2009:7031	2009:7032	2009:7033	2009:7034
2010:7028	2010:7029	2010:7030	2010:7031	2010:7032	2010:7033	2010:7034
3001:7028	3001:7029	3001:7030	3001:7031	3001:7032	3001:7033	3001:7034
3002:7028	3002:7029	3002:7030	3002:7031	3002:7032	3002:7033	3002:7034
3003:7028	3003:7029	3003:7030	3003:7031	3003:7032	3003:7033	3003:7034
3004:7028	3004:7029	3004:7030	3004:7031	3004:7032	3004:7033	3004:7034
3005:7028	3005:7029	3005:7030	3005:7031	3005:7032	3005:7033	3005:7034
3006:7028	3006:7029	3006:7030	3006:7031	3006:7032	3006:7033	3006:7034
3007:7028	3007:7029	3007:7030	3007:7031	3007:7032	3007:7033	3007:7034
3008:7028	3008:7029	3008:7030	3008:7031	3008:7032	3008:7033	3008:7034
4001:7028	4001:7029	4001:7030	4001:7031	4001:7032	4001:7033	4001:7034
4002:7028	4002:7029	4002:7030	4002:7031	4002:7032	4002:7033	4002:7034
4003:7028	4003:7029	4003:7030	4003:7031	4003:7032	4003:7033	4003:7034
4004:7028	4004:7029	4004:7030	4004:7031	4004:7032	4004:7033	4004:7034
4005:7028	4005:7029	4005:7030	4005:7031	4005:7032	4005:7033	4005:7034
5001:7028	5001:7029	5001:7030	5001:7031	5001:7032	5001:7033	5001:7034
5002:7028	5002:7029	5002:7030	5002:7031	5002:7032	5002:7033	5002:7034
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7035	1001:7036	1001:7037	1001:7038	1001:7039	1001:7040	1001:7041
1002:7035	1002:7036	1002:7037	1002:7038	1002:7039	1002:7040	1002:7041
1003:7035	1003:7036	1003:7037	1003:7038	1003:7039	1003:7040	1003:7041
1004:7035	1004:7036	1004:7037	1004:7038	1004:7039	1004:7040	1004:7041
1005:7035	1005:7036	1005:7037	1005:7038	1005:7039	1005:7040	1005:7041
1006:7035	1006:7036	1006:7037	1006:7038	1006:7039	1006:7040	1006:7041
1007:7035	1007:7036	1007:7037	1007:7038	1007:7039	1007:7040	1007:7041
1008:7035	1008:7036	1008:7037	1008:7038	1008:7039	1008:7040	1008:7041
1009:7035	1009:7036	1009:7037	1009:7038	1009:7039	1009:7040	1009:7041
1010:7035	1010:7036	1010:7037	1010:7038	1010:7039	1010:7040	1010:7041
1011:7035	1011:7036	1011:7037	1011:7038	1011:7039	1011:7040	1011:7041
1012:7035	1012:7036	1012:7037	1012:7038	1012:7039	1012:7040	1012:7041
1013:7035	1013:7036	1013:7037	1013:7038	1013:7039	1013:7040	1013:7041
1014:7035	1014:7036	1014:7037	1014:7038	1014:7039	1014:7040	1014:7041
2001:7035	2001:7036	2001:7037	2001:7038	2001:7039	2001:7040	2001:7041
2002:7035	2002:7036	2002:7037	2002:7038	2002:7039	2002:7040	2002:7041
2003:7035	2003:7036	2003:7037	2003:7038	2003:7039	2003:7040	2003:7041
2004:7035	2004:7036	2004:7037	2004:7038	2004:7039	2004:7040	2004:7041
2005:7035	2005:7036	2005:7037	2005:7038	2005:7039	2005:7040	2005:7041
2006:7035	2006:7036	2006:7037	2006:7038	2006:7039	2006:7040	2006:7041
2007:7035	2007:7036	2007:7037	2007:7038	2007:7039	2007:7040	2007:7041
2008:7035	2008:7036	2008:7037	2008:7038	2008:7039	2008:7040	2008:7041
2009:7035	2009:7036	2009:7037	2009:7038	2009:7039	2009:7040	2009:7041
2010:7035	2010:7036	2010:7037	2010:7038	2010:7039	2010:7040	2010:7041
3001:7035	3001:7036	3001:7037	3001:7038	3001:7039	3001:7040	3001:7041
3002:7035	3002:7036	3002:7037	3002:7038	3002:7039	3002:7040	3002:7041
3003:7035	3003:7036	3003:7037	3003:7038	3003:7039	3003:7040	3003:7041
3004:7035	3004:7036	3004:7037	3004:7038	3004:7039	3004:7040	3004:7041
3005:7035	3005:7036	3005:7037	3005:7038	3005:7039	3005:7040	3005:7041
3006:7035	3006:7036	3006:7037	3006:7038	3006:7039	3006:7040	3006:7041
3007:7035	3007:7036	3007:7037	3007:7038	3007:7039	3007:7040	3007:7041
3008:7035	3008:7036	3008:7037	3008:7038	3008:7039	3008:7040	3008:7041
4001:7035	4001:7036	4001:7037	4001:7038	4001:7039	4001:7040	4001:7041
4002:7035	4002:7036	4002:7037	4002:7038	4002:7039	4002:7040	4002:7041
4003:7035	4003:7036	4003:7037	4003:7038	4003:7039	4003:7040	4003:7041
4004:7035	4004:7036	4004:7037	4004:7038	4004:7039	4004:7040	4004:7041
4005:7035	4005:7036	4005:7037	4005:7038	4005:7039	4005:7040	4005:7041
5001:7035	5001:7036	5001:7037	5001:7038	5001:7039	5001:7040	5001:7041
5002:7035	5002:7036	5002:7037	5002:7038	5002:7039	5002:7040	5002:7041
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7042	1001:7043	1001:7044	1001:7045	1001:7046	1001:7047	1001:7048
1002:7042	1002:7043	1002:7044	1002:7045	1002:7046	1002:7047	1002:7048
1003:7042	1003:7043	1003:7044	1003:7045	1003:7046	1003:7047	1003:7048
1004:7042	1004:7043	1004:7044	1004:7045	1004:7046	1004:7047	1004:7048
1005:7042	1005:7043	1005:7044	1005:7045	1005:7046	1005:7047	1005:7048
1006:7042	1006:7043	1006:7044	1006:7045	1006:7046	1006:7047	1006:7048
1007:7042	1007:7043	1007:7044	1007:7045	1007:7046	1007:7047	1007:7048
1008:7042	1008:7043	1008:7044	1008:7045	1008:7046	1008:7047	1008:7048
1009:7042	1009:7043	1009:7044	1009:7045	1009:7046	1009:7047	1009:7048
1010:7042	1010:7043	1010:7044	1010:7045	1010:7046	1010:7047	1010:7048
1011:7042	1011:7043	1011:7044	1011:7045	1011:7046	1011:7047	1011:7048
1012:7042	1012:7043	1012:7044	1012:7045	1012:7046	1012:7047	1012:7048
1013:7042	1013:7043	1013:7044	1013:7045	1013:7046	1013:7047	1013:7048
1014:7042	1014:7043	1014:7044	1014:7045	1014:7046	1014:7047	1014:7048
2001:7042	2001:7043	2001:7044	2001:7045	2001:7046	2001:7047	2001:7048
2002:7042	2002:7043	2002:7044	2002:7045	2002:7046	2002:7047	2002:7048
2003:7042	2003:7043	2003:7044	2003:7045	2003:7046	2003:7047	2003:7048
2004:7042	2004:7043	2004:7044	2004:7045	2004:7046	2004:7047	2004:7048
2005:7042	2005:7043	2005:7044	2005:7045	2005:7046	2005:7047	2005:7048
2006:7042	2006:7043	2006:7044	2006:7045	2006:7046	2006:7047	2006:7048
2007:7042	2007:7043	2007:7044	2007:7045	2007:7046	2007:7047	2007:7048
2008:7042	2008:7043	2008:7044	2008:7045	2008:7046	2008:7047	2008:7048
2009:7042	2009:7043	2009:7044	2009:7045	2009:7046	2009:7047	2009:7048
2010:7042	2010:7043	2010:7044	2010:7045	2010:7046	2010:7047	2010:7048
3001:7042	3001:7043	3001:7044	3001:7045	3001:7046	3001:7047	3001:7048
3002:7042	3002:7043	3002:7044	3002:7045	3002:7046	3002:7047	3002:7048
3003:7042	3003:7043	3003:7044	3003:7045	3003:7046	3003:7047	3003:7048
3004:7042	3004:7043	3004:7044	3004:7045	3004:7046	3004:7047	3004:7048
3005:7042	3005:7043	3005:7044	3005:7045	3005:7046	3005:7047	3005:7048
3006:7042	3006:7043	3006:7044	3006:7045	3006:7046	3006:7047	3006:7048
3007:7042	3007:7043	3007:7044	3007:7045	3007:7046	3007:7047	3007:7048
3008:7042	3008:7043	3008:7044	3008:7045	3008:7046	3008:7047	3008:7048
4001:7042	4001:7043	4001:7044	4001:7045	4001:7046	4001:7047	4001:7048
4002:7042	4002:7043	4002:7044	4002:7045	4002:7046	4002:7047	4002:7048
4003:7042	4003:7043	4003:7044	4003:7045	4003:7046	4003:7047	4003:7048
4004:7042	4004:7043	4004:7044	4004:7045	4004:7046	4004:7047	4004:7048
4005:7042	4005:7043	4005:7044	4005:7045	4005:7046	4005:7047	4005:7048
5001:7042	5001:7043	5001:7044	5001:7045	5001:7046	5001:7047	5001:7048
5002:7042	5002:7043	5002:7044	5002:7045	5002:7046	5002:7047	5002:7048
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7049	1001:7050	1001:7051	1001:7052	1001:7053	1001:7054	1001:7055
1002:7049	1002:7050	1002:7051	1002:7052	1002:7053	1002:7054	1002:7055
1003:7049	1003:7050	1003:7051	1003:7052	1003:7053	1003:7054	1003:7055
1004:7049	1004:7050	1004:7051	1004:7052	1004:7053	1004:7054	1004:7055
1005:7049	1005:7050	1005:7051	1005:7052	1005:7053	1005:7054	1005:7055
1006:7049	1006:7050	1006:7051	1006:7052	1006:7053	1006:7054	1006:7055
1007:7049	1007:7050	1007:7051	1007:7052	1007:7053	1007:7054	1007:7055
1008:7049	1008:7050	1008:7051	1008:7052	1008:7053	1008:7054	1008:7055
1009:7049	1009:7050	1009:7051	1009:7052	1009:7053	1009:7054	1009:7055
1010:7049	1010:7050	1010:7051	1010:7052	1010:7053	1010:7054	1010:7055
1011:7049	1011:7050	1011:7051	1011:7052	1011:7053	1011:7054	1011:7055
1012:7049	1012:7050	1012:7051	1012:7052	1012:7053	1012:7054	1012:7055
1013:7049	1013:7050	1013:7051	1013:7052	1013:7053	1013:7054	1013:7055
1014:7049	1014:7050	1014:7051	1014:7052	1014:7053	1014:7054	1014:7055
2001:7049	2001:7050	2001:7051	2001:7052	2001:7053	2001:7054	2001:7055
2002:7049	2002:7050	2002:7051	2002:7052	2002:7053	2002:7054	2002:7055
2003:7049	2003:7050	2003:7051	2003:7052	2003:7053	2003:7054	2003:7055
2004:7049	2004:7050	2004:7051	2004:7052	2004:7053	2004:7054	2004:7055
2005:7049	2005:7050	2005:7051	2005:7052	2005:7053	2005:7054	2005:7055
2006:7049	2006:7050	2006:7051	2006:7052	2006:7053	2006:7054	2006:7055
2007:7049	2007:7050	2007:7051	2007:7052	2007:7053	2007:7054	2007:7055
2008:7049	2008:7050	2008:7051	2008:7052	2008:7053	2008:7054	2008:7055
2009:7049	2009:7050	2009:7051	2009:7052	2009:7053	2009:7054	2009:7055
2010:7049	2010:7050	2010:7051	2010:7052	2010:7053	2010:7054	2010:7055
3001:7049	3001:7050	3001:7051	3001:7052	3001:7053	3001:7054	3001:7055
3002:7049	3002:7050	3002:7051	3002:7052	3002:7053	3002:7054	3002:7055
3003:7049	3003:7050	3003:7051	3003:7052	3003:7053	3003:7054	3003:7055
3004:7049	3004:7050	3004:7051	3004:7052	3004:7053	3004:7054	3004:7055
3005:7049	3005:7050	3005:7051	3005:7052	3005:7053	3005:7054	3005:7055
3006:7049	3006:7050	3006:7051	3006:7052	3006:7053	3006:7054	3006:7055
3007:7049	3007:7050	3007:7051	3007:7052	3007:7053	3007:7054	3007:7055
3008:7049	3008:7050	3008:7051	3008:7052	3008:7053	3008:7054	3008:7055
4001:7049	4001:7050	4001:7051	4001:7052	4001:7053	4001:7054	4001:7055
4002:7049	4002:7050	4002:7051	4002:7052	4002:7053	4002:7054	4002:7055
4003:7049	4003:7050	4003:7051	4003:7052	4003:7053	4003:7054	4003:7055
4004:7049	4004:7050	4004:7051	4004:7052	4004:7053	4004:7054	4004:7055
4005:7049	4005:7050	4005:7051	4005:7052	4005:7053	4005:7054	4005:7055
5001:7049	5001:7050	5001:7051	5001:7052	5001:7053	5001:7054	5001:7055
5002:7049	5002:7050	5002:7051	5002:7052	5002:7053	5002:7054	5002:7055
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7056	1001:7057	1001:7058	1001:7059	1001:7060	1001:7061	1001:7062
1002:7056	1002:7057	1002:7058	1002:7059	1002:7060	1002:7061	1002:7062
1003:7056	1003:7057	1003:7058	1003:7059	1003:7060	1003:7061	1003:7062
1004:7056	1004:7057	1004:7058	1004:7059	1004:7060	1004:7061	1004:7062
1005:7056	1005:7057	1005:7058	1005:7059	1005:7060	1005:7061	1005:7062
1006:7056	1006:7057	1006:7058	1006:7059	1006:7060	1006:7061	1006:7062
1007:7056	1007:7057	1007:7058	1007:7059	1007:7060	1007:7061	1007:7062
1008:7056	1008:7057	1008:7058	1008:7059	1008:7060	1008:7061	1008:7062
1009:7056	1009:7057	1009:7058	1009:7059	1009:7060	1009:7061	1009:7062
1010:7056	1010:7057	1010:7058	1010:7059	1010:7060	1010:7061	1010:7062
1011:7056	1011:7057	1011:7058	1011:7059	1011:7060	1011:7061	1011:7062
1012:7056	1012:7057	1012:7058	1012:7059	1012:7060	1012:7061	1012:7062
1013:7056	1013:7057	1013:7058	1013:7059	1013:7060	1013:7061	1013:7062
1014:7056	1014:7057	1014:7058	1014:7059	1014:7060	1014:7061	1014:7062
2001:7056	2001:7057	2001:7058	2001:7059	2001:7060	2001:7061	2001:7062
2002:7056	2002:7057	2002:7058	2002:7059	2002:7060	2002:7061	2002:7062
2003:7056	2003:7057	2003:7058	2003:7059	2003:7060	2003:7061	2003:7062
2004:7056	2004:7057	2004:7058	2004:7059	2004:7060	2004:7061	2004:7062
2005:7056	2005:7057	2005:7058	2005:7059	2005:7060	2005:7061	2005:7062
2006:7056	2006:7057	2006:7058	2006:7059	2006:7060	2006:7061	2006:7062
2007:7056	2007:7057	2007:7058	2007:7059	2007:7060	2007:7061	2007:7062
2008:7056	2008:7057	2008:7058	2008:7059	2008:7060	2008:7061	2008:7062
2009:7056	2009:7057	2009:7058	2009:7059	2009:7060	2009:7061	2009:7062
2010:7056	2010:7057	2010:7058	2010:7059	2010:7060	2010:7061	2010:7062
3001:7056	3001:7057	3001:7058	3001:7059	3001:7060	3001:7061	3001:7062
3002:7056	3002:7057	3002:7058	3002:7059	3002:7060	3002:7061	3002:7062
3003:7056	3003:7057	3003:7058	3003:7059	3003:7060	3003:7061	3003:7062
3004:7056	3004:7057	3004:7058	3004:7059	3004:7060	3004:7061	3004:7062
3005:7056	3005:7057	3005:7058	3005:7059	3005:7060	3005:7061	3005:7062
3006:7056	3006:7057	3006:7058	3006:7059	3006:7060	3006:7061	3006:7062
3007:7056	3007:7057	3007:7058	3007:7059	3007:7060	3007:7061	3007:7062
3008:7056	3008:7057	3008:7058	3008:7059	3008:7060	3008:7061	3008:7062
4001:7056	4001:7057	4001:7058	4001:7059	4001:7060	4001:7061	4001:7062
4002:7056	4002:7057	4002:7058	4002:7059	4002:7060	4002:7061	4002:7062
4003:7056	4003:7057	4003:7058	4003:7059	4003:7060	4003:7061	4003:7062
4004:7056	4004:7057	4004:7058	4004:7059	4004:7060	4004:7061	4004:7062
4005:7056	4005:7057	4005:7058	4005:7059	4005:7060	4005:7061	4005:7062
5001:7056	5001:7057	5001:7058	5001:7059	5001:7060	5001:7061	5001:7062
5002:7056	5002:7057	5002:7058	5002:7059	5002:7060	5002:7061	5002:7062
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7063	1001:7064	1001:7065	1001:7066	1001:7067	1001:7068	1001:7069
1002:7063	1002:7064	1002:7065	1002:7066	1002:7067	1002:7068	1002:7069
1003:7063	1003:7064	1003:7065	1003:7066	1003:7067	1003:7068	1003:7069
1004:7063	1004:7064	1004:7065	1004:7066	1004:7067	1004:7068	1004:7069
1005:7063	1005:7064	1005:7065	1005:7066	1005:7067	1005:7068	1005:7069
1006:7063	1006:7064	1006:7065	1006:7066	1006:7067	1006:7068	1006:7069
1007:7063	1007:7064	1007:7065	1007:7066	1007:7067	1007:7068	1007:7069
1008:7063	1008:7064	1008:7065	1008:7066	1008:7067	1008:7068	1008:7069
1009:7063	1009:7064	1009:7065	1009:7066	1009:7067	1009:7068	1009:7069
1010:7063	1010:7064	1010:7065	1010:7066	1010:7067	1010:7068	1010:7069
1011:7063	1011:7064	1011:7065	1011:7066	1011:7067	1011:7068	1011:7069
1012:7063	1012:7064	1012:7065	1012:7066	1012:7067	1012:7068	1012:7069
1013:7063	1013:7064	1013:7065	1013:7066	1013:7067	1013:7068	1013:7069
1014:7063	1014:7064	1014:7065	1014:7066	1014:7067	1014:7068	1014:7069
2001:7063	2001:7064	2001:7065	2001:7066	2001:7067	2001:7068	2001:7069
2002:7063	2002:7064	2002:7065	2002:7066	2002:7067	2002:7068	2002:7069
2003:7063	2003:7064	2003:7065	2003:7066	2003:7067	2003:7068	2003:7069
2004:7063	2004:7064	2004:7065	2004:7066	2004:7067	2004:7068	2004:7069
2005:7063	2005:7064	2005:7065	2005:7066	2005:7067	2005:7068	2005:7069
2006:7063	2006:7064	2006:7065	2006:7066	2006:7067	2006:7068	2006:7069
2007:7063	2007:7064	2007:7065	2007:7066	2007:7067	2007:7068	2007:7069
2008:7063	2008:7064	2008:7065	2008:7066	2008:7067	2008:7068	2008:7069
2009:7063	2009:7064	2009:7065	2009:7066	2009:7067	2009:7068	2009:7069
2010:7063	2010:7064	2010:7065	2010:7066	2010:7067	2010:7068	2010:7069
3001:7063	3001:7064	3001:7065	3001:7066	3001:7067	3001:7068	3001:7069
3002:7063	3002:7064	3002:7065	3002:7066	3002:7067	3002:7068	3002:7069
3003:7063	3003:7064	3003:7065	3003:7066	3003:7067	3003:7068	3003:7069
3004:7063	3004:7064	3004:7065	3004:7066	3004:7067	3004:7068	3004:7069
3005:7063	3005:7064	3005:7065	3005:7066	3005:7067	3005:7068	3005:7069
3006:7063	3006:7064	3006:7065	3006:7066	3006:7067	3006:7068	3006:7069
3007:7063	3007:7064	3007:7065	3007:7066	3007:7067	3007:7068	3007:7069
3008:7063	3008:7064	3008:7065	3008:7066	3008:7067	3008:7068	3008:7069
4001:7063	4001:7064	4001:7065	4001:7066	4001:7067	4001:7068	4001:7069
4002:7063	4002:7064	4002:7065	4002:7066	4002:7067	4002:7068	4002:7069
4003:7063	4003:7064	4003:7065	4003:7066	4003:7067	4003:7068	4003:7069
4004:7063	4004:7064	4004:7065	4004:7066	4004:7067	4004:7068	4004:7069
4005:7063	4005:7064	4005:7065	4005:7066	4005:7067	4005:7068	4005:7069
5001:7063	5001:7064	5001:7065	5001:7066	5001:7067	5001:7068	5001:7069
5002:7063	5002:7064	5002:7065	5002:7066	5002:7067	5002:7068	5002:7069
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7070	1001:7071	1001:7072	1001:7073	1001:7074	1001:7075	1001:7076
1002:7070	1002:7071	1002:7072	1002:7073	1002:7074	1002:7075	1002:7076
1003:7070	1003:7071	1003:7072	1003:7073	1003:7074	1003:7075	1003:7076
1004:7070	1004:7071	1004:7072	1004:7073	1004:7074	1004:7075	1004:7076
1005:7070	1005:7071	1005:7072	1005:7073	1005:7074	1005:7075	1005:7076
1006:7070	1006:7071	1006:7072	1006:7073	1006:7074	1006:7075	1006:7076
1007:7070	1007:7071	1007:7072	1007:7073	1007:7074	1007:7075	1007:7076
1008:7070	1008:7071	1008:7072	1008:7073	1008:7074	1008:7075	1008:7076
1009:7070	1009:7071	1009:7072	1009:7073	1009:7074	1009:7075	1009:7076
1010:7070	1010:7071	1010:7072	1010:7073	1010:7074	1010:7075	1010:7076
1011:7070	1011:7071	1011:7072	1011:7073	1011:7074	1011:7075	1011:7076
1012:7070	1012:7071	1012:7072	1012:7073	1012:7074	1012:7075	1012:7076
1013:7070	1013:7071	1013:7072	1013:7073	1013:7074	1013:7075	1013:7076
1014:7070	1014:7071	1014:7072	1014:7073	1014:7074	1014:7075	1014:7076
2001:7070	2001:7071	2001:7072	2001:7073	2001:7074	2001:7075	2001:7076
2002:7070	2002:7071	2002:7072	2002:7073	2002:7074	2002:7075	2002:7076
2003:7070	2003:7071	2003:7072	2003:7073	2003:7074	2003:7075	2003:7076
2004:7070	2004:7071	2004:7072	2004:7073	2004:7074	2004:7075	2004:7076
2005:7070	2005:7071	2005:7072	2005:7073	2005:7074	2005:7075	2005:7076
2006:7070	2006:7071	2006:7072	2006:7073	2006:7074	2006:7075	2006:7076
2007:7070	2007:7071	2007:7072	2007:7073	2007:7074	2007:7075	2007:7076
2008:7070	2008:7071	2008:7072	2008:7073	2008:7074	2008:7075	2008:7076
2009:7070	2009:7071	2009:7072	2009:7073	2009:7074	2009:7075	2009:7076
2010:7070	2010:7071	2010:7072	2010:7073	2010:7074	2010:7075	2010:7076
3001:7070	3001:7071	3001:7072	3001:7073	3001:7074	3001:7075	3001:7076
3002:7070	3002:7071	3002:7072	3002:7073	3002:7074	3002:7075	3002:7076
3003:7070	3003:7071	3003:7072	3003:7073	3003:7074	3003:7075	3003:7076
3004:7070	3004:7071	3004:7072	3004:7073	3004:7074	3004:7075	3004:7076
3005:7070	3005:7071	3005:7072	3005:7073	3005:7074	3005:7075	3005:7076
3006:7070	3006:7071	3006:7072	3006:7073	3006:7074	3006:7075	3006:7076
3007:7070	3007:7071	3007:7072	3007:7073	3007:7074	3007:7075	3007:7076
3008:7070	3008:7071	3008:7072	3008:7073	3008:7074	3008:7075	3008:7076
4001:7070	4001:7071	4001:7072	4001:7073	4001:7074	4001:7075	4001:7076
4002:7070	4002:7071	4002:7072	4002:7073	4002:7074	4002:7075	4002:7076
4003:7070	4003:7071	4003:7072	4003:7073	4003:7074	4003:7075	4003:7076
4004:7070	4004:7071	4004:7072	4004:7073	4004:7074	4004:7075	4004:7076
4005:7070	4005:7071	4005:7072	4005:7073	4005:7074	4005:7075	4005:7076
5001:7070	5001:7071	5001:7072	5001:7073	5001:7074	5001:7075	5001:7076
5002:7070	5002:7071	5002:7072	5002:7073	5002:7074	5002:7075	5002:7076
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
1001:7077	1011:7077	2007:7077	3007:7077	—	—	—
1002:7077	1012:7077	2008:7077	3008:7077
1003:7077	1013:7077	2009:7077	4001:7077
1004:7077	1014:7077	2010:7077	4002:7077
1005:7077	2001:7077	3001:7077	4003:7077
1006:7077	2002:7077	3002:7077	4004:7077
1007:7077	2003:7077	3003:7077	4005:7077
1008:7077	2004:7077	3004:7077	5001:7077
1009:7077	2005:7077	3005:7077	5002:7077
1010:7077	2006:7077	3006:7077	—

TABLE B
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
6000:7000	6000:7001	6000:7002	6000:7003	6000:7004	6000:7005	6000:7006
6001:7000	6001:7001	6001:7002	6001:7003	6001:7004	6001:7005	6001:7006
6002:7000	6002:7001	6002:7002	6002:7003	6002:7004	6002:7005	6002:7006
6003:7000	6003:7001	6003:7002	6003:7003	6003:7004	6003:7005	6003:7006
6004:7000	6004:7001	6004:7002	6004:7003	6004:7004	6004:7005	6004:7006
6005:7000	6005:7001	6005:7002	6005:7003	6005:7004	6005:7005	6005:7006
6006:7000	6006:7001	6006:7002	6006:7003	6006:7004	6006:7005	6006:7006
6007:7000	6007:7001	6007:7002	6007:7003	6007:7004	6007:7005	6007:7006
6008:7000	6008:7001	6008:7002	6008:7003	6008:7004	6008:7005	6008:7006
6009:7000	6009:7001	6009:7002	6009:7003	6009:7004	6009:7005	6009:7006
6010:7000	6010:7001	6010:7002	6010:7003	6010:7004	6010:7005	6010:7006
6011:7000	6011:7001	6011:7002	6011:7003	6011:7004	6011:7005	6011:7006
6012:7000	6012:7001	6012:7002	6012:7003	6012:7004	6012:7005	6012:7006
6013:7000	6013:7001	6013:7002	6013:7003	6013:7004	6013:7005	6013:7006
6014:7000	6014:7001	6014:7002	6014:7003	6014:7004	6014:7005	6014:7006
6015:7000	6015:7001	6015:7002	6015:7003	6015:7004	6015:7005	6015:7006
6016:7000	6016:7001	6016:7002	6016:7003	6016:7004	6016:7005	6016:7006
6017:7000	6017:7001	6017:7002	6017:7003	6017:7004	6017:7005	6017:7006
6018:7000	6018:7001	6018:7002	6018:7003	6018:7004	6018:7005	6018:7006
6019:7000	6019:7001	6019:7002	6019:7003	6019:7004	6019:7005	6019:7006
6020:7000	6020:7001	6020:7002	6020:7003	6020:7004	6020:7005	6020:7006
6000:7007	6000:7008	6000:7009	6000:7010	6000:7011	6000:7012	6000:7013
6001:7007	6001:7008	6001:7009	6001:7010	6001:7011	6001:7012	6001:7013
6002:7007	6002:7008	6002:7009	6002:7010	6002:7011	6002:7012	6002:7013
6003:7007	6003:7008	6003:7009	6003:7010	6003:7011	6003:7012	6003:7013
6004:7007	6004:7008	6004:7009	6004:7010	6004:7011	6004:7012	6004:7013
6005:7007	6005:7008	6005:7009	6005:7010	6005:7011	6005:7012	6005:7013
6006:7007	6006:7008	6006:7009	6006:7010	6006:7011	6006:7012	6006:7013
6007:7007	6007:7008	6007:7009	6007:7010	6007:7011	6007:7012	6007:7013
6008:7007	6008:7008	6008:7009	6008:7010	6008:7011	6008:7012	6008:7013
6009:7007	6009:7008	6009:7009	6009:7010	6009:7011	6009:7012	6009:7013
6010:7007	6010:7008	6010:7009	6010:7010	6010:7011	6010:7012	6010:7013
6011:7007	6011:7008	6011:7009	6011:7010	6011:7011	6011:7012	6011:7013
6012:7007	6012:7008	6012:7009	6012:7010	6012:7011	6012:7012	6012:7013
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6020:7077
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6040:7006	6040:7007	6040:7008	6040:7009	6040:7010	6040:7011	6040:7012
6021:7013	6021:7014	6021:7015	6021:7016	6021:7017	6021:7018	6021:7019
6022:7013	6022:7014	6022:7015	6022:7016	6022:7017	6022:7018	6022:7019
6023:7013	6023:7014	6023:7015	6023:7016	6023:7017	6023:7018	6023:7019
6024:7013	6024:7014	6024:7015	6024:7016	6024:7017	6024:7018	6024:7019
6025:7013	6025:7014	6025:7015	6025:7016	6025:7017	6025:7018	6025:7019
6026:7013	6026:7014	6026:7015	6026:7016	6026:7017	6026:7018	6026:7019
6027:7013	6027:7014	6027:7015	6027:7016	6027:7017	6027:7018	6027:7019
6028:7013	6028:7014	6028:7015	6028:7016	6028:7017	6028:7018	6028:7019
6029:7013	6029:7014	6029:7015	6029:7016	6029:7017	6029:7018	6029:7019
6030:7013	6030:7014	6030:7015	6030:7016	6030:7017	6030:7018	6030:7019
6031:7013	6031:7014	6031:7015	6031:7016	6031:7017	6031:7018	6031:7019
6032:7013	6032:7014	6032:7015	6032:7016	6032:7017	6032:7018	6032:7019
6033:7013	6033:7014	6033:7015	6033:7016	6033:7017	6033:7018	6033:7019
6034:7013	6034:7014	6034:7015	6034:7016	6034:7017	6034:7018	6034:7019
6035:7013	6035:7014	6035:7015	6035:7016	6035:7017	6035:7018	6035:7019
6036:7013	6036:7014	6036:7015	6036:7016	6036:7017	6036:7018	6036:7019
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6038:7013	6038:7014	6038:7015	6038:7016	6038:7017	6038:7018	6038:7019
6039:7013	6039:7014	6039:7015	6039:7016	6039:7017	6039:7018	6039:7019
6040:7013	6040:7014	6040:7015	6040:7016	6040:7017	6040:7018	6040:7019
6021:7020	6021:7021	6021:7022	6021:7023	6021:7024	6021:7025	6021:7026
6022:7020	6022:7021	6022:7022	6022:7023	6022:7024	6022:7025	6022:7026
6023:7020	6023:7021	6023:7022	6023:7023	6023:7024	6023:7025	6023:7026
6024:7020	6024:7021	6024:7022	6024:7023	6024:7024	6024:7025	6024:7026
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6026:7020	6026:7021	6026:7022	6026:7023	6026:7024	6026:7025	6026:7026
6027:7020	6027:7021	6027:7022	6027:7023	6027:7024	6027:7025	6027:7026
6028:7020	6028:7021	6028:7022	6028:7023	6028:7024	6028:7025	6028:7026
6029:7020	6029:7021	6029:7022	6029:7023	6029:7024	6029:7025	6029:7026
6030:7020	6030:7021	6030:7022	6030:7023	6030:7024	6030:7025	6030:7026
6031:7020	6031:7021	6031:7022	6031:7023	6031:7024	6031:7025	6031:7026
6032:7020	6032:7021	6032:7022	6032:7023	6032:7024	6032:7025	6032:7026
6033:7020	6033:7021	6033:7022	6033:7023	6033:7024	6033:7025	6033:7026
6034:7020	6034:7021	6034:7022	6034:7023	6034:7024	6034:7025	6034:7026
6035:7020	6035:7021	6035:7022	6035:7023	6035:7024	6035:7025	6035:7026
6036:7020	6036:7021	6036:7022	6036:7023	6036:7024	6036:7025	6036:7026
6037:7020	6037:7021	6037:7022	6037:7023	6037:7024	6037:7025	6037:7026
6038:7020	6038:7021	6038:7022	6038:7023	6038:7024	6038:7025	6038:7026
6039:7020	6039:7021	6039:7022	6039:7023	6039:7024	6039:7025	6039:7026
6040:7020	6040:7021	6040:7022	6040:7023	6040:7024	6040:7025	6040:7026
6021:7027	6021:7028	6021:7029	6021:7030	6021:7031	6021:7032	6021:7033
6022:7027	6022:7028	6022:7029	6022:7030	6022:7031	6022:7032	6022:7033
6023:7027	6023:7028	6023:7029	6023:7030	6023:7031	6023:7032	6023:7033
6024:7027	6024:7028	6024:7029	6024:7030	6024:7031	6024:7032	6024:7033
6025:7027	6025:7028	6025:7029	6025:7030	6025:7031	6025:7032	6025:7033
6026:7027	6026:7028	6026:7029	6026:7030	6026:7031	6026:7032	6026:7033
6027:7027	6027:7028	6027:7029	6027:7030	6027:7031	6027:7032	6027:7033
6028:7027	6028:7028	6028:7029	6028:7030	6028:7031	6028:7032	6028:7033
6029:7027	6029:7028	6029:7029	6029:7030	6029:7031	6029:7032	6029:7033
6030:7027	6030:7028	6030:7029	6030:7030	6030:7031	6030:7032	6030:7033
6031:7027	6031:7028	6031:7029	6031:7030	6031:7031	6031:7032	6031:7033
6032:7027	6032:7028	6032:7029	6032:7030	6032:7031	6032:7032	6032:7033
6033:7027	6033:7028	6033:7029	6033:7030	6033:7031	6033:7032	6033:7033
6034:7027	6034:7028	6034:7029	6034:7030	6034:7031	6034:7032	6034:7033
6035:7027	6035:7028	6035:7029	6035:7030	6035:7031	6035:7032	6035:7033
6036:7027	6036:7028	6036:7029	6036:7030	6036:7031	6036:7032	6036:7033
6037:7027	6037:7028	6037:7029	6037:7030	6037:7031	6037:7032	6037:7033
6038:7027	6038:7028	6038:7029	6038:7030	6038:7031	6038:7032	6038:7033
6039:7027	6039:7028	6039:7029	6039:7030	6039:7031	6039:7032	6039:7033
6040:7027	6040:7028	6040:7029	6040:7030	6040:7031	6040:7032	6040:7033
6021:7034	6021:7035	6021:7036	6021:7037	6021:7038	6021:7039	6021:7040
6022:7034	6022:7035	6022:7036	6022:7037	6022:7038	6022:7039	6022:7040
6023:7034	6023:7035	6023:7036	6023:7037	6023:7038	6023:7039	6023:7040
6024:7034	6024:7035	6024:7036	6024:7037	6024:7038	6024:7039	6024:7040
6025:7034	6025:7035	6025:7036	6025:7037	6025:7038	6025:7039	6025:7040
6026:7034	6026:7035	6026:7036	6026:7037	6026:7038	6026:7039	6026:7040
6027:7034	6027:7035	6027:7036	6027:7037	6027:7038	6027:7039	6027:7040
6028:7034	6028:7035	6028:7036	6028:7037	6028:7038	6028:7039	6028:7040
6029:7034	6029:7035	6029:7036	6029:7037	6029:7038	6029:7039	6029:7040
6030:7034	6030:7035	6030:7036	6030:7037	6030:7038	6030:7039	6030:7040
6031:7034	6031:7035	6031:7036	6031:7037	6031:7038	6031:7039	6031:7040
6032:7034	6032:7035	6032:7036	6032:7037	6032:7038	6032:7039	6032:7040
6033:7034	6033:7035	6033:7036	6033:7037	6033:7038	6033:7039	6033:7040
6034:7034	6034:7035	6034:7036	6034:7037	6034:7038	6034:7039	6034:7040
6035:7034	6035:7035	6035:7036	6035:7037	6035:7038	6035:7039	6035:7040
6036:7034	6036:7035	6036:7036	6036:7037	6036:7038	6036:7039	6036:7040
6037:7034	6037:7035	6037:7036	6037:7037	6037:7038	6037:7039	6037:7040
6038:7034	6038:7035	6038:7036	6038:7037	6038:7038	6038:7039	6038:7040
6039:7034	6039:7035	6039:7036	6039:7037	6039:7038	6039:7039	6039:7040
6040:7034	6040:7035	6040:7036	6040:7037	6040:7038	6040:7039	6040:7040
6021:7041	6021:7042	6021:7043	6021:7044	6021:7045	6021:7046	6021:7047
6022:7041	6022:7042	6022:7043	6022:7044	6022:7045	6022:7046	6022:7047
6023:7041	6023:7042	6023:7043	6023:7044	6023:7045	6023:7046	6023:7047
6024:7041	6024:7042	6024:7043	6024:7044	6024:7045	6024:7046	6024:7047
6025:7041	6025:7042	6025:7043	6025:7044	6025:7045	6025:7046	6025:7047
6026:7041	6026:7042	6026:7043	6026:7044	6026:7045	6026:7046	6026:7047
6027:7041	6027:7042	6027:7043	6027:7044	6027:7045	6027:7046	6027:7047
6028:7041	6028:7042	6028:7043	6028:7044	6028:7045	6028:7046	6028:7047
6029:7041	6029:7042	6029:7043	6029:7044	6029:7045	6029:7046	6029:7047
6030:7041	6030:7042	6030:7043	6030:7044	6030:7045	6030:7046	6030:7047
6031:7041	6031:7042	6031:7043	6031:7044	6031:7045	6031:7046	6031:7047
6032:7041	6032:7042	6032:7043	6032:7044	6032:7045	6032:7046	6032:7047
6033:7041	6033:7042	6033:7043	6033:7044	6033:7045	6033:7046	6033:7047
6034:7041	6034:7042	6034:7043	6034:7044	6034:7045	6034:7046	6034:7047
6035:7041	6035:7042	6035:7043	6035:7044	6035:7045	6035:7046	6035:7047
6036:7041	6036:7042	6036:7043	6036:7044	6036:7045	6036:7046	6036:7047
6037:7041	6037:7042	6037:7043	6037:7044	6037:7045	6037:7046	6037:7047
6038:7041	6038:7042	6038:7043	6038:7044	6038:7045	6038:7046	6038:7047
6039:7041	6039:7042	6039:7043	6039:7044	6039:7045	6039:7046	6039:7047
6040:7041	6040:7042	6040:7043	6040:7044	6040:7045	6040:7046	6040:7047
6021:7048	6021:7049	6021:7050	6021:7051	6021:7052	6021:7053	6021:7054
6022:7048	6022:7049	6022:7050	6022:7051	6022:7052	6022:7053	6022:7054
6023:7048	6023:7049	6023:7050	6023:7051	6023:7052	6023:7053	6023:7054
6024:7048	6024:7049	6024:7050	6024:7051	6024:7052	6024:7053	6024:7054
6025:7048	6025:7049	6025:7050	6025:7051	6025:7052	6025:7053	6025:7054
6026:7048	6026:7049	6026:7050	6026:7051	6026:7052	6026:7053	6026:7054
6027:7048	6027:7049	6027:7050	6027:7051	6027:7052	6027:7053	6027:7054
6028:7048	6028:7049	6028:7050	6028:7051	6028:7052	6028:7053	6028:7054
6029:7048	6029:7049	6029:7050	6029:7051	6029:7052	6029:7053	6029:7054
6030:7048	6030:7049	6030:7050	6030:7051	6030:7052	6030:7053	6030:7054
6031:7048	6031:7049	6031:7050	6031:7051	6031:7052	6031:7053	6031:7054
6032:7048	6032:7049	6032:7050	6032:7051	6032:7052	6032:7053	6032:7054
6033:7048	6033:7049	6033:7050	6033:7051	6033:7052	6033:7053	6033:7054
6034:7048	6034:7049	6034:7050	6034:7051	6034:7052	6034:7053	6034:7054
6035:7048	6035:7049	6035:7050	6035:7051	6035:7052	6035:7053	6035:7054
6036:7048	6036:7049	6036:7050	6036:7051	6036:7052	6036:7053	6036:7054
6037:7048	6037:7049	6037:7050	6037:7051	6037:7052	6037:7053	6037:7054
6038:7048	6038:7049	6038:7050	6038:7051	6038:7052	6038:7053	6038:7054
6039:7048	6039:7049	6039:7050	6039:7051	6039:7052	6039:7053	6039:7054
6040:7048	6040:7049	6040:7050	6040:7051	6040:7052	6040:7053	6040:7054
6021:7055	6021:7056	6021:7057	6021:7058	6021:7059	6021:7060	6021:7061
6022:7055	6022:7056	6022:7057	6022:7058	6022:7059	6022:7060	6022:7061
6023:7055	6023:7056	6023:7057	6023:7058	6023:7059	6023:7060	6023:7061
6024:7055	6024:7056	6024:7057	6024:7058	6024:7059	6024:7060	6024:7061
6025:7055	6025:7056	6025:7057	6025:7058	6025:7059	6025:7060	6025:7061
6026:7055	6026:7056	6026:7057	6026:7058	6026:7059	6026:7060	6026:7061
6027:7055	6027:7056	6027:7057	6027:7058	6027:7059	6027:7060	6027:7061
6028:7055	6028:7056	6028:7057	6028:7058	6028:7059	6028:7060	6028:7061
6029:7055	6029:7056	6029:7057	6029:7058	6029:7059	6029:7060	6029:7061
6030:7055	6030:7056	6030:7057	6030:7058	6030:7059	6030:7060	6030:7061
6031:7055	6031:7056	6031:7057	6031:7058	6031:7059	6031:7060	6031:7061
6032:7055	6032:7056	6032:7057	6032:7058	6032:7059	6032:7060	6032:7061
6033:7055	6033:7056	6033:7057	6033:7058	6033:7059	6033:7060	6033:7061
6034:7055	6034:7056	6034:7057	6034:7058	6034:7059	6034:7060	6034:7061
6035:7055	6035:7056	6035:7057	6035:7058	6035:7059	6035:7060	6035:7061
6036:7055	6036:7056	6036:7057	6036:7058	6036:7059	6036:7060	6036:7061
6037:7055	6037:7056	6037:7057	6037:7058	6037:7059	6037:7060	6037:7061
6038:7055	6038:7056	6038:7057	6038:7058	6038:7059	6038:7060	6038:7061
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6066:7039	6066:7040	6066:7041	6066:7042	6066:7043	6066:7044	6066:7045
6067:7039	6067:7040	6067:7041	6067:7042	6067:7043	6067:7044	6067:7045
6068:7039	6068:7040	6068:7041	6068:7042	6068:7043	6068:7044	6068:7045
6069:7039	6069:7040	6069:7041	6069:7042	6069:7043	6069:7044	6069:7045
6070:7039	6070:7040	6070:7041	6070:7042	6070:7043	6070:7044	6070:7045
6071:7039	6071:7040	6071:7041	6071:7042	6071:7043	6071:7044	6071:7045
6072:7039	6072:7040	6072:7041	6072:7042	6072:7043	6072:7044	6072:7045
6073:7039	6073:7040	6073:7041	6073:7042	6073:7043	6073:7044	6073:7045
6074:7039	6074:7040	6074:7041	6074:7042	6074:7043	6074:7044	6074:7045
6075:7039	6075:7040	6075:7041	6075:7042	6075:7043	6075:7044	6075:7045
6076:7039	6076:7040	6076:7041	6076:7042	6076:7043	6076:7044	6076:7045
6077:7039	6077:7040	6077:7041	6077:7042	6077:7043	6077:7044	6077:7045
6078:7039	6078:7040	6078:7041	6078:7042	6078:7043	6078:7044	6078:7045
6061:7046	6061:7047	6061:7048	6061:7049	6061:7050	6061:7051	6061:7052
6062:7046	6062:7047	6062:7048	6062:7049	6062:7050	6062:7051	6062:7052
6063:7046	6063:7047	6063:7048	6063:7049	6063:7050	6063:7051	6063:7052
6064:7046	6064:7047	6064:7048	6064:7049	6064:7050	6064:7051	6064:7052
6065:7046	6065:7047	6065:7048	6065:7049	6065:7050	6065:7051	6065:7052
6066:7046	6066:7047	6066:7048	6066:7049	6066:7050	6066:7051	6066:7052
6067:7046	6067:7047	6067:7048	6067:7049	6067:7050	6067:7051	6067:7052
6068:7046	6068:7047	6068:7048	6068:7049	6068:7050	6068:7051	6068:7052
6069:7046	6069:7047	6069:7048	6069:7049	6069:7050	6069:7051	6069:7052
6070:7046	6070:7047	6070:7048	6070:7049	6070:7050	6070:7051	6070:7052
6071:7046	6071:7047	6071:7048	6071:7049	6071:7050	6071:7051	6071:7052
6072:7046	6072:7047	6072:7048	6072:7049	6072:7050	6072:7051	6072:7052
6073:7046	6073:7047	6073:7048	6073:7049	6073:7050	6073:7051	6073:7052
6074:7046	6074:7047	6074:7048	6074:7049	6074:7050	6074:7051	6074:7052
6075:7046	6075:7047	6075:7048	6075:7049	6075:7050	6075:7051	6075:7052
6076:7046	6076:7047	6076:7048	6076:7049	6076:7050	6076:7051	6076:7052
6077:7046	6077:7047	6077:7048	6077:7049	6077:7050	6077:7051	6077:7052
6078:7046	6078:7047	6078:7048	6078:7049	6078:7050	6078:7051	6078:7052
6061:7053	6061:7054	6061:7055	6061:7056	6061:7057	6061:7058	6061:7059
6062:7053	6062:7054	6062:7055	6062:7056	6062:7057	6062:7058	6062:7059
6063:7053	6063:7054	6063:7055	6063:7056	6063:7057	6063:7058	6063:7059
6064:7053	6064:7054	6064:7055	6064:7056	6064:7057	6064:7058	6064:7059
6065:7053	6065:7054	6065:7055	6065:7056	6065:7057	6065:7058	6065:7059
6066:7053	6066:7054	6066:7055	6066:7056	6066:7057	6066:7058	6066:7059
6067:7053	6067:7054	6067:7055	6067:7056	6067:7057	6067:7058	6067:7059
6068:7053	6068:7054	6068:7055	6068:7056	6068:7057	6068:7058	6068:7059
6069:7053	6069:7054	6069:7055	6069:7056	6069:7057	6069:7058	6069:7059
6070:7053	6070:7054	6070:7055	6070:7056	6070:7057	6070:7058	6070:7059
6071:7053	6071:7054	6071:7055	6071:7056	6071:7057	6071:7058	6071:7059
6072:7053	6072:7054	6072:7055	6072:7056	6072:7057	6072:7058	6072:7059
6073:7053	6073:7054	6073:7055	6073:7056	6073:7057	6073:7058	6073:7059
6074:7053	6074:7054	6074:7055	6074:7056	6074:7057	6074:7058	6074:7059
6075:7053	6075:7054	6075:7055	6075:7056	6075:7057	6075:7058	6075:7059
6076:7053	6076:7054	6076:7055	6076:7056	6076:7057	6076:7058	6076:7059
6077:7053	6077:7054	6077:7055	6077:7056	6077:7057	6077:7058	6077:7059
6078:7053	6078:7054	6078:7055	6078:7056	6078:7057	6078:7058	6078:7059
6061:7060	6061:7061	6061:7062	6061:7063	6061:7064	6061:7065	6061:7066
6062:7060	6062:7061	6062:7062	6062:7063	6062:7064	6062:7065	6062:7066
6063:7060	6063:7061	6063:7062	6063:7063	6063:7064	6063:7065	6063:7066
6064:7060	6064:7061	6064:7062	6064:7063	6064:7064	6064:7065	6064:7066
6065:7060	6065:7061	6065:7062	6065:7063	6065:7064	6065:7065	6065:7066
6066:7060	6066:7061	6066:7062	6066:7063	6066:7064	6066:7065	6066:7066
6067:7060	6067:7061	6067:7062	6067:7063	6067:7064	6067:7065	6067:7066
6068:7060	6068:7061	6068:7062	6068:7063	6068:7064	6068:7065	6068:7066
6069:7060	6069:7061	6069:7062	6069:7063	6069:7064	6069:7065	6069:7066
6070:7060	6070:7061	6070:7062	6070:7063	6070:7064	6070:7065	6070:7066
6071:7060	6071:7061	6071:7062	6071:7063	6071:7064	6071:7065	6071:7066
6072:7060	6072:7061	6072:7062	6072:7063	6072:7064	6072:7065	6072:7066
6073:7060	6073:7061	6073:7062	6073:7063	6073:7064	6073:7065	6073:7066
6074:7060	6074:7061	6074:7062	6074:7063	6074:7064	6074:7065	6074:7066
6075:7060	6075:7061	6075:7062	6075:7063	6075:7064	6075:7065	6075:7066
6076:7060	6076:7061	6076:7062	6076:7063	6076:7064	6076:7065	6076:7066
6077:7060	6077:7061	6077:7062	6077:7063	6077:7064	6077:7065	6077:7066
6078:7060	6078:7061	6078:7062	6078:7063	6078:7064	6078:7065	6078:7066
6061:7067	6061:7068	6061:7069	6061:7070	6061:7071	6061:7072	6061:7073
6062:7067	6062:7068	6062:7069	6062:7070	6062:7071	6062:7072	6062:7073
6063:7067	6063:7068	6063:7069	6063:7070	6063:7071	6063:7072	6063:7073
6064:7067	6064:7068	6064:7069	6064:7070	6064:7071	6064:7072	6064:7073
6065:7067	6065:7068	6065:7069	6065:7070	6065:7071	6065:7072	6065:7073
6066:7067	6066:7068	6066:7069	6066:7070	6066:7071	6066:7072	6066:7073
6067:7067	6067:7068	6067:7069	6067:7070	6067:7071	6067:7072	6067:7073
6068:7067	6068:7068	6068:7069	6068:7070	6068:7071	6068:7072	6068:7073
6069:7067	6069:7068	6069:7069	6069:7070	6069:7071	6069:7072	6069:7073
6070:7067	6070:7068	6070:7069	6070:7070	6070:7071	6070:7072	6070:7073
6071:7067	6071:7068	6071:7069	6071:7070	6071:7071	6071:7072	6071:7073
6072:7067	6072:7068	6072:7069	6072:7070	6072:7071	6072:7072	6072:7073
6073:7067	6073:7068	6073:7069	6073:7070	6073:7071	6073:7072	6073:7073
6074:7067	6074:7068	6074:7069	6074:7070	6074:7071	6074:7072	6074:7073
6075:7067	6075:7068	6075:7069	6075:7070	6075:7071	6075:7072	6075:7073
6076:7067	6076:7068	6076:7069	6076:7070	6076:7071	6076:7072	6076:7073
6077:7067	6077:7068	6077:7069	6077:7070	6077:7071	6077:7072	6077:7073
6078:7067	6078:7068	6078:7069	6078:7070	6078:7071	6078:7072	6078:7073
6061:7074	6061:7075	6061:7076	6061:7077	—	—	—
6062:7074	6062:7075	6062:7076	6062:7077
6063:7074	6063:7075	6063:7076	6063:7077
6064:7074	6064:7075	6064:7076	6064:7077
6065:7074	6065:7075	6065:7076	6065:7077
6066:7074	6066:7075	6066:7076	6066:7077
6067:7074	6067:7075	6067:7076	6067:7077
6068:7074	6068:7075	6068:7076	6068:7077
6069:7074	6069:7075	6069:7076	6069:7077
6070:7074	6070:7075	6070:7076	6070:7077
6071:7074	6071:7075	6071:7076	6071:7077
6072:7074	6072:7075	6072:7076	6072:7077
6073:7074	6073:7075	6073:7076	6073:7077
6074:7074	6074:7075	6074:7076	6074:7077
6075:7074	6075:7075	6075:7076	6075:7077
6076:7074	6076:7075	6076:7076	6076:7077
6077:7074	6077:7075	6077:7076	6077:7077
6078:7074	6078:7075	6078:7076	6078:7077

TABLE C
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
8000:7000	8000:7026	8000:7052	8001:7000	8001:7026	8001:7052
8000:7001	8000:7027	8000:7053	8001:7001	8001:7027	8001:7053
8000:7002	8000:7028	8000:7054	8001:7002	8001:7028	8001:7054
8000:7003	8000:7029	8000:7055	8001:7003	8001:7029	8001:7055
8000:7004	8000:7030	8000:7056	8001:7004	8001:7030	8001:7056
8000:7005	8000:7031	8000:7057	8001:7005	8001:7031	8001:7057
8000:7006	8000:7032	8000:7058	8001:7006	8001:7032	8001:7058
8000:7007	8000:7033	8000:7059	8001:7007	8001:7033	8001:7059
8000:7008	8000:7034	8000:7060	8001:7008	8001:7034	8001:7060
8000:7009	8000:7035	8000:7061	8001:7009	8001:7035	8001:7061
8000:7010	8000:7036	8000:7062	8001:7010	8001:7036	8001:7062
8000:7011	8000:7037	8000:7063	8001:7011	8001:7037	8001:7063
8000:7012	8000:7038	8000:7064	8001:7012	8001:7038	8001:7064
8000:7013	8000:7039	8000:7065	8001:7013	8001:7039	8001:7065
8000:7014	8000:7040	8000:7066	8001:7014	8001:7040	8001:7066
8000:7015	8000:7041	8000:7067	8001:7015	8001:7041	8001:7067
8000:7016	8000:7042	8000:7068	8001:7016	8001:7042	8001:7068
8000:7017	8000:7043	8000:7069	8001:7017	8001:7043	8001:7069
8000:7018	8000:7044	8000:7070	8001:7018	8001:7044	8001:7070
8000:7019	8000:7045	8000:7071	8001:7019	8001:7045	8001:7071
8000:7020	8000:7046	8000:7072	8001:7020	8001:7046	8001:7072
8000:7021	8000:7047	8000:7073	8001:7021	8001:7047	8001:7073
8000:7022	8000:7048	8000:7074	8001:7022	8001:7048	8001:7074
8000:7023	8000:7049	8000:7075	8001:7023	8001:7049	8001:7075
8000:7024	8000:7050	8000:7076	8001:7024	8001:7050	8001:7076
8000:7025	8000:7051	8000:7077	8001:7025	8001:7051	8001:7077
8002:7000	8002:7026	8002:7052	8003:7000	8003:7026	8003:7052
8002:7001	8002:7027	8002:7053	8003:7001	8003:7027	8003:7053
8002:7002	8002:7028	8002:7054	8003:7002	8003:7028	8003:7054
8002:7003	8002:7029	8002:7055	8003:7003	8003:7029	8003:7055
8002:7004	8002:7030	8002:7056	8003:7004	8003:7030	8003:7056
8002:7005	8002:7031	8002:7057	8003:7005	8003:7031	8003:7057
8002:7006	8002:7032	8002:7058	8003:7006	8003:7032	8003:7058
8002:7007	8002:7033	8002:7059	8003:7007	8003:7033	8003:7059
8002:7008	8002:7034	8002:7060	8003:7008	8003:7034	8003:7060
8002:7009	8002:7035	8002:7061	8003:7009	8003:7035	8003:7061
8002:7010	8002:7036	8002:7062	8003:7010	8003:7036	8003:7062
8002:7011	8002:7037	8002:7063	8003:7011	8003:7037	8003:7063
8002:7012	8002:7038	8002:7064	8003:7012	8003:7038	8003:7064
8002:7013	8002:7039	8002:7065	8003:7013	8003:7039	8003:7065
8002:7014	8002:7040	8002:7066	8003:7014	8003:7040	8003:7066
8002:7015	8002:7041	8002:7067	8003:7015	8003:7041	8003:7067
8002:7016	8002:7042	8002:7068	8003:7016	8003:7042	8003:7068
8002:7017	8002:7043	8002:7069	8003:7017	8003:7043	8003:7069
8002:7018	8002:7044	8002:7070	8003:7018	8003:7044	8003:7070
8002:7019	8002:7045	8002:7071	8003:7019	8003:7045	8003:7071
8002:7020	8002:7046	8002:7072	8003:7020	8003:7046	8003:7072
8002:7021	8002:7047	8002:7073	8003:7021	8003:7047	8003:7073
8002:7022	8002:7048	8002:7074	8003:7022	8003:7048	8003:7074
8002:7023	8002:7049	8002:7075	8003:7023	8003:7049	8003:7075
8002:7024	8002:7050	8002:7076	8003:7024	8003:7050	8003:7076
8002:7025	8002:7051	8002:7077	8003:7025	8003:7051	8003:7077
8004:7000	8004:7026	8004:7052	8005:7000	8005:7026	8005:7052
8004:7001	8004:7027	8004:7053	8005:7001	8005:7027	8005:7053
8004:7002	8004:7028	8004:7054	8005:7002	8005:7028	8005:7054
8004:7003	8004:7029	8004:7055	8005:7003	8005:7029	8005:7055
8004:7004	8004:7030	8004:7056	8005:7004	8005:7030	8005:7056
8004:7005	8004:7031	8004:7057	8005:7005	8005:7031	8005:7057
8004:7006	8004:7032	8004:7058	8005:7006	8005:7032	8005:7058
8004:7007	8004:7033	8004:7059	8005:7007	8005:7033	8005:7059
8004:7008	8004:7034	8004:7060	8005:7008	8005:7034	8005:7060
8004:7009	8004:7035	8004:7061	8005:7009	8005:7035	8005:7061
8004:7010	8004:7036	8004:7062	8005:7010	8005:7036	8005:7062
8004:7011	8004:7037	8004:7063	8005:7011	8005:7037	8005:7063
8004:7012	8004:7038	8004:7064	8005:7012	8005:7038	8005:7064
8004:7013	8004:7039	8004:7065	8005:7013	8005:7039	8005:7065
8004:7014	8004:7040	8004:7066	8005:7014	8005:7040	8005:7066
8004:7015	8004:7041	8004:7067	8005:7015	8005:7041	8005:7067
8004:7016	8004:7042	8004:7068	8005:7016	8005:7042	8005:7068
8004:7017	8004:7043	8004:7069	8005:7017	8005:7043	8005:7069
8004:7018	8004:7044	8004:7070	8005:7018	8005:7044	8005:7070
8004:7019	8004:7045	8004:7071	8005:7019	8005:7045	8005:7071
8004:7020	8004:7046	8004:7072	8005:7020	8005:7046	8005:7072
8004:7021	8004:7047	8004:7073	8005:7021	8005:7047	8005:7073
8004:7022	8004:7048	8004:7074	8005:7022	8005:7048	8005:7074
8004:7023	8004:7049	8004:7075	8005:7023	8005:7049	8005:7075
8004:7024	8004:7050	8004:7076	8005:7024	8005:7050	8005:7076
8004:7025	8004:7051	8004:7077	8005:7025	8005:7051	8005:7077
8006:7000	8006:7026	8006:7052	8007:7000	8007:7026	8007:7052
8006:7001	8006:7027	8006:7053	8007:7001	8007:7027	8007:7053
8006:7002	8006:7028	8006:7054	8007:7002	8007:7028	8007:7054
8006:7003	8006:7029	8006:7055	8007:7003	8007:7029	8007:7055
8006:7004	8006:7030	8006:7056	8007:7004	8007:7030	8007:7056
8006:7005	8006:7031	8006:7057	8007:7005	8007:7031	8007:7057
8006:7006	8006:7032	8006:7058	8007:7006	8007:7032	8007:7058
8006:7007	8006:7033	8006:7059	8007:7007	8007:7033	8007:7059
8006:7008	8006:7034	8006:7060	8007:7008	8007:7034	8007:7060
8006:7009	8006:7035	8006:7061	8007:7009	8007:7035	8007:7061
8006:7010	8006:7036	8006:7062	8007:7010	8007:7036	8007:7062
8006:7011	8006:7037	8006:7063	8007:7011	8007:7037	8007:7063
8006:7012	8006:7038	8006:7064	8007:7012	8007:7038	8007:7064
8006:7013	8006:7039	8006:7065	8007:7013	8007:7039	8007:7065
8006:7014	8006:7040	8006:7066	8007:7014	8007:7040	8007:7066
8006:7015	8006:7041	8006:7067	8007:7015	8007:7041	8007:7067
8006:7016	8006:7042	8006:7068	8007:7016	8007:7042	8007:7068
8006:7017	8006:7043	8006:7069	8007:7017	8007:7043	8007:7069
8006:7018	8006:7044	8006:7070	8007:7018	8007:7044	8007:7070
8006:7019	8006:7045	8006:7071	8007:7019	8007:7045	8007:7071
8006:7020	8006:7046	8006:7072	8007:7020	8007:7046	8007:7072
8006:7021	8006:7047	8006:7073	8007:7021	8007:7047	8007:7073
8006:7022	8006:7048	8006:7074	8007:7022	8007:7048	8007:7074
8006:7023	8006:7049	8006:7075	8007:7023	8007:7049	8007:7075
8006:7024	8006:7050	8006:7076	8007:7024	8007:7050	8007:7076
8006:7025	8006:7051	8006:7077	8007:7025	8007:7051	8007:7077
8008:7000	8008:7026	8008:7052	8009:7000	8009:7026	8009:7052
8008:7001	8008:7027	8008:7053	8009:7001	8009:7027	8009:7053
8008:7002	8008:7028	8008:7054	8009:7002	8009:7028	8009:7054
8008:7003	8008:7029	8008:7055	8009:7003	8009:7029	8009:7055
8008:7004	8008:7030	8008:7056	8009:7004	8009:7030	8009:7056
8008:7005	8008:7031	8008:7057	8009:7005	8009:7031	8009:7057
8008:7006	8008:7032	8008:7058	8009:7006	8009:7032	8009:7058
8008:7007	8008:7033	8008:7059	8009:7007	8009:7033	8009:7059
8008:7008	8008:7034	8008:7060	8009:7008	8009:7034	8009:7060
8008:7009	8008:7035	8008:7061	8009:7009	8009:7035	8009:7061
8008:7010	8008:7036	8008:7062	8009:7010	8009:7036	8009:7062
8008:7011	8008:7037	8008:7063	8009:7011	8009:7037	8009:7063
8008:7012	8008:7038	8008:7064	8009:7012	8009:7038	8009:7064
8008:7013	8008:7039	8008:7065	8009:7013	8009:7039	8009:7065
8008:7014	8008:7040	8008:7066	8009:7014	8009:7040	8009:7066
8008:7015	8008:7041	8008:7067	8009:7015	8009:7041	8009:7067
8008:7016	8008:7042	8008:7068	8009:7016	8009:7042	8009:7068
8008:7017	8008:7043	8008:7069	8009:7017	8009:7043	8009:7069
8008:7018	8008:7044	8008:7070	8009:7018	8009:7044	8009:7070
8008:7019	8008:7045	8008:7071	8009:7019	8009:7045	8009:7071
8008:7020	8008:7046	8008:7072	8009:7020	8009:7046	8009:7072
8008:7021	8008:7047	8008:7073	8009:7021	8009:7047	8009:7073
8008:7022	8008:7048	8008:7074	8009:7022	8009:7048	8009:7074
8008:7023	8008:7049	8008:7075	8009:7023	8009:7049	8009:7075
8008:7024	8008:7050	8008:7076	8009:7024	8009:7050	8009:7076
8008:7025	8008:7051	8008:7077	8009:7025	8009:7051	8009:7077
8010:7000	8010:7026	8010:7052	8011:7000	8011:7026	8011:7052
8010:7001	8010:7027	8010:7053	8011:7001	8011:7027	8011:7053
8010:7002	8010:7028	8010:7054	8011:7002	8011:7028	8011:7054
8010:7003	8010:7029	8010:7055	8011:7003	8011:7029	8011:7055
8010:7004	8010:7030	8010:7056	8011:7004	8011:7030	8011:7056
8010:7005	8010:7031	8010:7057	8011:7005	8011:7031	8011:7057
8010:7006	8010:7032	8010:7058	8011:7006	8011:7032	8011:7058
8010:7007	8010:7033	8010:7059	8011:7007	8011:7033	8011:7059
8010:7008	8010:7034	8010:7060	8011:7008	8011:7034	8011:7060
8010:7009	8010:7035	8010:7061	8011:7009	8011:7035	8011:7061
8010:7010	8010:7036	8010:7062	8011:7010	8011:7036	8011:7062
8010:7011	8010:7037	8010:7063	8011:7011	8011:7037	8011:7063
8010:7012	8010:7038	8010:7064	8011:7012	8011:7038	8011:7064
8010:7013	8010:7039	8010:7065	8011:7013	8011:7039	8011:7065
8010:7014	8010:7040	8010:7066	8011:7014	8011:7040	8011:7066
8010:7015	8010:7041	8010:7067	8011:7015	8011:7041	8011:7067
8010:7016	8010:7042	8010:7068	8011:7016	8011:7042	8011:7068
8010:7017	8010:7043	8010:7069	8011:7017	8011:7043	8011:7069
8010:7018	8010:7044	8010:7070	8011:7018	8011:7044	8011:7070
8010:7019	8010:7045	8010:7071	8011:7019	8011:7045	8011:7071
8010:7020	8010:7046	8010:7072	8011:7020	8011:7046	8011:7072
8010:7021	8010:7047	8010:7073	8011:7021	8011:7047	8011:7073
8010:7022	8010:7048	8010:7074	8011:7022	8011:7048	8011:7074
8010:7023	8010:7049	8010:7075	8011:7023	8011:7049	8011:7075
8010:7024	8010:7050	8010:7076	8011:7024	8011:7050	8011:7076
8010:7025	8010:7051	8010:7077	8011:7025	8011:7051	8011:7077
8012:7000	8012:7026	8012:7052	—	—	—
8012:7001	8012:7027	8012:7053
8012:7002	8012:7028	8012:7054
8012:7003	8012:7029	8012:7055
8012:7004	8012:7030	8012:7056
8012:7005	8012:7031	8012:7057
8012:7006	8012:7032	8012:7058
8012:7007	8012:7033	8012:7059
8012:7008	8012:7034	8012:7060
8012:7009	8012:7035	8012:7061
8012:7010	8012:7036	8012:7062
8012:7011	8012:7037	8012:7063
8012:7012	8012:7038	8012:7064
8012:7013	8012:7039	8012:7065
8012:7014	8012:7040	8012:7066
8012:7015	8012:7041	8012:7067
8012:7016	8012:7042	8012:7068
8012:7017	8012:7043	8012:7069
8012:7018	8012:7044	8012:7070
8012:7019	8012:7045	8012:7071
8012:7020	8012:7046	8012:7072
8012:7021	8012:7047	8012:7073
8012:7022	8012:7048	8012:7074
8012:7023	8012:7049	8012:7075
8012:7024	8012:7050	8012:7076
8012:7025	8012:7051	8012:7077

TABLE D
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y
9000:7000	9000:7026	9000:7052
9000:7001	9000:7027	9000:7053
9000:7002	9000:7028	9000:7054
9000:7003	9000:7029	9000:7055
9000:7004	9000:7030	9000:7056
9000:7005	9000:7031	9000:7057
9000:7006	9000:7032	9000:7058
9000:7007	9000:7033	9000:7059
9000:7008	9000:7034	9000:7060
9000:7009	9000:7035	9000:7061
9000:7010	9000:7036	9000:7062
9000:7011	9000:7037	9000:7063
9000:7012	9000:7038	9000:7064
9000:7013	9000:7039	9000:7065
9000:7014	9000:7040	9000:7066
9000:7015	9000:7041	9000:7067
9000:7016	9000:7042	9000:7068
9000:7017	9000:7043	9000:7069
9000:7018	9000:7044	9000:7070
9000:7019	9000:7045	9000:7071
9000:7020	9000:7046	9000:7072
9000:7021	9000:7047	9000:7073
9000:7022	9000:7048	9000:7074
9000:7023	9000:7049	9000:7075
9000:7024	9000:7050	9000:7076
9000:7025	9000:7051	9000:7077

EXAMPLES

Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

Example 1

Preparation of 1-O-acetyl-2,3-O-dibenzoyl-5(S)—C-methyl-5-O-(4-nitrobenzoyl)-D-ribofuranose (P1)

Step 1. Preparation of 2,3-O-isopropylidene-L-rhamnofuranose (P1-2)

To a suspension of L-rhamnose hydrate (P1-1) (550 g×3, 3354 mmol×3) and anhydrous CuSO₄ (1000 g×3, 6250 mmol×3) in acetone (4000 mL×3) was added conc. H₂SO₄ (98%, 20 mL×3) dropwise. The mixture was stirred at RT (room temperature) for 20 h. The mixture was neutralized with saturated aq. ammonia, and the precipitate was removed by filtration on celite. The filtrate was concentrated to nearly dryness and then chloroform (5000 mL) was added. The mixture was stirred at RT for 2 h, and the precipitate was removed by filtration. The filtrate was concentrated to give crude P1-2 as light yellow oil (2010 g, 98%) which was used in the next step without further purification.

Step 2. Preparation of 2,3-O-isopropylidene-5-O-tosyl-L-rhamnofuranose (P1-3)

To a solution of compound P1-2 (670 g×3, 3267 mmol×3) in anhydrous pyridine (1000 mL×3) was added a solution of TsCl (749 g×3, 3933 mmol×3) in dry CHCl₃ dropwise at 0° C. After addition, the mixture was warmed to RT and stirred for 20 h. The reaction was quenched with H₂O, and the solution was concentrated under reduced pressure. The residue was taken up to EA (ethyl acetate) and washed with water, cold H₂SO₄ (5%), saturated NaHCO₃ aqueous solution and brine in sequence. The organic phase was dried over Na₂SO₄ and concentrated to give a residue, which was subjected to crystallization in toluene and petroleum ether to give P1-3 as white solid (1800 g, 51%).

Step 3. Preparation of 1-O,5(R)—C-dimethyl-2,3-O-isopropylidene-D-ribofuranose (P1-4)

To a stirred solution of compound P1-3 (450 g×4, 1257 mmol×4) in anhydrous MeOH (1000 mL×4) was added NaOMe (137 g×4, 2537 mmol×4) in portions at 0° C. The mixture was then stirred at RT for 20 h. The mixture was bubbled with CO₂ to adjust the pH value to about 8. The solvent was removed under reduced pressure. The residue was taken up to EA and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated to give crude P1-4 (690 g), which was used in the next step without further purification.

Step 4. Preparation of 1-O,5(S)—C-dimethyl-2,3-O-isopropylidene-5-O-(4-nitrobenzoyl)-D-ribofuranose (P1-5)

To a stirred solution of compound P1-4 (166 g×3, 761 mmol×3), p-nitrobenzoic acid (127 g×3, 761 mmol×3) and PPh₃ (600 g×3, 2290 mmol×3) in anhydrous THF (tetrahydrofuran) (1200 mL×3) was added DEAD (Diethyl azodicarboxylate) (400 g×3, 2290 mmol×3) dropwise at 0° C. After addition, the mixture was warmed to RT and stirred overnight. The solvent was removed, and the residue was re-dissolved in DCM (dichloromethane). The mixture was then treated with H₂O₂ (10% aqueous solution) at 0-5° C. The organic phase was concentrated and dissolved in MTBE (methyl tert-butyl ether). PPh₃O was filtered out, and 1600 g of the crude product was obtained. The crude product was then purified on silica gel column (pure PE (petroleum ether) to PE:EA=5:1 gradient) to give P1-5 as white solid (400 g, 48%).

Step 5. Preparation of 1-O,5(S)—C-dimethyl-5-O-(4-nitrobenzoyl)-D-ribofuranose (P1-6)

Compound P1-5 (200 g×2, 545 mmol×2) was dissolved in conc. HCl and MeOH (2000 mL×2, 1% HCl in MeOH), and the mixture was refluxed for 8 h. The mixture was then cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NaHCO₃ aqueous solution, 5% H₂SO₄ and brine in sequence. The organic layer was dried over Na₂SO₄ and concentrated to give crude P1-6 (320 g), which was used in the next step without further purification.

Step 6. Preparation of 2,3-O-dibenzoyl-1-O,5(S)—C-dimethyl-5-O-(4-nitrobenzoyl)-D-ribofuranose (P1-7)

To a stirred solution of crude P1-6 (160 g×2, 489 mmol×2) in dry pyridine (2000 mL×2) was added BzCl (212 g×2, 1504 mmol×2) at 0° C. dropwise. After addition, the mixture was stirred at RT for 20 h as checked by TLC. The reaction was quenched with H₂O and concentrated. The residue was taken up to EA and washed with saturated NaHCO₃ aqueous solution, 5% cold H₂SO₄ and brine in sequence. The organic phase was dried over Na₂SO₄ and concentrated to give crude P1-7 (520 g), which was used in the next step without further purification.

Step 7. Preparation of 1-O-acetyl-2,3-O-dibenzoyl-5(S)—C-methyl-5-O-(4-nitrobenzoyl)-D-ribofuranose (P1)

To a stirred solution of crude P1-7 (130 g×4, 243 mmol×4) in HOAc (1000 mL×4) and Ac₂O (70 mL×4) was added conc. H₂SO₄ (70 mL×4) at 0° C. dropwise. After addition, the mixture was warmed to RT and stirred for 20 h as checked by TLC. The mixture was poured into ice-water with vigorous stirring. The precipitate was collected by filtration, and the filter cake was washed with water. The cake was then dissolved in EA and washed with saturated NaHCO₃ aqueous solution. The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified on silica gel column (PE:EA=50:1 to 5:1) to give 1-O-acetyl-2,3-O-dibenzoyl-5(R)—C-methyl-5-O-(4-nitrobenzoyl)-D-ribofuranose (P1) as white foam (270 g, 49%); ¹H NMR (CDCl₃) δ 8.31-7.29 (m, 14H), 6.74 & 6.42 (d, J=4.8 Hz), brs, 1H), 5.85 (dd, J=4.8, 7.2 Hz, 1H), 5.74-5.43 (m, 2H), 4.65-4.61-5.43 (m, 1H), 2.19, 2.14 (2s, 3H), 1.55, 1.49 (2d, J=6.4 Hz, 3H), ESI-LCMS: m/z 586.2 [M+Na]⁺.

Example 2

Preparation of 1-O-acetyl-5(R)—C-methyl-2,3,5-O-tribenzoyl-D-ribofuranose (P2)

Step 1. Preparation of 5-O-benzoyl-1-O, 5(R)—C-dimethyl-2,3-O-isopropylidene-D-ribofuranose (P2-1)

To a stirred solution of 1-O,5(R)—C-dimethyl-2,3-O-isopropylidene-D-ribofuranose (P1-4) (30 g, 137.61 mmol) in anhydrous pyridine (300 mL) was added BzCl (38.53 g, 275.23 mmol) dropwise at 0° C. The mixture was then stirred at RT for 20 h as checked by TLC. The reaction was quenched with water, and the solution was concentrated. The residue was diluted with EA and washed with saturated NaHCO₃ aqueous solution, cold 5% H₂SO₄ and brine in sequence. The organic phase was dried over Na₂SO₄ and concentrated to give crude P2-1 (40 g).

Step 2. Preparation of 5-O-benzoyl-1-O,5(R)—C-dimethyl-D-ribofuranose (P2-2)

Compound P2-1 (40 g) was dissolved in conc. HCl and MeOH (300 mL, 1% HCl in MeOH). The mixture was refluxed for 4 h as checked by TLC. The mixture was then cooled to RT and concentrated. The residue was diluted with DCM and washed with saturated NaHCO₃ aqueous solution. The organic phase was dried over Na₂SO₄ and concentrated to give crude P2-2 (38 g), which was used in the next step without further purification.

Step 3. Preparation of 1-O,5(R)—C-dimethyl-2,3,5-O-tribenzoyl-D-ribofuranose (P2-3)

To a stirred solution of crude P2-2 (38 g) in anhydrous pyridine (350 mL) was added BzCl (66.03 g, 471.63 mmol) dropwise at 0° C. After addition, the mixture was warmed to RT and stirred for 20 h as checked by TLC. The reaction was quenched with water, and the solution was concentrated. The residue was diluted with EA and washed with saturated NaHCO₃ aqueous solution, 5% H₂SO₄ and brine in sequence. The organic phase was dried over Na₂SO₄ and concentrated to give crude P2-3 (40 g), which was used in the next step without further purification.

Step 4. Preparation of 1-O-acetyl-5(R)—C-methyl-2,3,5-O-tribenzoyl-D-ribofuranose (P2)

To a stirred solution of crude P2-3 (40 g) in HOAc (500 mL) and Ac₂O (35 mL) was added conc. H₂SO₄ (98%, 20 mL) dropwise at 0° C. After addition, the mixture was stirred at RT for 20 h as checked with TLC. The solution was poured into ice water with vigorous stirring. The precipitate was collected by filtration, and the filter cake was washed with water. The filter cake was then dissolved in EA and washed with saturated NaHCO₃ aqueous solution and brine. The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified by column on silica gel (PE:EA=100:1 to 5:1) to give 1-O-acetyl-5(R)—C-methyl-2,3,5-O-tribenzoyl-D-ribofuranose (P2) (25 g, 59.12%); ¹H NMR (CDCl₃) δ 8.10-7.26 (m, 15H), 6.61 & 6.37 (2d, J=4.8, 0.8 Hz, 1H), 6.03-5.96 (m, 1H), 5.75, 5.59 (2dd, J=4.8, 0.8 & J=4.4, 6.4 Hz, 1H), 5.51-5.45 (m, 1H), 4.62-4.59 (m, 1H), 2.12, 1.81 (2s, 3H), 1.51, 1.45 (2d, J=6.4 Hz, 3H), ESI-LCMS: m/z 541.4 [M+Na]⁺.

Example 3

Preparation of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)—C-methyladenosine (P3)

Step 1. Preparation of 9-(2,3-O-dibenzoyl-5-O-4-nitrobenzoyl-5(S)—C-methyl-β-D-ribofuranosyl)-6-chloropurine (P3-1)

To a stirred suspension of 1-O-acetyl-2,3-O-dibenzoyl-5(S)—C-methyl-5-O-(4-nitribenzoyl)-D-ribofuranose (P1) (75 g×3, 133 mmol×3) and 6-chloro-9H-purine (20.9 g×3, 135 mmol×3) in anhydrous MeCN (400 mL×3) was added DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) (61 g×3, 400 mmol×3) at 0° C. The mixture was stirred at 0° C. for 5 min and then TMSOTf (105 mL×3, 536 mmol×3) was added dropwise at 0° C. After addition, the mixture was stirred at 0° C. for 20 min until a clear solution achieved. Then the mixture was heated to 70° C. and stirred for 3 h. The reaction was cooled to room temperature and diluted with EA. The solution was washed with saturated NaHCO₃ and brine in sequence. The organic layer was dried over Na₂SO₄ and then concentrated. The residue was purified on silica gel column (PE:EA=4:1 to 3:1) to give P3-1 as light yellow foam (201 g, 76%).

Step 2. Preparation of 5′(S)—C-methyladenosine (P3-2)

Compound P3-1 (100 g×2, 152 mmol×2) was dissolved in a (200 ml×2) of 1,4-dioxane and then saturated aqueous ammonia was added (200 mL×2). The mixture was stirred at 100° C. in a sealed vessel for 10 h. The mixture was cooled to room temperature and diluted with MeOH. The solvent was removed under reduced pressure, and the residue was purified column on silica gel column (MeOH:DCM=1:20 to 1:8) to give 5′ (S)—C-methyladenosine (P3-2) as white solid (76 g, 88%); ¹H NMR (CD₃OD) δ 8.31 (s, 1H), 8.17 (s, 1H), 5.95 (d, J=6.8 Hz, 1H), 4.73 (m, 1H), 4.27 (dd, J=5.2 Hz, 2.4 Hz, 1H), 4.07 (t, J=2.4 Hz, 1H), 3.96-3.91 (m, 1H), 3.30 (m, 1H), 1.25 (d, J=6.8 Hz, 3H); ESI-LCMS: m/z 282 [M+H]⁺.

Step 3. Preparation of 2′,3′-O-methoxymethylidene-5′(S)—C-methyladenosine (P3-3)

A mixture of compound P3-2 (17 g, 60.5 mmol), trimethyl orthoformate (170 mL) and p-toluenesulfonic acid monohydrate (18 g, 94.7 mmol) in 1,4-dioxane (160 mL) was stirred at 50° C. for 12 h, cooled with ice and quenched by triethylamine (15 mL), The mixture was then concentrated. The residue was purified by chromatography on silica gel with 0-0.5% MeOH in EA gave product P3-3 as white solid (15 g, 77%).

Step 4. Preparation of 2′,3′-O-methoxymethylidene-N⁶-(4′-methoxytrityl)-5′(S)—C-methyladenosine (P3)

A mixture of compound P3-3 (15 g, 46.4 mmol, co-evaporated with dry pyridine for twice) and MMTrCl (21 g, 68 mmol) were suspended in anhydrous pyridine (150 mL). The mixture was stirred at 50° C. for 12 h. The mixture was then quenched with H₂O and concentrated. The residue was purified by column on silica gel (PE/EA=3:1 to 1:1) to afford 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)—C-methyladenosine (P3) as white foam (12 g, 44%).

Example 4

Preparation of 2′,3′-O-methoxymethylidene-N⁴-(4-methoxytrityl)-5′(S)—C-methylcytidine (P4)

Step 1. Preparation of 5′(S)—C-methyl-5′-O-(4-nitrobenzoyl)-2′,3′-O, N4-tribenzoylcytidine (P4-1)

N⁴-Benzoylcytosine (3.5 g, 16.87 mmol) in dry dichloroethane (100 mL) was treated with excess 1,1,1,3,3,3-hexamethyl-disilazane (15 mL) in the presence of ammonium sulfate (100 mg) under argon and refluxed at 125° C. for 2 h until all the solid dissolved. Excess solvent was evaporated under reduced pressure, and the resulting syrup was dissolved in dry dichloroethane (100 mL). Compound P1 (5 g, 8.88 mmol) was added, followed by addition of SnCl₄ (10 mL). The resulting mixture was heated under reflux overnight, cooled with ice, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous Na₂SO₄ and concentrated. Chromatography on silica gel with 10-15% ethyl acetate in DCM gave 5.5 g of compound P4-1.

Step 2. Preparation of 5′(S)—C-methylcytidine (P4-2)

Compound P4-1 (5.5 g, 7.66 mmol) in saturated ammonia in MeOH (200 mL) was stirred at RT overnight. The solvent was removed and the residue was re-dissolved in MeOH. Precipitation from MeOH/DCM gave P4-2 (1.5 g, 76.19%). ¹H NMR (400 MHz, MeOD): δ 8.08 (d, J=7.6 Hz, 1H), 5.85 (d, J=7.6 Hz, 1H), 5.82 (d, J=3.6 Hz, 1H), 4.11-4.13 (m, 1H), 4.05-4.08 (m, 1H), 3.89-3.94 (m, 1H), 3.79-3.81 (m, 1H), 1.27 (d, J=6.8 Hz, 3H); ESI-MS: m/z 515 [2M+H]⁺, 258 [M+H]⁺.

Step 3. Preparation of 2,3′-O-methoxymethylidene-5′(R)—C-methylcytidine (P4-3)

A mixture of compound P4-2 (500 mg, 1.95 mmol), trimethyl orthoformate (3 mL) and p-toluenesulfonic acid monohydrate (450 mg, 2.33 mmol) in 1,4-dioxane (10 mL) was stirred at RT for 24 h, cooled with ice and quenched by adding triethylamine (5 mL) and concentrated. The residue was purified by column on silica gel with 5-6% MeOH in DCM gave compound P4-3 as white foam (450 mg, 77.36%).

Step 4. Preparation of 5′-O-(tert-butyldimethylsilyl)-2′,3′-O-methoxymethylidene-N4-(4-methoxytrityl)-5′(S)—C-methylcytidine (P4-4)

To a stirred solution of compound P4-3 (450 mg 1.51 mmol) in pyridine (5 ml) was added TBSCl (t-butyldimethylsilyl chloride) (450 mg, 3.01 mmol) and AgNO₃ (0.51 g, 3.01 mmol). The mixture was stirred at 50-60° C. for 3 h. MMTrCl (0.93 g, 3.01 mmol) was then added. The mixture was stirred overnight at 50-60° C. until the reaction was complete, as determined by TLC. The reaction was cooled to RT and diluted with EA. The precipitate was removed by filtration, and the filtrate was washed with brine in sequence. The organic layer was dried over Na₂SO₄ and then concentrated to give 800 mg crude product of P4-4.

Step 5. Preparation of 2,3′-O-methoxymethylidene-N4-(4-methoxytrityl)-5′(S)—C-methylcytidine (P4)

Compound P4-4 (800 mg crude) in 1M TBAF in THF (20 mL) was stirred at RT overnight. The solvent was removed and the residue was purified on silica gel column and then by prep. TLC to give P4 (100 mg), ¹H NMR (400 MHz, CDCl₃): δ 7.25-6.76 (m, 14H), 5.79 (d, 1H), 5.28-4.99 (m, 4H), 4.09 (m, 3H), 3.72 (s, 3H), 3.28, 3.21 (2s, 3H), 1.17 (brs, 3H); ESI-MS: m/z 572 [M+H]⁺.

Example 5

Synthesis of 2′,3′-O-methoxymethylidene-N4-(4-methoxytrityl)-5′(R)—C-methylcytidine (P5)

Step 1. Preparation of 5′(R)—C-methyl-5′-O-(4-nitrobenzoyl)-2′,3′-O,N4-tribenzoylcytidine (P5-1)

N⁴-Benzoylcytosine (1.5 g, 6.95 mmol) in dry dichloroethane (100 mL) was treated with excess 1,1,1,3,3,3-hexamethyl-disilazane (15 mL) in the presence ammonium sulfate (75 mg) under argon and refluxed at 125° C. for 2 h until all the solid dissolved. Excess solvent was evaporated under reduced pressure, and the resulting syrup was dissolved in dry dichloroethane (100 mL). Compound P2 (3 g, 5.79 mmol) was added, followed by addition of SnCl₄ (5 mL). The resulting mixture was heated under reflux overnight, cooled with ice, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous Na₂SO₄ and concentrated. Chromatography on silica gel with 10-15% ethyl acetate in DCM gave 2.8 g of compound P5-1.

Step 2. Preparation of 5′(R)—C-methylcytidine (P5-2)

Compound P5-1 (2.8 g, 4.16 mmol) in dioxane (5 mL) and saturated ammonia in H₂O (30 mL) was stirred at 100° C. in a sealed vessel overnight. The solvent was removed, and the residue was re-dissolved in MeOH. Precipitation from MeOH/DCM gave 5′(R)—C-methylcytidine (P5-2) (750 mg, 70.1%). ¹H NMR (400 MHz, MeOD): δ 7.87 (d, J=7.6 Hz, 1H), 5.81 (d, J=7.2 Hz, 1H), 5.75 (d, J=4.8 Hz, 1H), 4.10-4.15 (m, 2H), 3.90-3.96 (m, 1H), 3.76-3.78 (m, 1H), 1.16 (d, J=6.8 Hz, 3H); ESI-LCMS: m/z 515 [2M+H]⁺, 258 [M+H]⁺.

Step 3. Preparation of 2,3′-O-methoxymethylidene-5′(R)—C-methylcytidine (P5-3)

A mixture of compound P5-2 (750 mg, 2.92 mmol), trimethyl orthoformate (5 mL) and p-toluenesulfonic acid monohydrate (670 mg, 3.5 mmol) in 1,4-dioxane (10 mL) was stirred at RT for 24 h, cooled with ice, quenched by adding triethylamine (5 mL) and concentrated. The residue was purified by column on silica gel with 5-6% MeOH in DCM gave compound P5-3 as white foam (700 mg, 80.3%).

Step 4. Preparation of 5′-O-(tert-butyldimethylsilyl)-2′,3′-O-methoxymethylidene-N4-(4-methoxytrityl)-5′ (R)—C-methylcytidine (P5-4)

To a stirred solution of compound P5-3 (700 mg 2.34 mmol) in pyridine (5 mL) was added TBSCl (700 mg, 4.68 mmol) and AgNO₃ (0.79 g, 4.68 mmol). The mixture was stirred at 50-60° C. for 3 h as checked by LCMS. MMTrCl (1.44 g, 4.68 mmol) was added. The mixture was stirred overnight at 50-60° C. The reaction was cooled to room temperature and diluted with EA. The precipitate was removed by filtration, and the filtrate was washed with brine. The organic layer was dried over Na₂SO₄ and then concentrated to give crude product of compound P5-4.

Step 5. Preparation of 2,3′-O-methoxymethylidene-N4-(4-methoxytrityl)-5′ (R)—C-methylcytidine (P5)

Compound P5-4 (1.2 g crude) in 1M TBAF in THF (20 mL) was stirred at RT overnight. The solvent was removed, and the residue was purified by prep. TLC to give 220 mg of 2′,3′-O-methoxymethylidene-N⁴-(4-methoxytrityl)-5′(R)—C-methylcytidine (P5).

Example 6

Preparation of 2′,3′-O-methoxymethylidene-5′(S)—C-methyluridine (P6)

Step 1. Preparation of 2,3′-O-dibenzoyl-5′(S)—C-methyl-5′-O-(4-nitrobenzoyl)uridine

Uracil (2 g, 8.25 mmol) in dry dichloroethane (50 mL) was treated with excess 1,1,1,3,3,3-hexamethyl-disilazane (20 mL) in the presence ammonium sulfate (100 mg) under argon. The mixture was refluxed at 125° C. for 2 h until all the solid had dissolved. Excess solvent was evaporated under reduced pressure, and the resulting syrup was dissolved in dry dichloroethane (50 mL). 1-O-acetyl-2,3-O-dibenzoyl-5(5)-C-methyl-5-O-(4-nitro-benzoyl)-D-ribofuranose (P1) (4 g, 7.10 mmol) was added, followed by addition of SnCl₄ (10 mL). The resulting mixture was heated under reflux overnight, cooled with ice, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous Na₂SO₄ and concentrated. Chromatography on silica gel with 10-15% ethyl acetate in DCM gave 4 g of P6-1.

Step 2. Preparation of 5′(S)—C-methyluridine (P6-2)

2′,3′-O-dibenzoyl-5′(S)—C-methyl-5′-O-(4-nitrobenzoyl)uridine (P6-1) (4 g, 6.51 mmol) in methanol (100 mL) and saturated ammonia in MeOH (200 mL) was stirred at RT overnight. The solvent was removed, and the residue was re-dissolved in MeOH. Precipitation from MeOH/DCM gave 1.5 g of 5′(S)—C-methyluridine (P6-2) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.07 (d, J=8.0 Hz, 1H), 5.88 (d, J=5.2 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H), 4.15 (s, 1H), 4.10-4.08 (m, 1H), 3.92-3.90 (m, 1H), 3.80 (dd, J₁=4.4 Hz, J₂=2.4 Hz, 1H), 1.25 (d, J=6.4 Hz, 3H); ESI-LCMS: m/z 281 [M+Na]⁺, 259 [M+H]⁺.

Step 3. Preparation of 2′,3′-O-methoxymethylidene-5′(S)—C-methyluridine (P6)

A mixture of 5′(S)—C-methyluridine (P6-2) (500 mg, 1.8 mmol), trimethyl orthoformate (2.5 mL) and p-toluenesulfonic acid monohydrate (500 mg, 0.6 mmol) in THF (100 mL) was stirred at RT for 24 h, the crude product was purified by HPLC to give 300 mg of 2′,3′-O-methoxymethylidene-5′(S)—C-methyluridine (P6); ¹H NMR (400 MHz, CD₃OD): δ 8.04 (brs, 1H), 7.30, 7.25 (2×d, J=8.0 Hz, 1H), 5.88, 5.92 (2×s, 1H), 5.70, 5.68 (dd, J=2.8, 8.0 Hz, 1H), 5.6, 5.52 (2×d, J=3.2 Hz, 1H), 5.02 (m, 1H), 4.87-4.93 (m, 1H), 4.10-3.91 (m, 2H), 3.34 (s, 3H), 2.51, 2.38 (2×d, J=6.8, 5.6 Hz, 1H), 1.23, 1.21 (2×d, J=2.4, 2.8 Hz, 3H); ESI-LCMS: m/z 323.08 [M+Na]⁺.

Example 7

Preparation of 2′,3′-O-methoxymethylidene-5′(R)—C-methyluridine (P7)

Step 1. Preparation of 2′,3′,5′-O-tribenzoyl-5′(R)—C-methyluridine (P7)

Uracil (2 g, 8.9 mmol) in dry dichloroethane (50 mL) was treated with excess 1,1,1,3,3,3-hexamethyl-disilazane (20 mL) in the presence of ammonium sulfate (100 mg) under argon. The mixture was refluxed at 125° C. for 2 h until all the solid had dissolved. Excess solvent was evaporated under reduced pressure, and the resulting syrup was dissolved in dry dichloroethane (50 mL). 1-O-acetyl-2,3,5-O-tribenzoyl-5(R)—C-methyl-D-ribofuranose (P2) (2.3 g, 4.5 mmol) was added, followed by addition of SnCl₄ (5 mL). The resulting mixture was heated under reflux overnight, cooled with ice, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous Na₂SO₄ and concentrated. Chromatography on silica gel with 10-15% ethyl acetate in DCM gave 1.2 g of 2′,3′,5′-O-tribenzoyl-5′(R)—C-methyluridine (P7-1).

Step 2. Preparation of 5′(R)—C-methyluridine (P7-2)

2′,3′,5′-O-tribenzoyl-5′(R)—C-methyl-uridine (P7-1) (1.2 g, 2.1 mmol) in methanol (100 mL) and saturated ammonia in MeOH (200 mL) was stirred at 100° C. in a sealed vessel for 10 h. The mixture was cooled to RT and diluted with MeOH. The solvent was removed under reduced pressure, and the residue was purified by column on silica gel (MeOH:DCM=1:20 to 1:8) to give 400 mg of P7-2 as white solid; ¹H NMR (400 MHz, CD3OD): δ7.95 (d, J=8.4 Hz, 1H), 5.89 (d, J=6 Hz, 1H), 5.69 (d, J=8.4 Hz, 1H), 4.21-4.15 (m, 2H), 3.97-3.95 (m, 1H), 3.80 (t, J=3.2 Hz, 1H), 1.23 (d, J=6.8 Hz, 3H); MS: m/z 259 [M+H]⁺.

Step 3. Preparation of 2′,3′-O-methoxymethylidene-5′(R)—C-methyluridine (P7)

A mixture of 5′(R)—C-methyluridine (P7-2) (500 mg, 1.8 mmol), trimethyl orthoformate (2.5 mL) and p-toluenesulfonic acid monohydrate (500 mg, 0.6 mmol) in THF (100 mL) was stirred at RT for 24 h, the crude product was purified by reverse-phase HPLC (HCOOH) to gave 320 mg of 2′,3′-O-methoxymethylidene-5′(R)—C-methyluridine (P7); ¹H NMR (400 MHz, CD₃OD): δ 9.04, 8.98 (2×brs, 1H), 7.30, 7.26 (2×d, J=8.0 Hz, 1H), 5.97, 5.91 (2×s, 1H), 5.73 (d, J=8.0 Hz, 1H), 5.58, 5.48 (2×d, J=2.8 Hz, 1H), 5.16-5.08 (m, 2H), 4.15-3.97 (m, 2H), 3.37, 3.31 (2×s, 3H), 1.26, 1.25 (2×d, J=2.4, 2.8 Hz, 3H); ESI-LCMS: m/z 301.1 [M+H]⁺.

Example 8

Preparation of 2′-deoxy-2′-α-fluoro-3′-O, N4-di(4-methoxytrityl)-2′-β,5′(S)—C-dimethylcytidine (P8)

Step 1. Preparation of 5′-O-(tert-butyldimethylsilyl)-2′-deoxy-2′-α-fluoro-2′-β-C-methylcytidine (P8-2)

To an ice-cold solution of 2′-α-fluoro-2′-β-C-methylcytidine (P8-1) (2.5 g, 9.6 mmol) in anhydrous pyridine (20 mL) was added TBSCl (1.6 g, 10.6 mmol) in small portions under N₂. The reaction mixture was stirred at RT overnight. LCMS showed the reaction was completed. The solvent was removed under vacuum. The residue was diluted with EA (100 mL), washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give crude compound P8-2 (3.5 g) without further purification.

Step 2. Preparation of 5′-O-(tert-butyldimethylsilyl)-2′-deoxy-2′-α-fluoro-2′-β-C-methylcytidine (P8-3)

To a mixture of crude P8-2 (3.5 g, 9.38 mmol), AgNO₃ (3.1 g, 18.7 mmol) and collidine (3.4 g, 28.1 mmol) in anhydrous DCM (300 mL) was added MMTrCl (6.1 g, 20 mmol) in small portions under N₂. The reaction mixture was stirred at RT overnight under N₂. The reaction mixture was filtered on celite. The filtrate was washed with saturated NaHCO₃ solution and followed by brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give the crude P8-3 (4.8 g), which was used in the next step without further purification.

Step 3: Preparation of 2′-deoxy-2′-O,N4-di(4-methoxytrityl)-2′-β-C-methylcytidine (P8-4)

To an ice-cold crude P8-3 (4.8 g, 5.2 mmol) was added TBAF (1M solution in THF, 26 mmol) dropwise under N₂. The reaction mixture was stirred at RT overnight. The solvent was removed, and the residue was dissolved in EA (200 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel column (PE/EA=6/1 to 2/1) to give compound P8-4 (4.8 g, 62%).

Step 4: Preparation of 2′-deoxy-5′-C,5′-O-didehydro-3′-O,N4-di(4-methoxytrityl)-2′-α-fluoro-2′-β-C-methylcytidine (P8-5)

To a stirred solution of anhydrous pyridine (567 mg, 7.2 mmol) in anhydrous DMSO (10 mL) was added TFA (trifluoroacetic acid) (681 mg, 5.98 mmol) 0-5° C. The mixture was stirred at RT until a clear solution formed. The solution was then added to a mixture of compound P8-4 (4.8 g, 5.98 mmol) and DCC(N-dicyclohexylcarbodiimide) (4.9 g, 17.9 mmol) in 15 mL anhydrous DMSO under N₂. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EA (200 mL), and washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give an oil which was purified by silica gel column (PE/EA=10/1 to 2/1) to give compound P8-5 (3.5 g, 72%).

Step 5: Preparation of 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine (P8)

To a solution of compound P8-5 (3.5 g, 4.3 mmol) in anhydrous THF (10 mL) was added MeMgBr (3 M solution in ether) (4.4 mL, 13.1 mmol) dropwise under N₂ at −78° C. The reaction mixture was stirred at RT overnight as monitored by TLC. The mixture was cooled to 0° C. The mixture was then quenched with saturated NH₄Cl and extracted with EA (100 mL×2). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified on silica gel column (PE/EA=3/1 to 1/1) to give 1.5 g (42.8%) of 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(S)—C-dimethyl-2′-α-fluoro-cytidine (P8). Further purification by prep. HPLC afforded pure compound P8; ¹H NMR (400 Hz, CDCl₃): 7.45-6.78 (m, 30H), 6.19 (m, 1H), 4.90 (d, J=7.6 Hz, 1H), 4.08 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.50-3.52 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 0.78 (d, J=22 Hz, 3H); MS: m/z 918 [M+H]⁺.

Example 9

Preparation of 2′-deoxy-3′-O, N⁴-di(4-methoxytrityl)-2′-β,5′-(R)—C-dimethyl-2′-α-fluorocytidine (P9)

Step 1. Preparation of 2′-deoxy-5′-C,5′-O-didehydro-3′-O, N⁴-di(4-methoxytrityl)-2′-β,5′(R)—C-dimethyl-12′-α-fluorocytidine (P9-1)

To an ice-cooled suspension of CrO₃ (100 mg, 1 mmol) in anhydrous DCM (5 mL) was added anhydrous pyridine (0.14 mL, 1.8 mmol) and Ac₂O (0.1 mL, 0.8 mmol) under N₂. The mixture was stirred at RT for about 10 min until the mixture became homogeneous. The mixture was cooled to 0° C., and a solution of compound P8 (240 mg, 0.3 mmol) in anhydrous DCM (5 mL) was added. The resulting mixture was stirred at RT for 1 h. The reaction went to completion as determined by TLC. The reaction mixture was diluted with DCM (50 mL), washed with NaHCO₃ solution twice and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give P9-1 (200 mg, 83%) without further purification.

Step 2. Preparation of 2′-deoxy-3′-O, N⁴-di(4-methoxytrityl)-2′-β,5′(R)—C-dimethyl-2′-α-fluorocytidine (P9)

To an ice-cold solution of compound P9-1 (200 mg, 0.25 mmol) in anhydrous EtOH (10 mL) was added NaBH₄ (19 mg, 0.5 mmol) under N₂. The reaction mixture was stirred at RT overnight. The reaction went to completion as determined by TLC. The solvent was evaporated. The residue was diluted with EA (30 mL), washed with saturated NaHCO₃ and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated. Purification by preparative TLC gave 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(R)—C-dimethyl-2′-α-fluorocytidine (P9) (190 mg, 95%).

Example 10

Preparation of 5′(R)—C-methyl-2′,3′-O, N4-tri(4-methoxytrityl)arabinocytidine (P10)

Step 1. Preparation of 5′-O-(tert-butyldimethylsilyl)arabinocytidine (P10-1)

To an ice-cooled solution of arabinocytidine (P10-1) (20.0 g, 82.2 mmol) in anhydrous pyridine (200 mL) was added TBSCl (14.9 g, 98.7 mmol) in small portions under N₂. The reaction mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was diluted with EA (300 mL), washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give compound P10-2 (25.1 g, 85.4%) as a white solid, which was used without further purification.

Step 2. Preparation of 5′-O-(tert-butyldimethylsilyl)-2′,3′-O,N4-tri(4-methoxytrityl)arabinocytidine (P10-3)

To a mixture of compound P10-2 (15.0 g, 41.96 mmol), AgNO₃ (43.5 g, 252 mmol) and collidine (61 g, 503.5 mmol) in anhydrous DCM (300 mL) was added MMTrCl (77.7 g, 252 mmol) in small portions under N₂. The reaction mixture was stirred at RT for two days under N₂. The reaction mixture was filtered with celite. The filtrate was washed with saturated NaHCO₃ solution and followed by brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give the residue which was purified on silica gel column (PE/EA=2/1) to give compound P10-3 (33.5 g, 67.9%).

Step 3. Preparation of 2,3′-O,N4-tri(4-methoxytrityl)arabinocytidine (P10-4)

To an ice-cooled solution compound P10-3 (10.45 g, 8.9 mmol) in anhydrous THF (50 mL) was added TBAF (1M solution in THF) (49.8 mL, 49.8 mmol) dropwise under N₂. The reaction mixture was stirred at RT overnight. The solvent was removed, and the residue was dissolved in EA (180 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified by silica gel column (PE/EA=5/1 to 1/1) to give compound P10-4 (6.15 g, 97.0% and 4.17 g, 70%).

Step 4. Preparation of 5′-C, 5′-O-didehydro-2′,3′-O,N4-tri(4-methoxytrityl)arabinocytidine (P10-5)

To a Stirred Solution of Dry Pyridine (588 Mg, 7.44 Mmol) in Anhydrous DMSO (12 mL) was added TFA (707 mg, 5.79 mmol) at about 5° C. The mixture was stirred at RT for 30 min until a clear solution formed. The solution was added to a solution of DCC (5.2 g, 25.2 mmol) and compound P10-4 (6.55 g, 6.17 mmol) in DMSO (18 mL) dropwise. The mixture was stirred at RT overnight. The reaction was quenched with H₂O, and the precipitate was removed by filtration. The filtrate was diluted with EA and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on silica gel (PE:EA=5:1 to 1:2) to give compound P10-5 (5.06 g, 77%).

Step 5. Preparation of 5′(S)—C-methyl-2,3′-O,N4-tri(4-methoxytrityl)arabinocytidine (P10-6)

To a solution of compound P10-5 (3.348 g, 3.16 mmol) in anhydrous THF (20 mL) was added MeMgBr (3M solution in ether) (6.27 mL, 15.8 mmol) dropwise at −78° C. The reaction mixture was stirred at RT overnight. After the reaction was complete, the mixture was cooled to 0° C. and quenched by saturated NH₄Cl. The product was extracted with EA (150 mL×2). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated to give 3.24 g (95%) of crude P10-6, which was further purified by chromatography on silica gel (PE/EA=10:1 to 1:1).

Step 6. Preparation of 5′-C, 5′-O-didehydro-5′(S)—C-methyl-2,3′-O,N4-tri(4-methoxytrityl)arabinocytidine (P10-7)

To an ice-cooled suspension of CrO₃ (697.5 mg, 6.98 mmol) in anhydrous DCM (12.5 mL) was added anhydrous pyridine (1.125 mL, 13.98 mmol) and Ac₂O (0.7 mL, 6.98 mmol) under N₂. The mixture was stirred at RT for about 10 min until the mixture became homogeneous. The mixture was cooled to 0° C., and a solution of compound P10-6 (2.5 g, 2.33 mmol) in anhydrous DCM (12.5 mL) was added. The resultant mixture was stirred at RT overnight. The reaction mixture was diluted with EA (100 mL), washed with NaHCO₃ solution twice and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give a crude product P10-7 (2.5 g).

Step 7. Preparation of 5′ (R)—C-methyl-2′,3′-O,N4-tri(4-methoxytrityl)arabinocytidine (P10)

To an ice-cold solution of compound P10-7 (2.5 g, 2.33 mmol) in anhydrous EtOH (50 mL) was added NaBH₄ (250 mg, 6.47 mmol) under N₂. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was diluted with EA (30 mL), washed with saturated NaHCO₃ and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated to give the crude product. The crude was further purified by prep. TLC to give 5′(R)—C-methyl-2′,3′-O,N⁴-tri(4-methoxytrityl)arabinocytidine (P10) (1.4 g, 95% purity). ESI-MS: m/z 1074.2 [M+H]⁺.

Example 11

Preparation of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(S)—C-methylguanosine (P11)

Step 1. Preparation of 9-(2′,3′-O-dibenzoyl-5′(S)—C-methyl-5′-O-(4-nitrobenzoyl)-β-D-ribofuranosyl)-2-amino-6-chloropurine (P11-1)

To a stirred suspension of P1 (10 g, 17.8 mmol) and 2 (3.1 g, 18.2 mmol) in anhydrous MeCN (200 mL) was added DBU (8.1 g, 53.4 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min. TMSOTf (13.9 mL, 71.2 mmol) was added dropwise at 0° C. After addition, the mixture was stirred at 0° C. for 20 min until a clear solution achieved. The mixture was heated to 70° C. and stirred for 3 h. The reaction was cooled to room temperature and diluted with EA. The solution was washed with saturated NaHCO₃ and brine in sequence. The organic layer was dried over Na₂SO₄ and then concentrated. The residue was purified by chromatography on silica gel (PE:EA=4:1 to 2:1) to give compound P11-1 as light yellow foam (7 g, 58%).

Step 2. Preparation of 5′(S)—C-methylguanosine (P11-2)

Compound P11-1 (7 g, 10.4 mmol) was treated with 2-meraptoethanol (4.6 ml, 64.4 mmol) and sodium methoxide (3.5 g, 64.8 mmol) in MeOH (200 mL). The mixture was refluxed at 70-80° C. for 24 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to 7.0 by using glacial acetic acid. The solvent was evaporated, and the crude product was purified by HPLC to give compound P11-2 (2.4 g, 77%). ¹H NMR (400 MHz, CD₃OD): δ 7.89 (s, 1H), 5.76 (d, J=7.2 Hz, 1H), 4.63 (dd, J=7.2, 5.6 Hz, 1H), 4.29 (dd, J=5.2, 1.6 Hz, 1H), 4.02 (m, 1H), 3.93 (dd, J=3.2, 1.6 Hz, 1H), 1.27 (d, J=6.4 Hz, 3H).

Step 3. Preparation of 2,3′-O-methoxymethylidene-5′(S)—C-methylguanosine (P11-3)

A mixture of compound P11-2 (1.0 g, 3.4 mmol), trimethyl orthoformate (5.0 mL) and p-toluenesulfonic acid monohydrate (1.0 g, 5.8 mmol) in 1,4-dioxane (130 mL) was stirred at RT for 24 h, cooled with ice, quenched by adding triethylamine (4 mL) and concentrated. The residue was purified by HPLC to give compound P11-3 as white foam (500 mg, 44%).

Step 4. Preparation of 2,3′-O-methoxymethylidene-N2-(4-methoxytrityl)-5′(S)—C-methylguanosine (P11)

A solution of compound P11-3 (500 mg, 1.47 mmol) and 4-methoxytrityl chloride (500 mg, 1.62 mmol) in pyridine (10 mL) was stirred at 20° C. for 48 h. The solution was then diluted with ethyl acetate and washed with brine three times. Solvent was evaporated, and the residue was chromatographed on silica gel with 1-2% methanol in dichloromethane to give 187 mg of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(S)—C-methylguanosine (P11) as foam solid.

Example 12

Preparation of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(R)—C-methylguanosine (P12)

Step 1. Preparation of 9-(2′,3′,5′-O-tribenzoyl-5′(R)—C-methyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (P12-1)

To a stirred suspension of P2 (8 g, 15.4 mmol) and 2-amino-6-chloropurine (2.7 g, 15.8 mmol) in anhydrous MeCN (150 mL) was added DBU (7 g, 46.1 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min and then TMSOTf (12.1 mL, 62 mmol) was added dropwise at 0° C. After addition, the mixture was stirred at 0° C. for 20 min until a clear solution was achieved. The mixture was heated to 70° C. and stirred for 3 h. The reaction was cooled to RT and diluted with EA. The solution was washed with saturated NaHCO₃ and brine in sequence. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by chromatography on silica gel (PE:EA=4:1 to 2:1) to give P12-1 as light yellow foam (5.5 g, 57%).

Step 2. Preparation of 5′(R)-methylguanosine (P12-2)

Compound P12-1 (3.5 g, 17.1 mmol) was treated with 2-meraptoethanol (2.5 ml, 35 mmol) and sodium methoxide (1.8 g, 33.3 mmol) in MeOH (100 mL), and the mixture was refluxed for 24 h. The reaction mixture was then cooled to RT, and the pH was adjusted to 7.0 by using acetic acid. The solvent was evaporated, and the crude product was purified by HPLC to give product P12-2 (1.1 g, 67%); ¹H NMR (400 MHz, CD3OD): δ 7.89 (s, 1H), 5.76 (d, J=7.2 Hz, 1H), 4.63 (dd, J=7.2, 5.6 Hz, 1H), 4.29 (dd, J=5.2, 1.6 Hz, 1H), 4.02 (m, 1H), 3.93 (dd, J=3.2, 1.6 Hz, 1H), 1.270 (d, J=6.4 Hz, 3H).

Step 3. Preparation of 2′,3′-O-methoxymethylidene-5′(R)—C-methylguanosine (P12-3)

A mixture of compound P12-2 (1.1 g, 3.7 mmol), trimethyl orthoformate (5 mL) and p-toluenesulfonic acid monohydrate (1.1 g, 6.4 mmol) in 1,4-dioxane (150 mL) was stirred at RT for 24 h, cooled with ice, quenched by adding triethylamine (4 mL) and concentrated. The residue was purified by HPLC to give product P12-3 as white foam (700 mg, 56%).

Step 4. Preparation of 2′,3′-O-methoxymethylidene-N2-(4-methoxytrityl)-5′(R)—C-methylguanosine (P12)

A solution of compound P12-3 (700 mg, 2.06 mmol) and 4-methoxytrityl chloride (700 mg, 2.27 mmol) in pyridine (10 mL) was stirred at 20° C. for 48 h. The mixture was diluted with ethyl acetate and washed with brine three times. Solvent was evaporated, and the residue was chromatographed on silica gel with 1-2% methanol in dichloromethane to give 317 mg of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(R)—C-methylguanosine (P12) as foam solid. MS m/z 611.9 (MH⁺).

Example 13

Preparation of 2′,3′-O-methoxymethylidene-5′(S)—C-methylinosine (P13)

A solution of compound P3-1 (2 g, 2.97 mmol), 2-mercaptoethanol (1.3 mL, 18.2 mmol) and sodium methoxide (1.0 g, 18.5 mmol) in MeOH (100 mL) was refluxed for 24 h. The reaction mixture was cooled to RT and neutralized to pH 7.0 with acetic acid. The solvent was evaporated, and the crude product was purified by reverse-phase HPLC to give 657 mg (77%) of 5′(S)—C-methylinosine as white solid; ¹H NMR (CD₃OD) δ 8.37 (s, 1H), 8.06 (s, 1H), 4.01 (d, J=6.0 Hz, 1H), 4.61 (t, J=5.6 Hz, 1H), 4.28 (dd, J=5.2, 3.2 Hz, 1H), 4.02 (m, 2H), 1.26 (d, J=6.4 Hz, 3H).

A mixture of 5′(S)—C-methylinosine (657 mg, 2.3 mmol), trimethyl orthoformate (5.0 mL) and p-toluenesulfonic acid monohydrate (1.0 g, 5.8 mmol) in 1,4-dioxane (130 mL) was stirred at RT for 24 h. The mixture was then cooled with ice, quenched by adding triethylamine (4 mL) and concentrated. The residue was purified by reverse-phase HPLC to give 128 mg (17%) of 2′,3′-O-methoxymethylidene-5′(S)—C-methylinosine (P13) as white foam; ¹H NMR (CD₃OD) δ8.37, 8.36 (2s, 1H), 8.06, 8.04 (2s, 1H), 6.34, 6.18 (2d, J=3.2 Hz, 1H), 6.08, 5.98 (2s, 1H), 5.28, 5.23 (2m, 1H), 5.04, 4.96 (2m, 1H), 4.21, 4.09 (2m, 1H), 2.95 (m, 1H), 1.21, 1.17 (2d, J=6.4 Hz, 3H). MS m/z 324.8 (MH⁺).

Example 14

Preparation of 2′-deoxy-2′,2′-difluoro-3′4-(4-methoxytrityl)-5′(S)—C-methyluridine

Preparation of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′,2′-difluoro-3′-O,N4-di(4-methoxytrityl) cytidine (P14-2)

To a solution of gemcitabine (P14-1) (48.3 g, 162 mmol) in anhydrous pyridine (500 mL) was added TBSCl (29.2 g, 194.4 mmol) in small portions at 0° C. under N₂. The reaction mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was diluted with EA (1000 mL), washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to give 62 g (92%) of 3′-O-(t-butyldimethylsilyl)-2′-deoxy-2′,2′-difluorocytidine as a white solid, which was used without further purification.

To a mixture of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′,2′-difluorocytidine (60 g, 160 mmol), AgNO₃ (77.8 g, 510 mmol) and sym-collidine (159.8 g, 1.32 mol) in anhydrous DCM (800 mL) was added MMTrCl (156.8 g, 510 mmol) in small portions under N₂. The reaction mixture was stirred at RT overnight. The reaction mixture was then filtered through Buchner funnel. The filtrate was washed with saturated NaHCO₃ solution and followed by brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated. Chromatography on silica gel (PE/EA=3/1 to 2/1) gave 200 g of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′,2′-difluoro-3′-O,N⁴-di(4-methoxytrityl) cytidine (P14-2) contaminated with collidine.

Preparation of 2′-deoxy-5′-C, 5′-O-didehydro-2′,2′-O,N4-di(4-methoxytrityl)cytidine (P14-3)

To a solution of compound P14-2 (200 g, crude) in anhydrous THF (322 mL) was added TBAF (1M solution in THF) (85.3 g, 330 mmol) dropwise at 0° C. under N₂. The reaction mixture was stirred at RT overnight. The solvent was removed. The residue was dissolved in EA (800 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated. Chromatography on silica gel column (CH₂Cl₂/EA=10/1 to 5/1) gave 128 g of 2′-deoxy-2′,2′-difluoro-3′-O,N⁴-di(4-methoxytrityl) cytidine.

To a solution of pyridine (2.85 g, 36 mmol) in anhydrous DMSO (30 mL) at 10° C. was added TFA (2.05 g, 18 mmol) dropwise. After addition, the mixture was stirred at RT until a clear solution formed. The solution was then added to a solution of 2′-deoxy-2′,2′-difluoro-3′-O,N⁴-di(4-methoxytrityl) cytidine (24.2 g, 30 mmol) and DCC (18.6 g, 90 mmol) in anhydrous DMSO at 10° C. dropwise. Stirring was continued at RT for 12 h. Water (200 mL) was then added, and the mixture was stirred at RT for another hour. The precipitate was removed by filtration, and the filtrate was extracted with EtOAc (1000 mL). The organic layer was washed with brine (200 mL) and then dried over Na₂SO₄. The solvent was removed, and the residue was purified on silica gel column (EA:PE=1/1 to 2/1) to give 21.0 g (88%) of 2′-deoxy-5′-C,5′-O-didehydro-2′,2′-difluoro-3′-O,N⁴-di(4-methoxytrityl)cytidine (P14-3).

Preparation of 2′-deoxy-2′,2′-O,N4-di(4-methoxytrityl)-5′(S)—C-methylcytidine (P14-4)

To a stirred solution of compound P14-3 (26 g, 32.3 mmol) in anhydrous THF (250 mL) was added MeMgBr (3 M solution in ether) (80 mL, 161.5 mmol) dropwise at −78° C. under N₂. The reaction mixture was stirred at RT overnight. The reaction was quenched by saturated NH₄Cl, and the mixture was extracted with EA (500 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated. The resulting residue was purified by silica gel column (EA:PE=10/1 to 3/2) two times to give 8 g (44%) of crude 2′-deoxy-2′,2′-difluoro-3′-O,N⁴-di(4-methoxytrityl)-5′(S)—C-methylcytidine (P14-4). ¹H NMR (400 Hz, CDCl₃) 7.44-7.48 (m, 4H), 7.08-7.37 (m, 21H), 6.92 (br, 1H), 6.81-6.84 (m, 4H), 6.28 (t, J=8.4 Hz, 1H), 4.99 (d, J=7.6 Hz, 1H), 4.20-4.25 (m, 1H), 3.81 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.07-3.12 (m, 1H), 1.05 (d, J=6.4 Hz, 3H); ESI-MS: 822 [M+H]⁺.

Preparation of 2′-deoxy-2′,2′-difluoro-5′(S)—C-methyl-3′,5′-O,N4-tribenzoylcytidine (P14-5)

Compound P14-4 (8 g, 9.73 mmol) was dissolved in 125 mL AcOH/H₂O (v/v=4:1). The mixture was stirred at 60° C. for 6 h. The solvent was removed, and the residue was purified on silica gel column (CH₂Cl₂:MeOH=100/1 to 10/1 with 0.5% TEA) two times to give 2.0 g of 2′-deoxy-2′,2′-difluoro-5′(S)—C-methylcytidine as white solid. ¹H NMR (CD₃OD) δ 7.87 (d, J=7.6 Hz, 1H), 6.18 (t, J=7.6 Hz, 1H), 5.90 (d, J=7.6 Hz, 1H), 4.25-4.17 (m, 1H), 3.97 (dd, J=6.4 Hz, 3.6 Hz, 1H), 3.68 (dd, J=8.4 Hz, 2.8 Hz, 1H), 1.31 (d, J=6.4 Hz, 3H); ¹³C NMR (100 Hz, CD₃OD): δ 166.3, 156.5, 141.2, 122.6 (t, J=267 Hz), 94.9, 84.6 (t, J=30.6 Hz), 83.4 (t, J=25 Hz), 70.2 (t, J=23 Hz), 65.0, 18.2; ESI-MS: 555 [2M+H]⁺, 278 [M+H]⁺.

To a stirred solution of 2′-deoxy-2′,2′-difluoro-5′(S)—C-methylcytidine (0.975 g, 3.5 mmol, co-evaporated with dry pyridine for three times) in anhydrous pyridine (40 mL) was added BzCl (1.73 g, 12 mmol) dropwise at 0° C. under N₂. After addition, the mixture was warmed to RT and stirred for 3 h. The reaction was quenched with H₂O, and the solvent was removed under reduced pressure. The residue was taken up into DCM and washed with saturated NaHCO₃, 1% H₂SO₄ and brine in sequence. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on silica gel (PE:EA=10:1 to 3:1) to afford 1.43 g (69%) of 2′-deoxy-2′,2′-difluoro-5′(S)—C-methyl-3′,5′-O,N⁴-tribenzoylcytidine (P14-5) as white solid.

Preparation of 5′-O-benzoyl-2′-deoxy-2′,2′-difluoro-5′(S)—C-methyluridine (P14-6)

Compound P14-5 (1.43 g) was dissolved in a mixture of DME (dimethoxyethane) (36 mL) and H₂O (24 mL), and the resulting solution in a sealed vessel was then stirred at 125° C. overnight. The solvent was removed under reduced pressure, and the residue was purified on silica gel (PE:EA=10:1 to 3:1) to give 0.98 g (85%) of 2′-deoxy-3′,5′-O-dibenzoyl-2′,2′-difluoro-5′(S)—C-methyluridine as white solid, which was dissolved in methanol (30 mL). Aqueous ammonia 25%, 30 mL) was added, and the resulting mixture was stirred at RT for 3 h. The solvent was removed, and the residue was purified by column chromatography on silica gel eluting with a mixture of PE:EA=10:1-3:2 to afford 0.58 g (75%) of 5′-O-benzoyl-2′-deoxy-2′,2′-difluoro-5′(S)—C-methyluridine (P14-6).

Preparation of 2′-deoxy-2′,2′-difluoro-5′ (S)—C-methyl-3′-O-(4-methoxymethyl)uridine (P14)

To a solution of compound P14-6 (0.53 g, 1.39 mmol) in dry DCM (25 mL) were added AgNO₃ (0.29 g, 1.67 mmol) and 2,4,6-collidine (0.22 g, 1.8 mmol). A solution of MMTrCl (0.51 g, 1.67 mmol) in dry DCM (15 mL) was then added. The resulting mixture was stirred at room temperature overnight and filtered through celite. The cake was washed with EA (300 mL). Combined organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of PE:EA=10:1-3:1 to afford 0.8 g (88%) of 5′-O-benzoyl-2′-deoxy-2′,2′-difluoro-5′(S)—C-methyl-3′-O-(4-methoxytrityl)uridine, which was dissolved in MeOH (40 mL). The resulting solution was bubbled with ammonia gas for 30 min at −78° C. Another 30 mL of aq. ammonia was added to the mixture and heated at 40-50° C. overnight. The mixture was concentrated and purified by column chromatography on silica gel eluting with a mixture of PE:EA=5:1-2:1 to give 0.2 g, (29%) of 2′-deoxy-2′,2′-difluoro-5′ (S)—C-methyl-3′-O-(4-methoxymethyl)uridine (P14) as white solid; ¹H NMR (CDCl₃, 400 MHz): δ 8.52 (s, 1H), 7.50-7.47 (m, 5H), 7.37 (d, J=8.8 Hz, 2H), 7.32-7.26 (m, 4H), 6.85 (d, J=8.8 Hz, 1H), 6.19 (t, J=9.6 Hz, 1H), 5.63 (d, J=7.6 Hz, 1H), 4.27 (dd, J=11.6, 18.4 Hz, 1H), 3.84 (d, J=6.8 Hz, 1H), 3.18 (br s, 1H); ESI-MS: m/z 573 [M+Na]⁺.

Example 15

Preparation of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A1)

To a solution of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)-methyladenosine (P3) (595 mg, 1.0 mmol) in THF (8 mL) under argon was added dropwise 1.0 M tert-BuMgBr in THF (3.0 mL). The resulting solution was stirred at RT for 30 min. 1-naphth-yl(cyclohexoxy-L-alaninyl) phosphorochloridate was prepared according to a general procedure (McGuigan et al. J. Med. Chem. 2008, 51, 5807) (0.95 M in THF, 4.0 mL) was added. The reaction mixture was stirred at RT for 3 days, cooled with ice, quenched with water, diluted with ethyl acetate, washed with brine three times, dried over sodium sulfate, and concentrated. Chromatography on silica gel with ethyl acetate/hexanes (3:2 to 4:1) gave a mixture of four isomers. The mixture was dissolved in 80% formic acid (25 mL), and the resulting solution stood at RT overnight. Solvent was evaporated at RT and co-evaporated with MeOH/toluene three times. Chromatography on silica gel with 5-8% MeOH in DCM gave 112 mg of pure 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A1) as white solid. The second chromatography of the impure portion gave 322 mg of the pure product, and then the third chromatography gave 101 mg of the pure product. Total yield of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate was 535 mg as white solid; ¹H NMR (CD₃OD, two isomers) δ 1.20, 1.23 (2dd, J=7.2, 1.2 Hz, 3H), 1.41, 1.56 (2d, J=6.4 Hz, 3H), 1.16-1.76 (m, 10H), 3.88-3.99 (m, 1H), 4.05-4.08 (m, 1H), 4.02-4.06 (m, 1H), 4.32-4.65 (m, 3H), 4.82-4.97 (m, 1H), 5.96, 6.03 (2d, J=4.4 Hz, 1H), 7.31, 7.38 (2t, J=8.0 Hz, 1H), 7.39-7.53 (m, 3H), 7.62, 7.68 (2d, J=8.0 Hz, 1H), 7.81, 8.06 (2m, 1H), 7.87, 8.12 (2m, 1H), 8.09, 8.20 (2s, 1H), 8.15, 8.28 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 3.31 (s), 3.48 (s). MS m/z 641.4 (MH⁺).

Example 16

Preparation of 5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A2)

Following the general procedure described for 5′(S)—C-methyladenosine, 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A1), 509 mg of 5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A2) was obtained as white solid from 714 mg (1.2 mmol) of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)-methyladenosine (P3) and 1-naphthyl(neopentoxy-L-alaninyl)]phosphorochloridate prepared according to a general procedure (McGuigan et al. J. Med. Chem. 2008, 51, 5807). ¹H NMR (CD₃OD, two isomers) δ0.83, 0.87 (2s, 9H), 1.23, 1.26 (2dd, J=7.2, 0.8 Hz, 3H), 1.40, 1.66 (2d, J=6.4 Hz, 3H), 3.64, 3.71 (2AB, J=35.2/29.2, 10.4 Hz, 2H), 3.95-4.06 (m, 2H), 4.42-4.58 (m, 2H), 4.81-4.96 (m, 1H), 5.96, 6.02 (2d, J=4.4 Hz, 1H), 7.31, 7.38 (2t, J=8.0 Hz, 1H), 7.39-7.53 (m, 3H), 7.62, 7.68 (2d, J=8.0 Hz, 1H), 7.81, 8.05 (2d, J=8.0 Hz, 1H), 7.86, 8.12 (2m, 1H), 8.10, 8.20 (2s, 1H), 8.15, 8.27 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 3.36 (s), 3.48 (s). MS m/z 629.5 (MH⁺).

Example 17

Preparation of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A3)

A solution of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A1) (159 mg, 0.248 mmol) and carbonyldiimidazole (97 mg, 0.6 mmol) in anhydrous DMF (2.5 mL) was stirred at RT for 5 h and then evaporated at RT under high vacuum. The crude was purified on silica gel with 5-8% MeOH in DCM. The collected fractions were concentrated and purified on reverse-phase HPLC (C-18) with acetonitrile/water system. The collected fractions were concentrated again and subjected to a chromatography on silica gel with 6-8% EtOAc in DCM. The collected fractions were concentrated and purified on silica gel with 6-9% isopropanol in DCM to give 58 mg of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A3) as white solid; ¹H NMR (CDCl₃, two isomers) δ 1.20, 1.26 (2d, J=7.2 Hz, 3H), 1.31, 1.53 (2d, J=6.4 Hz, 3H), 1.28-1.81 (m, 10H), 3.87, 4.38 (2t, J=10.4 Hz, 1H), 3.92-4.08 (m, 1H), 4.30-4.34 (m, 1H), 4.67-4.75 (m, 1H), 4.80-4.92 (m, 1H), 5.15, 5.23 (2dd, J=7.6, 3.6/2.4 Hz, 1H), 5.64, 5.95 (2dd, J=7.6, 3.6/2.0, Hz, 1H), 5.90, 6.13 (2s, br, 2H), 6.07, 6.20 (2d, J=6.8/6.0 Hz, 1H), 7.32, 7.33 (2t, J=8.0/7.6 Hz, 1H), 7.35-7.51 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.72, 8.07 (2s, 1H), 7.78-7.83 (m, 1H); 7.87-7.91 (m, 1H), 7.95-8.0 (m, 1H), 8.25, 8.29 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 2.41 (s), 2.80 (s).

Example 18

Preparation of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A4)

Following the general procedure described for 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A3), 67 mg (two isomers) of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A4) was obtained as white solid from 126 mg (0.2 mmol) of 5′ (S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A2) and 1-naphthyl(neopentoxy-L-alaninyl) phosphorochloridate. ¹H NMR (CDCl₃, two isomers) δ 0.88, 0.92 (2s, 9H), (2d, J=7.2 Hz, 3H), 1.25, 1.54 (2d, J=6.8 Hz, 3H), 1.27-1.30 (2d, J=7.2 Hz, 1H), 3.70, 3.84 (2dd, J=11.6/16.0, 10.4 Hz, 1H), 3.82, 4.52 (2t, J=10.0 Hz, 1H), 3.96-4.15 (m, 1H), 4.30-4.36 (m, 1H), 4.82-4.93 (m, 1H), 5.21, 5.30 (2dd, J=7.6, 3.6/2.8 Hz, 1H), 5.63, 5.93 (2dd, J=7.2, 4.0/2.4, Hz, 1H), 5.99, 6.29 (2s, br, 2H), 6.09, 6.19 (2d, J=2.8/2.0 Hz, 1H), 7.32, 7.33 (2t, J=8.0/7.6 Hz, 1H), 7.35-7.51 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.76, 8.10 (2s, 1H), 7.79-8.0 (m, 2H); 8.24, 8.29 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 2.39 (s), 2.80 (s).

Example 19

Preparation of 2′,3′-O-carbonyl-N6-methoxycarbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A5) and N6-methoxycarbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A6)

A solution of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A1) (130 mg, 0.20 mmol) and carbonyldiimidazole (810 mg, 5.0 mmol) in anhydrous DMF (12 mL) was stirred at RT for 5 h and then evaporated at RT under high vacuum. The crude was purified on silica gel with 5-8% MeOH in DCM. The higher R_f fractions were collected and evaporated. A portion of the higher R_f minor product was further purified by chromatography on silica gel to give 17 mg of 2′,3′-O-carbonyl-N⁶-methoxycarbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A5) as white solid; ¹H NMR (acetonitrile-d₃, two isomers) δ 1.13, 1.19 (2dd, J=7.2, 0.8 Hz, 3H), 1.41, 1.55 (2d, J=6.4 Hz, 3H), 1.21-1.76 (m, 10H), 3.79-4.93 (m, 1H), 3.798, 3.803 (2s, 3H), 4.13, 4.25 (2t, J=10.4 Hz, 1H), 4.46, 4.50 (2dd, J=6.4/4.8, 4.4 Hz, 1H), 4.55-4.66 (m, 1H), 4.82-4.98 (m, 1H), 5.50, 5.60 (2dd, J=8.0, 4.0 Hz, 1H), 5.63, 5.87 (2dd, J=8.0, 2.4/2.0 Hz, 1H), 6.38, 6.46 (2d, J=2.4/2.0 Hz, 1H), 7.28-7.57 (m, 4H), 7.3, 7.69 (2dd, J=8.0, 0.8 Hz, 1H), 7.82-8.03 (m, 2H), 8.19, 8.29 (2s, 1H), 8.54, 8.61 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 2.50 (s), 2.87 (s). MS m/z 725.3 (MH⁺).

The remainder of the higher R_f product was dissolved in acetonitrile/water, and the resulting solution stood at RT for 5 days. Chromatography on silica gel with 6-10% i-PrOH in DCM gave 15.5 mg of N⁶-methoxycarbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate (A6) as white solid; ¹H NMR (CD₃OD, two isomers) δ1.18, 1.21 (2dd, J=7.2, 1.2 Hz, 3H), 1.42, 1.57 (2d, J=6.4 Hz, 3H), 1.2-1.78 (m, 10H), 3.84 (s, 3H), 3.85-3.97 (m, 1H), 4.02-4.09 (m, 1H), 4.37, 4.48 (2t, J=5.2 Hz, 1H), 4.48 (2dd, J=5.2, 4.4 Hz, 1H), 4.48-4.64 (m, 1H), 4.82-4.98 (m, 1H), 6.04, 6.11 (2d, J=4.8/4.4 Hz, 1H), 7.29, 7.37 (2t, J=8.0/7.6 Hz, 1H), 7.36-7.52 (m, 3H), 7.59, 7.67 (2d, J=8.0 Hz, 1H), 7.79, 8.00 (2m, 1H), 7.83-7.87, 8.08-8.13 (2m, 1H), 8.31, 8.52 (2s, 1H), 8.47, 8.58 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 3.23 (s), 3.43 (s). MS m/z 699.4 (MH⁺), 828.5 (MH⁺+6-methyl-2-heptylamine).

Example 20

Preparation of 2′,3′-O-carbonyl-N6-methoxycarbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A7)

A solution of 5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A2) (126 mg, 0.20 mmol) and carbonyldiimidazole (810 mg, 5.0 mmol) in anhydrous DMF (12 mL) was stirred at RT for 5 h and then evaporated at RT under high vacuum. The crude was purified on silica gel with 5-8% MeOH in DCM. The higher R_f fractions were collected and re-purified by chromatography on silica gel to give 11 mg of 2′,3′-O-carbonyl-N⁶-methoxycarbonyl-5′(S)—C-methyladenosine 5′-[1-naphthyl(neopentoxy-L-alaninyl)]phosphate (A7) as white solid; ¹H NMR (acetonitrile-d₃, two isomers) δ 0.87, 0.90 (2s, 9H), 1.17, 1.22 (2dd, J=7.2, 0.8/1.2 Hz, 3H), 1.41, 1.55 (2d, J=6.4 Hz, 3H), 3.68, 3.72 (2AB, J=18.4/37.2, 10.4 Hz, 2H), 3.802, 3.807 (2s, 3H), 3.88-4.04 (m, 1H), 4.17, 4.28 (2t, J=10.4 Hz, 1H), 4.46, 4.51 (2dd, J=6.0/4.8, 4.4/4.0 Hz, 1H), 4.82-4.98 (m, 1H), 5.52, 5.60 (2dd, J=8.0, 4.0 Hz, 1H), 5.64, 5.87 (2dd, J=8.0, 2.4 Hz, 1H), 6.39, 6.46 (2d, J=2.4/2.8 Hz, 1H), 7.29-7.57 (m, 4H), 7.63, 7.70 (2d, J=8.0 Hz, 1H), 7.82-8.03 (m, 2H), 8.22, 8.62 (2s, 1H), 8.31, 8.54 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 2.58 (s), 2.83 (s). MS m/z 713.4 (MH⁺).

Example 21

Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A8)

Step 1. Preparation of phenyl(isopropoxy-L-alaninyl) phosphorochloridate

A solution of triethylamine (5.7 g, 56.4 mmol) in anhydrous dichloromethane (50 mL) was added dropwise to a solution of phenyl phosphorodichloridate (6 g, 28.4 mmol) and isopropyl L-alaninate hydrochloride (4.7 g, 28.1 mmol) in dichloromethane (120 mL) with vigorous stirring at −78° C. over 2 h. After addition, the reaction was allowed to warm to RT gradually and stirred for 2 h. The solvent was removed under vacuum and anhydrous ether (20 mL) was added. The precipitated salt was filtered, and the filtrate was washed with ether. The combined filtrate was concentrated and purified by flash chromatography on silica gel (DCM) to give phenyl(isopropoxy-L-alaninyl) phosphorochloridate as colorless syrup.

Step 2. Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A8)

To a solution of 2′,3′-O-methoxymethylene-N⁶-(4-methoxytrityl)-5′(5)-methyladenosine (P3) (1.0 g, 16.8 mmol) in THF (30 mL) under argon was added 1.0 M t-BuMgBr in THF (5.0 mL, 5.0 mmol) at 0° C. The resulting solution was stirred at RT for 30 min and phenyl(isopropoxy-L-alaninyl) phosphorochloridate (5 mL, 1M in THF) was added at 0° C. The reaction mixture was stirred at RT for 20 h, cooled with ice, quenched with water, diluted with ethyl acetate, washed with brine, extracted with ethyl acetate three times, and dried over MgSO₄. After concentration, the residue was purified by chromatography on silica gel (PE:EA=2:1 to 1:1) to give 1.3 g (89%) of a coupling product, which was dissolved in 80% formic acid (25 mL). The resulting solution was stirred at RT overnight, solvent evaporated at RT, and the residue purified by chromatography on silica gel with 10-15% MeOH in DCM. Re-purification by reverse-phase HPLC with acetonitrile/water with HCOOH, gave 5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A8) as a mixture of two P-isomers (370 mg, 36%); ¹H NMR (CD₃OD, two isomers) δ 1.13, 1.19 (2dd, 6H), 1.223, 1.226 (2d, J=7.2, 3H), 1.42, 1.51 (2d, J=6.4 Hz, 3H), 3.8-3.9 (m, 2H), 4.0-4.05 (m, 1H), 4.33, 4.42 (2t, J=5.2 Hz, 1H), 4.52, 4.56 (2t, J=5.2 Hz, 1H), 4.75-4.85 (m, 1H), 4.94 (m, 1H), 6.02 6.03 (2s, 1H), 7.19-7.34 (m, 5H), 8.18, 8.20 (2s, 1H), 8.26, 8.30 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 0.78 (s), 0.85 (s). MS m/z 550.9 (MH⁺).

Example 22

Preparation of 2′,3′-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A9)

A solution of compound A8 (110 mg, 0.2 mmol) in anhydrous dichloromethane (20 mL) was added CDI (1,1′-carbonyldiimidazole) (100 mg, 0.6 mmol) at RT. The mixture was stirred for about 2 h. The solvent was removed under vacuum at 0° C. and purified by preparative HPLC to give 46 mg (40%) of 2′,3′-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A9) as a mixture of two P-isomers; ³¹P NMR (CD₃OD, two isomers) δ 1.95 (s), 2.32 (s). MS m/z 577.1 (MH⁺).

Example 23

Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A10)

Step 1. Preparation of phenyl(cyclohexoxy-L-alaninyl) phosphorochloridate

To a stirred solution of phenyl phosphorodichloridate (6.33 g, 30 mmol) and cyclohexyl alaninate hydrochloride (6.24 g, 30 mmol) in anhydrous DCM (130 mL) was added a solution of TEA (triethylamine) (8.3 mL, 60 mmol) in DCM (20 mL) dropwise at −78° C. After addition, the mixture was warmed to RT gradually and stirred overnight. The solvent was removed, and the residue was dissolved in methyl-butyl ether. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was purified by column on silica gel with DCM to give pure phenyl(cyclohexoxy-L-alaninyl) phosphorochloridate (7.20 g, 70%).

Step 2. Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A10)

To a stirred solution of compound P3 (850 mg, 1.43 mmol) in anhydrous THF (20 mL) was added a solution of t-BuMgCl (4 mL, 1M in THF) dropwise at 0° C. The mixture was then stirred at RT for 40 min and re-cooled to 0° C. A solution of phenyl(cyclohexoxy-L-alaninyl) phosphorochloridate (4 mL, 1.0 M in THF) was added dropwise. After addition, the mixture was stirred at RT for 40 h. The reaction was quenched with H₂O and extracted EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by column on silica gel (PE:EA=2:1 to 1:1) to give 1.1 g of a protected form of A10 (85%).

The protected form of A10 (810 mg) was dissolved in 80% HCOOH aqueous solution, and the mixture was stirred at RT for 50 h. The solvent was removed, and the residue was purified by RP HPLC (HCOOH system) to give 5′(S)—C-methyladenosine 5′-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A10) as a mixture of two P-isomers (370 mg, 59%); ³¹P NMR (CD₃OD, two isomers) δ 0.74 (s), 0.80 (s). MS m/z 591.0 (MH⁺).

Example 24

Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A11)

Step 1. Preparation of phenyl(neopentoxy-L-alaninyl) phosphorochloridate

A solution of triethylamine (6 g, 59.4 mmol) in anhydrous dichloromethane (50 mL) was added dropwise to a solution of phenyl phosphorodichloridate (5.5 g, 28.2 mmol) and neopentyl alaninate hydrochloride (6 g, 28.4 mmol) in DCM (120 mL) with vigorous stirring at −78° C. over a period of 2 h. After addition, the reaction temperature was allowed to warm to RT gradually and stirred for about 2 h. The solvent was removed under vacuum and anhydrous ether 20 mL was added. The precipitated salt was filtered, and the precipitate was washed with ether. The combined organic phase was concentrated and purified by column chromatography to give the colorless oil of phenyl(neopentoxy-L-alaninyl) phosphorochloridate.

Step 2. Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A11)

To a solution of compound P3 (850 mg, 1.43 mmol) in THF (30 mL) under argon was added 1.0 M t-BuMgBr in THF (4.3 mL, 4.3 mmol) at 0° C. The resulting solution was stirred at RT for 30 min and phenyl(neopentoxy-L-alaninyl) phosphorochloridate (4.3 mL, 1M in THF) was added at 0° C. The reaction mixture was stirred at RT for 20 h, cooled with ice, quenched with water, diluted with ethyl acetate, washed with brine, extracted with ethyl acetate three times, and dried over MgSO₄. After concentration, the residue was purified by column on silica gel (PE:EA=2:1 to 1:1) to give 1.1 g of a protected product of A11, which was dissolved in 80% formic acid (25 mL) and stirred at RT overnight. The solvent was evaporated at RT, and the residue was purified by chromatography on silica gel with 10-15% MeOH in DCM. The residue was then re-purification by reverse-phase HPLC with acetonitrile/water, to give 5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A11) as a mixture of two P-isomers (240 mg, 34%); ³¹P NMR (CD₃OD, two isomers) δ 2.26 (s), 2.36 (s). MS m/z 578.9 (MH⁺).

Example 25

Preparation of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A12)

A solution of compound A11 (132 mg, 0.23 mmol) in anhydrous dichloromethane (20 mL) was added CDI (120 mg, 0.70 mmol) at RT, and stirred about 2 h. The solvent was removed under vacuum at 0° C. and purified by prep. HPLC (neutral) to give mg (47%) of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A12) as a mixture of 2 P-isomers; ³¹P NMR (CD₃OD, two isomers) δ 2.03 (s), 2.44 (s). MS m/z 605.2 (MH⁺).

Example 26

Preparation of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A13)

A solution of compound A10 (120 mg, 0.30 mmol) in anhydrous dichloromethane (20 mL) was added CDI (150 mg, 0.90 mmol) at RT. The mixture was stirred for about 2 h. The solvent was removed under vacuum at 0° C. and purified by prep. HPLC (neutral) to give 60 mg (32%) of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A13) as a mixture of two P-isomers; ³¹P NMR (160 MHz, CDCl₃): δ1.98 (s), 2.35 (s). MS m/z 617.1 (MH⁺).

Example 27

Preparation of 2′,3′-O-dipropionyl-5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A14)

To a solution of compound A8 (150 mg, 0.27 mmol) in anhydrous pyridine (5 mL) was added propionic anhydride (150 mg, 1.15 mmol) and DMAP (4-dimethylaminopyridine) (50 mg, 0.41 mmol) at RT. The mixture was stirred for about 18 h. The solvent was removed under vacuum at 0° C. and purified by column chromatography to give 120 mg (67%) of 2′,3′-O-dipropionyl-5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A14) as a mixture of 2 P-isomers; ³¹P NMR (160 MHz, CDCl₃): δ1.98 (s), 2.35 (s). MS m/z 663.2 (MH⁺).

Example 28

Preparation of 5′(S)—C-methyladenosine 5′-[phenylmethoxy-L-alaninyl)]phosphate (A15) and 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[phenylmethoxy-L-alaninyl)]phosphate (A16)

Step 1. Preparation of phenyl(methoxy-L-alaninyl) phosphorochloridate

A solution of TEA (6 g, 59.4 mmol) in anhydrous dichloromethane (50 mL) was added dropwise to a solution of phenyl phosphorodichloridate (6 g, 28.4 mmol) and methyl alaninate hydrochloride (4 g, 28.8 mmol) in DCM (120 mL) with vigorous stirring at −78° C. over a period of 2 h. After addition, the reaction temperature was allowed to warm to RT gradually and stirred about 2 h. The solvent was removed under vacuum. Anhydrous ether 20 mL was added. The precipitated salt was filtered, and the precipitate was washed with ether. The combined organic phase was concentrated and purified by column chromatography to give phenyl(methoxy-L-alaninyl) phosphorochloridate as colorless syrup.

Step 2. Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (A15)

To a solution of 2′,3′-O-methoxymethylene-N⁶-(4-methoxytrityl)-5′(S)-methyladenosine (P3) (500 mg, 0.84 mmol) in THF (30 mL) under argon was added 1.0 M t-BuMgBr in THF (2.1 mL, 2.1 mmol) at 0° C. The resulting solution was stirred at RT for 30 min and phenyl(methyl-L-alaninyl) phosphorochloridate (700 mg, 2.5 mmol) was added at 0° C. The reaction mixture was stirred at RT for 20 h, cooled with ice, quenched with water, diluted with ethyl acetate, washed with brine, extracted with ethyl acetate three times, and dried over MgSO₄. After concentration of organic layer, a protected product of A15 was obtained as a solid. The protect product of A15 was dissolved in 80% formic acid (25 mL) and stirred at RT overnight. Solvent was evaporated at RT and co-evaporated with MeOH/toluene three times. Chromatography on silica gel with 10-15% MeOH in DCM, followed by re-purification on reverse-phase HPLC with acetonitrile/water, gave 110 mg of 5′(S)—C-methyladenosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (A15) as white solid (two separated P-isomers A15-1 and A-15-2); ¹H NMR (major isomer A15-1, CD₃OD) δ 1.24 (d, J=6.8 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H), 3.58 (s, 3H), 3.88-3.95 (m, 1H), 4.02-4.05 (m, 1H), 4.42 (t, J=4.4 Hz, 1H), 4.58 (t, J=4.8 Hz, 1H), 4.74-4.83 (m, 1H), 6.04 (d, J=4.8 Hz, 1H), 7.15-7.36 (m, 5H), 8.21 (s, 1H), 8.31 (s, 1H); MS m/z 522.8 (MH⁺); ¹H NMR (CD₃OD, minor isomer A15-2) δ 1.24 (d, J=6.8 Hz, 3H), 1.52 (d, J=6.4 Hz, 3H), 3.66 (s, 3H), 3.91-3.95 (m, 1H), 4.06-4.08 (m, 1H), 4.35 (t, J=4.4 Hz, 1H), 4.52 (t, J=5.2 Hz, 1H), 4.82-4.85 (m, 1H), 6.05 (d, J=5.2 Hz, 1H), 7.13-7.31 (m, 5H), 8.20 (s, 1H), 8.29 (s, 1H); MS m/z 522.9 (MH⁺).

Step 3. Preparation of 2,3′-O-carbonyl-5′ (S)—C-methyladenosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (A16)

A solution of compound A15-1 (200 g, 0.38 mmol) in anhydrous dichloromethane (20 mL) was added CDI (200 g, 1.23 mmol) at RT and stirred about 2 h. The solvent was removed under vacuum at 0° C. and purified by prep. HPLC (neutral) to give mg (10%) of 2′,3′-O-carbonyl-5′(S)—C-methyladenosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (A16) as white solid; ¹H NMR (CDCl₃) δ1.26 (d, J=6.8 Hz, 3H), 1.50 (d, J=6.4 Hz, 3H), 3.68 (s, 3H), 3.71-3.76 (m, 1H), 3.92-3.98 (m, 1H), 4.37 (t, J=4 Hz, 1H), 4.77-4.82 (m, 1H), 5.42 (dd, J₁=7.6 Hz, J₂=3.6 Hz, 1H), 5.67 (dd, J₁=7.6 Hz, J₂=2.0 Hz, 1H), 5.77 (s, 2H), 6.05 (d, J=4.8 Hz, 1H), 6.95-6.98 (m, 2H), 7.08-7.12 (m, 1H), 7.19-7.23 (m, 2H), 7.91 (s, 1H), 8.30 (s, 1H); ³¹P NMR (160 MHz, CDCl₃): δ 1.70 (s). MS m/z 549.0 (MH⁺).

Example 29

Preparation of 2′,3′-O-dipropionyl-5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A17)

To a solution of compound A11 (200 mg, 0.35 mmol) in anhydrous pyridine (10 mL) were added propionic anhydride (182 mg, 1.4 mmol) and DMAP (68 mg, 0.52 mmol) at RT. The mixture was stirred about 18 h as checked with LCMS. The solvent was removed under reduced pressure at RT, and the residue was purified by reverse-phase HPLC to give 102 mg (43%) of 2′,3′-O-dipropionyl-5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A17) as a mixture of two P-isomers; ³¹P NMR (160 MHz, CDCl₃): δ1.88 (s). MS m/z 690.9 (MH⁺).

Example 30

Preparation of 2′,3′-O-dipropionyl-F(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A18)

To a solution of compound A10 (270 mg, 0.46 mmol) in anhydrous pyridine (10 mL) were added propionic anhydride (270 mg, 2.07 mmol) and DMAP (65 mg, 0.53 mmol) at RT. The resulting mixture was stirred about 18 h. The solvent was removed under vacuum at RT and purified by reverse-phase HPLC to give 110 mg (34%) of 2′,3′-O-dipropionyl-5′(S)—C-methyladenosine 5′-[phenyl(neopentoxy-L-alaninyl)]phosphate (A18) as a mixture of two P-isomers, ³¹P NMR (160 MHz, CDCl₃): δ1.92 (s). MS m/z 703.5 (MH⁺).

Example 31

Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(ethoxy-L-alaninyl)]phosphate (A19)

Following the general procedure for 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate, 50 mg of 5′(S)—C-methyladenosine 5′-[1-naphthyl(ethoxy-L-alaninyl)]phosphate (A19) was obtained as white solid from 112 mg of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)-methyladenosine (P3). ³¹P NMR (CD₃OD, two isomers) δ 3.32 (s), 3.48 (s). MS m/z 587.2 (MH⁺).

Example 32

Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A20)

Following the general procedure for 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate, 20.3 mg of 5′(S)—C-methyladenosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (A20) was obtained as white solid from 121 mg of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)-methyladenosine (P3). ³¹P NMR (CD₃OD, two isomers) δ 3.41 (s), 3.51 (s). MS m/z 601.2 (MH⁺).

Example 33

Preparation of 5′(S)—C-methyladenosine 5′-[phenyl(benzyloxy-L-alaninyl)]phosphate (A21)

Following the general procedure for 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate, 50 mg of 5′(S)—C-methyladenosine 5′-[1-naphthyl(benzyloxy-L-alaninyl)]phosphate (A21) was obtained as white solid from 87 mg of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(S)-methyladenosine (P3). ³¹P NMR (CD₃OD, two isomers) δ 5.88 (s), 5.90 (s). MS m/z 647.4 (M⁻).

Example 34

Preparation of 2′,3′-O-dipropionyl-5′-(S)—C-methyladenosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (A22)

To a solution of 5′-(S)—C-methyladenosine-5′-[1-naphthyl-(isopropoxy-L-alaninyl)]phosphate (A20) (148 mg, 0.25 mmol) in DMF (3 mL), were added DCC (153 mg, 0.74 mmol), propionic acid (55 μl, 0.74 mmol), DMAP (30 mg, 0.25 mmol). The mixture was stirred to RT for overnight. Reaction mixture was filtered, and filtrate was concentrated with a rotary evaporator until half of its original volume. EA was added to the reaction mixture. The reaction mixture was then washed with water, followed by brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue which was purified by silica gel with DCM/MeOH=95:5 to give 110.0 mg (62%) of 2′,3′-O-dipropionyl-5′-(S)—C-methyladenosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (A22) as white foam after lyophilization; ¹H NMR (DMSO-d₆, two isomers) δ 1.01-1.16 (m, 10H), 1.26, 1.42 (2d, J=6.4 Hz, 2H), 1.27, 1.42 (2d, J=6.4 Hz, 3H), 2.24-2.31 (m, 4H), 3.82-3.87 (m, 1H), 4.24-4.26 (m, 1H), 4.7-4.4.81 (m, 2H), 5.69-4.5.7 (m, 1H), 5.85-5.89 (m, 1H), 6.10 (dd, J=10.4, 11.2 Hz, 1H), 7.34 (br s, 2H), 7.38-7.54 (m, 4H), 7.88-7.92 (m, 1H), 8.05-8.09 (m, 1H), 8.10, 8.13 (2s, 1H), 8.16, 8.27 (2s, 1H); ³¹P NMR (DMSO-d6, two isomers) δ 3.36 (s), 4.03 (s); MS m/z 713.4 (MH⁺).

Example 35

Preparation of 2′,3′-O-carbonyl-5(S)—C-methyladenosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (A23)

To a solution of 5′(S)—C-methyladenosine-5′-[1-naphthyl-(isopropyloxy-L-alaninyl)]phosphate (A20) (100 mg, 0.17 mmol) in DMF (2 mL) at 0-5° C., was added DCC (62 mg, 0.38 mmol). The mixture was allowed to warm to RT and was stirred for 2 h. The solvent was removed with a rotary evaporator, and the residue was subjected to column chromatography on silica gel with 5-8% MeOH in DCM, and gave 18 mg of pure 2′,3′-carbonyl-5′-(S)—C-methyladenosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate. Re-purification of the impure fractions on silica gel with 5-10% isopropanol in DCM gave 61 mg of 2′,3′-carbonate-5′-(S)—C-methyladenosine-5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (A23) as white foam. (total amount=79 mg, 74%); ¹H NMR (DMSO-d₆, two isomers) δ 1.01-1.16 (m, 10H), 1.26, 1.42 (2d, J=6.4 Hz, 2H), 3.76-3.83 (m, 1H), 4.41-4.46 (m, 1H), 4.72-4.86 (m, 1H), 5.46, 5.24 (2×dd, J=8.8, 14.0 Hz, 1H), 5.77-5.87 (m, 1H), 5.92, 6.08 (2×dd, J=3.2, 10.0 Hz, 1H), 6.45, 6.47 (2×d, J=3.6 Hz, 1H), 7.35 (br s, 2H), 7.38-7.70 (m, 7H), 7.85-7.95 (m, 2H), 8.11, 8.22 (2s, 1H), 8.24, 8.26 (2s, 1H); ³¹P NMR (DMSO-d₆, two isomers) δ 3.05 (s), 3.93 (s). MS m/z 627.3 (MH⁺).

Example 36

Preparation of 5′(S)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B1)

To a solution of 2′,3′-O-methoxymethylidene-N⁶-(4-methoxytrityl)-5′(5)-methylguanosine (P11) (79 mg, 0.13 mmol) in THF (1.3 mL) under argon was added dropwise 1.0 M tert-BuMgBr in THF (0.52 mL). The resulting solution was stirred at RT for 30 min and phenyl(methoxy-L-alaninyl) phosphorochloridate (1.0 M in THF, 0.65 mL) was added. The reaction mixture was stirred at RT for 3 days. The mixture was then cooled with ice, quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with aqueous ammonium three times, dried over sodium sulfate, and concentrated. Chromatography on silica gel with 5-7% MeOH in DCM gave a mixture of four isomers. The mixture was dissolved in 80% formic acid (9 mL), and the resulting solution stood at RT overnight. Solvent was evaporated at RT and co-evaporated with MeOH/toluene three times. Purification on reverse-phase HPLC (C18) using 1% formic acid in acetonitrile and water, followed by lyophilization, gave 5′(S)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B1) (9.9 mg of major isomer and 2.2 mg of minor isomer) as white solid; ¹H NMR (CD₃OD, major isomer) δ 1.17 (dd, J=7.2, 1.2 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H), 3.58 (s, 3H), 3.81-3.89 (m, 1H), 3.93 (m, 1H), 4.24 (dd, J=5.2, 4.0 Hz, 1H), 4.33 (t, J=5.2 Hz, 1H), 4.70-4.78 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 7.03-7.10 (m, 3H), 7.19-7.23 (m, 2H), 7.78 (s, 1H); ³¹P NMR (CD₃OD, major isomer) δ 3.09 (s). MS m/z 539.3 (MH⁺).

Example 37

Preparation of 5′(R)—C-methylguanosine 5′-[phenylmethoxy-L-alaninyl)]phosphate (B2)

Following the general procedure for 5′(S)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B1), 20.1 mg of 5′(R)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B2) was obtained as white solid from 120 mg (0.2 mmol) of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(R)-methylguanosine (P12). ¹H NMR (CD₃OD, two isomers) δ 1.12, 1.20 (2dd, J=6.4, 1.2/0.8 Hz, 3H), 1.34 (d, J=6.4 Hz, 3H), 3.53, 3.57 (2s, 3H), 3.73-3.89 (m, 2H), 4.32, 4.46 (2dd, J=5.6, 3.2/4.0 Hz, 1H), 4.62, 4.63 (2t, J=6.0/5.6 Hz, 1H), 4.78-4.87 (m, 1H), 5.69, 5.73 (2d, J=6.0/5.6 Hz, 1H), 7.05-7.15 (m, 3H), 7.22-7.29 (m, 2H), 7.78 (2s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 2.93 (s), 3.23 (s). MS m/z 539.0 (MH⁺).

Example 38

Preparation of 5′(R)—C-methylguanosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (B3)

Following the general procedure for 5′(S)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B1), 11 mg (two isomers) of 5′ (R)—C-methylguanosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (B3) was obtained as white solid from 73 mg (0.12 mmol) of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(R)—C-methylguanosine (P12) and 1-naphthyl(isopropoxy-L-alaninyl) phosphorochloridate. ¹H NMR (CD₃OD, two isomers) δ 1.12-1.20 (m, 6H), 1.22, 1.26 (2dd, J=7.2, 1.2 Hz, 3H), 1.35, 1.46 (2d, J=6.8/6.4 Hz, 3H), 3.89-3.99 (m, 2H), 4.41, 4.51 (2dd, J=5.6, 3.2 Hz, 1H), 4.63, 4.71 (2t, J=6.0 Hz, 1H), 4.87-5.02 (m, 2H), 5.77, 5.79 (2d, J=6.0 Hz, 1H), 7.35-7.54 (m, 4H), 7.67, 7.05 (2d, J=8.0 Hz, 1H), 7.83-7.89 (m, 1H); 7.85 (s, 1H), 8.09-8.16 (m, 1H); ³¹P NMR (CD₃OD, two isomers) δ 3.32 (s), 3.58 (s). MS m/z 746.6 (MH⁺+6-methyl-2-heptylamine).

Example 39

Preparation of 5′(S)—C-methylguanosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (B4)

Following the general procedure for 5′(S)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B1), 8.5 mg (two separated P-isomers) of 5′(S)—C-methylguanosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (B4) was obtained as white solid from 73 mg (0.12 mmol) of 2′,3′-O-methoxymethylidene-N²-(4-methoxytrityl)-5′(S)—C-methylguanosine (P11) and 1-naphthyl(isopropoxy-L-alaninyl) phosphorochloridate. ¹H NMR (CD₃OD, isomer I) δ 1.09, 1.11 (2d, J=6.4 Hz, 6H), 1.21 (dd, J=7.2, 0.8 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H), 3.86-3.95 (m, 1H), 3.98 (m, 1H), 4.42-4.50 (m, 2H), 4.79-4.89 (m, 2H), 5.85 (d, J=4.8 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.45-7.56 (m, 3H), 7.69 (d, J=8.0 Hz, 1H), 7.85-7.89 (m, 1H); 7.89 (s, 1H), 8.12-8.17 (m, 1H); ³¹P NMR (CD₃OD, isomer I) δ 3.62 (s). MS m/z 746.5 (MH⁺+6-methyl-2-heptylamine). ¹H NMR (CD₃OD, isomer II) δ 1.13, 1.15 (2d, J=6.4 Hz, 6H), 1.23 (dd, J=7.2, 1.2 Hz, 3H), 1.55 (d, J=6.4 Hz, 3H), 3.89-3.98 (m, 1H), 4.00 (m, 1H), 4.22 (t, J=5.6 Hz, 1H), 4.29 (dd, J=5.6, 4.0 Hz, 1H), 4.85-4.96 (m, 2H), 5.77 (d, J=5.6 Hz, 1H), 7.27-7.51 (m, 4H), 7.63 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.81-7.84 (m, 1H); 8.04-8.08 (m, 1H); ³¹P NMR (CD₃OD, isomer II) δ 3.46 (s). MS m/z 746.5 (MH⁺+6-methyl-2-heptylamine).

Example 40

Preparation of 5′(S)—C-methylinosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (B5)

Following the general procedure for 5′(S)—C-methylguanosine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (B1), 44.4 mg (two separated P-isomers) of 5′(S)—C-methylinosine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (B5) was obtained as white solid from 45.5 mg (0.14 mmol) of 2′,3′-O-methoxymethylidene-5′(S)—C-methylinosine (P13) and 1-naphthyl(isopropoxy-L-alaninyl) phosphorochloridate. ¹H NMR (CD₃OD, P-isomer I) δ 1.13, 1.14 (2d, J=6.0 Hz, 6H), 1.22 (dd, J=7.2, 1.2 Hz, 3H), 1.56 (d, J=6.4 Hz, 3H), 3.88-3.96 (m, 1H), 4.04 (dt, J=4.0, 1.2 Hz, 1H), 4.32 (dd, J=5.6, 4.0 Hz, 1H), 4.36 (t, 5.6 Hz, 1H), 4.87 9q, J=6.0 Hz, 1H), 4.90-4.98 (m, 1H), 5.95 (d, J=4.8 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.42-7.51 (m, 3H), 7.63 (d, J=8.0 Hz, 1H), 7.80-7.84 (m, 1H); 7.92 (s, 1H), 8.03-8.05 (m, 1H), 8.06 (s, 1H); ³¹P NMR (CD₃OD, isomer I) δ 3.38 (s). MS m/z 731.5 (MH⁺+6-methyl-2-heptylamine). ¹H NMR (CD₃OD, P-isomer II) δ 1.09, 1.11 (2d, J=6.4 Hz, 6H), 1.21 (dd, J=7.2, 0.8 Hz, 3H), 1.40 (d, J=6.4 Hz, 3H), 3.85-3.93 (m, 1H), 4.03 (dt, J=4.4, 1.2 Hz, 1H), 4.45 (t, J=5.2 Hz, 1H), 4.57 (t, 5.2 Hz, 1H), 4.79-4.90 (m, 2H), 6.03 (d, J=5.2 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.46-7.55 (m, 3H), 7.69 (dd, J=8.0, 0.8 Hz, 1H), 7.85-7.89 (m, 1H); 8.02 (s, 1H), 8.11-8.16 (m, 1H), 8.24 (s, 1H); ³¹P NMR (CD₃OD, isomer II) δ 3.55 (s). MS m/z 731.4 (MH⁺+6-methyl-2-heptylamine).

Example 41

Preparation of 2′-deoxy-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C1)

To a solution of 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine (P8) (75 mg, 0.09 mmol) in THF (1 mL) under argon was added dropwise 1.0 M tert-BuMgBr in THF (0.45 mL). The resulting solution was stirred at RT for 30 min and phenyl(methoxy-L-alaninyl) phosphorochloridate (1.0 M in THF, 0.50 mL) was added. The reaction mixture was stirred at RT for 5 days. The mixture was then cooled with ice, quenched with aqueous NH₄Cl, diluted with ethyl acetate, washed with aqueous ammonium three times, dried over sodium sulfate, and concentrated. Chromatography on silica gel with EtOAc/hexanes (2:1 to 9:1) gave 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (18 mg of P-isomer 1 and 48 mg of P-isomer II). The P-isomer II was dissolved in 80% formic acid (3 mL), and the resulting solution stood at RT overnight and then 40° C. for 2 h. Solvent was evaporated and co-evaporated with MeOH/toluene three times. Purification on reverse-phase HPLC (C18) using 1% formic acid in acetonitrile and water, followed by lyophilization, gave 10.2 mg of 2′-deoxy-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C1) as white solid; ¹H NMR (DMSO-d₆, P-isomer II) δ 1.19 (d, J=22.4 Hz, 3H), 1.25 (d, J=7.2 Hz, 3H), 1.38 (d, J=6.4 Hz, 3H), 3.55 (s, 3H), 3.75-3.96 (m, 3H), 4.69 (m, 1H), 5.74 (d, J=7.6 Hz, 1H), 5.95 (s, br, 1H), 6.14 (d, br, J=20 Hz, 1H), 7.16-7.24 (m, 4H), 7.32 (s, br, 1H), 7.36-7.41 (m, 2H), 7.53 (d, J=7.6 Hz, 1H); ³¹P NMR (DMSO-d₆, major isomer) δ 3.63 (s). MS m/z 644.3 (MH⁺+6-methyl-2-heptylamine).

Example 42

Preparation of 5′(S)—C-methylcytidine-[naphthyl(isopropoxy-L-alaninyl)]phosphate (C2)

5′-(S)—C-Methylcytidine-[naphthyl(isopropoxy-L-alaninyl)]phosphate (C2) (20 mg) were prepared from 57 mg of 5′-C—(S)-methyl-2′,3′-O-methoxymethylene-N⁴-methoxytrityl)cytidine (P4) using procedure for synthesis of compound B1. ¹H NMR (CD₃OD, two P-isomers) δ8.38 (2H, bs); 8.10-8.04 (1H, m), 7.82-7.78 (1H, m), 7.63-7.58 (2H, m), 7.47-7.26 (5H, m), 5.78-5.74 (1H, two d), 5.71-5.56 (1H, two d), 5.05-4.95 (2H, m), 4.06-3.85 (6H, m), 1.49-1.34 (3H, two d), 1.22-1.18 (4H, m), 1.09-1.04 (6H, m). ³¹P NMR (CD₃OD, two isomers): δ 3.70 (s), 3.43 (s) MS: m/z 706.4 (M+H+129).

Example 43

Preparation of 2′-deoxy-2′-β,5′(R)—C-dimethyl-2′-α-fluorocytidine 5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (C3)

Following the general procedure for 2′-deoxy-2′-β-C-,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate, 41 mg (two P-isomers) of 2′-deoxy-2′-β,5′(R)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C3) was obtained as white solid from 122 mg (0.15 mmol) of 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine (P9) and 1-naphthyl(methoxy-L-alaninyl) phosphorochloridate. ¹H NMR (CD₃OD, two P-isomers)δ 1.14, 1.17 (2d, J=6.0 Hz, 6H), 1.20 (d, J=22.4 Hz, 3H), 1.24, 1.30 (2dd, J=7.6, 1.2 Hz, 3H), 1.58 (d, J=6.8 Hz, 1H), 3.88-4.16 (m, 3H), 4.87-4.97 (m, 1H), 5.05-5.17 (m, 1H), 5.55, 5.73 (2d, J=7.6 Hz, 1H), 6.20 (d, br, J=20.4 Hz, 1H), 7.24, 7.43 (2t, J=8.0 Hz, 1H), 7.49-7.56 (m, 3H), 7.61, 7.75 (2d, J=7.6 Hz, 1H), 7.69-7.4 (m, 1H), 7.85-7.91 (m, 1H), 8.16-8.21 (m, 1H); ³¹P NMR (CD₃OD) δ 3.21 (s), 3.38 (s). MS m/z 722.3 (MH⁺+6-methyl-2-heptylamine).

Example 44

Preparation of 2′-deoxy-2′,2′-difluoro-5′(S)—C-methylcytidine 5′-[phenylmethoxy-L-alaninyl)]phosphate (C5)

2′-Deoxy-2′,2′-difluoro-5′(S)—C-methylcytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C5) (5 mg) was prepared from 82 mg of 2′-deoxy-2′,2′-difluoro-3′-O,N⁴-di(4-methoxytrityl)-5′(S)—C-methylcytidine (C4) using procedure described for synthesis of 2′-deoxy-2′-β,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate. ¹H NMR (CD₃OD, two P-isomers): δ 67.53-7.51 (1H, two d); 7.47-7.10 (5H, m); 6.15-6.08 (1H, m); 5.85-5.79 (1H, two d); 4.20-3.72 (3H, m); 3.60-3.58 (3H, two s), 1.48-1.21 (6H, m). ³¹P NMR (CD₃OD, two isomers): δ 63.08 (bs). MS m/z 517.5 (M−1).

Example 45

Preparation of 5′(S)—C-methylcytidine 5′-[phenylmethoxy-L-alaninyl)]phosphate (C6)

5′(S)—C-Methylcytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C6) (12 mg) was prepared from 86 mg of 5′-C—(S)-methyl-2′,3′-O-methoxymethylene-N⁴-(4-methoxytrityl)cytidine using procedure for synthesis of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate. ¹H NMR (CD₃OD, two isomers): δ 7.71-7.68 (1H, t); 7.29-7.06 (5H, m); 5.81-5.74 (2H, m); 4.72-3.62 (1H, m); 4.04-3.82 (4H, m); 3.60-3.58 (3H, two s), 1.46-1.19 (6H, m). ³¹P NMR (CD₃OD, two isomers): δ 3.15, 2.96 (1:1) MS: m/z 628.4 (MH⁺+2-methylheptylamine).

Example 46

Preparation of 5′(R)—C-methylcytidine 5′-[phenylmethoxy-L-alaninyl)]phosphate (C7)

5′(R)—C-Methylcytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C7) (6.7 mg) was prepared from 57 mg of 5′-C—(R)-methyl-2′,3′-O-methoxymethylidene-N⁴-methoxytrityl)cytidine (P5) using procedure for synthesis of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate. ¹H NMR (CD₃OD, two isomers): δ 7.82, 7.61 (0.8H, two bs); 7.49-7.41 (1H, d); 7.02-6.81 (5H, m); 5.55-5.54 (1H, d); 5.45-5.43 (1H, d); 4.72-3.62 (1H, m); 3.88-3.85 (1H, m); 3.62-3.58 (3H, m), 3.30-3.29 (3H, s); 1.12-1.11 (3H, two s), 0.97-0.96 (3H, two s). ³¹P NMR (CD₃OD, two isomers): δ 2.86 MS: m/z 497.3 (M−H).

Example 47

Preparation of 5′(S)—C-methylcytidine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (C8)

5′(S)—C-Methylcytidine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (C8) (6.4 mg) was prepared from 57 mg of 5′-C—(S)-methyl-2′,3′-O-methoxymethylidene-N⁴-(4-methoxytrityl)cytidine (P4) using procedure for synthesis of 5′(S)—C-methyladenosine 5′-[1-naphthyl(cyclohexoxy-L-alaninyl)]phosphate. ¹H NMR (CD₃OD, two P-isomers): δ 7.79-7.78 (1H, d); 7.53-7.14 (5H, m); 5.93-5.88 (2H, m); 5.00-4.80 (1H, m); 4.25-3.85 (4H, m); 1.53-1.44 (3H, two d); 1.32-1.05 (7H, m). ³¹P NMR (CD₃OD, two isomers): δ 3.32, 2.97 (1:1) MS: m/z 656.4 (M+H+129).

Example 48

Preparation of 2′-deoxy-2′-C-β-fluoro-5′(R/S)—C-methylcytidine-5′-[phenyl-(methoxy-L-alaninyl)]phosphate (C9)

According to the procedure described for Example 41, 20.7 mg of 2′-deoxy-2′-C-β-fluoro-5′(R/S)—C-methylcytidine-5′-[phenyl-(methoxy-L-alaninyl)]phosphate (C9) was synthesized from 80.0 mg (0.1 mmol) of 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-C-β-fluoro-5′-(R/S)—C-methylcytidine. ¹H NMR (CD₃OD, four isomers) δ 1.21, 1.24, 1.27 (3d, J=7.2, 6.8, 7.2 Hz, 3H), 1.31, 1.39, 1.44 (4d, J=6.4, 6.4, 6.8, 6.4 Hz, 3H), 3.55, 3.58 (2s, 3H), 3.75-3.78 (m, 1H), 3.86-3.91 (m, 1H), 4.19-4.26 (m, 1H), 4.61-4.66 (m, 1H), 4.83, 4.97 (2dd, 1H), 5.67, 5.79 (2d, 1H), 7.09-7.17 (m, 3H), 7.18-7.28 (m, 2H), 7.74 (dd, J=7.6 Hz 1H); ¹⁹F NMR (CD₃OD) δ −200.56 to −200.85 (m); ³¹P NMR (CD₃OD, 4 isomer) δ 2.59 (s), 2.78 (s), 2.9 (s), 2.99 (s); MS m/z 499.4 (MH⁺).

Example 49

Preparation of 2′-deoxy-2′-C-β-methyl-5′(R/S)—C-methylcytidine 5′-[1-naphthyl (isopropoxy-L-alaninyl)]phosphate (C10)

Step 1. Preparation of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-3′-O-(4-methoxytrityl)-2′-β,5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C12)

To a solution of 2′-deoxy-2′-β,5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C11) (390 mg, 0.74 mmol) in DMF (10 mL), were added imidazole (251 mg, 3.7 mmol), TBSCl (334 mg, 2.21 mmol), DMAP (180 mg, 1.47 mmol) successively. The reaction mixture was at stirred at 65° C. under N₂ for overnight. The reaction was monitored to completion by TLC. The reaction mixture was then cooled, diluted with EA, washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/MeOH; 95:5) to give 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′-β,5′ (R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C12) (416 g, 88%) as a white solid.

Step 2. Preparation of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′-β,5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)cytidine (C13)

To a solution of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′-β,5′ (R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C12) (160 mg, 0.25 mmol) in anhydrous CH₃CN (3.0 mL), TEA (0.11 mL, 0.75 mmol), N-methylpiperidine (50 μL, 0.5 mmol) and TsCl (143 mg, 0.75 mmol) were added successively. The resulting mixture was stirred at RT for 2 h. After cooling the reaction to 0° C., 29% NH₄OH (2.5 mL) was then added. The resulting mixture was stirred for 2 h at RT and evaporated. The residue was purified by silica gel column chromatography (DCM/MeOH; 95:5-93:7) to give 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′-β,5′ (R/S)—C-dimethyl-3′-O-(4-methoxytrityl)cytidine (C13) (131 mg, 82%) as a white solid.

Step 3. Preparation of 2′-deoxy-3′-O,N4-di(4-methoxytrityl)-2′-β,5′(R/S)—C-dimethylcytidine (C15)

MMTrCl (452 mg, 1.47 mmol) was added to a solution of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′-β,5′ (R/S)—C-dimethyl-3′-O-(4-methoxytrityl)cytidine (C13) (378 mg, 0.49 mmol) in anhydrous DCM (6 mL). AgNO₃ (250.0 mg, 1.47 mmol) and collidine (178 mg, 1.47 mmol) were added. The reaction mixture was stirred at RT overnight under N₂. The reaction was monitored by TLC. The reaction mixture was filtered. The mixture was then washed with saturated NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel DCM/MeOH; 95:5) to give 5′-O-(t-butyldimethylsilyl)-2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(R/S)—C-dimethylcytidine (C14) (527 mg).

TBAF (tetra-n-butylammonium fluoride) (1.0M solution in THF) (1.1 ml, 1.1 mmol) was added to a solution of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-3′-O,N⁴-di-(4-methoxytrityl)-2′-C-(β)-methyl-5′(R/S)—C-methylcytidine (500 mg, 0.55 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at RT overnight, and the reaction was monitored by TLC. EA was added to the reaction mixture. The mixture was then washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/MeOH=95:5) to give 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′(R/S)—C-dimethylcytidine (C15) (414 mg, 94%).

Step 4. Preparation of 2′-deoxy-2′-C-β-methyl-5′(R/S)—C-methylcytidine-5-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (C10)

According to the procedure described for Example 41, 13.3 mg of 2′-deoxy-2′-C-β-methyl-5′ (R/S)—C-methylcytidine-5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (C10) was synthesized from 111 mg (0.14 mmol) of 2′-deoxy-3′-O,N⁴-di(4-methoxytrityl)-2′-β,5′ (R/S)—C-dimethylcytidine (C15). ¹H NMR (CD₃OD, two isomers) δ0.83 (d, J=7.2 Hz, 3H), 1.13-1.15 & 1-16-1.19 (2m, 6H), 1.31 (d, J=6.8 Hz, 3H), 1.44, 1.57 (2d, J=each 6.4 Hz, 3H), 2.50-2.56 (m, 1H), 3.67-3.7 (m, 1H), 3.78 (t, J=6.4 Hz, 1H), 3.96 (dd, J=6.8, 9.6 Hz, 1H), 4.85-4.88 (m, 1H), 5.77, 6.2 (d, J=7.2, 7.6 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.51-7.54 (m, 4H), 7.66 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.88-7.90 (m, 1H), 8.16-8.18 (m, 1H); ³¹P NMR (CD₃OD, major isomer) δ 3.49 (s); MS m/z 704.5 (MH⁺+2-methylheptylamine).

Example 50

Preparation of 2′O,5′(R)—C-dimethylcytidine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (C16)

Step 1. Preparation of 5′-O-(t-butyldimethylsilyl)-2′-O,5′(R)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C18)

To a solution of compound C17 (140 mg, 0.26 mmol in DMF (2.5 mL), imidazole (87 mg, 1.28 mmol), TBSCl (194 mg, 1.28 mmol), DMAP (4-dimethylaminopyridine) (156 mg, 1.28 mmol) were added successively. The reaction mixture was at stirred at 80° C. under N₂ for overnight. TLC showed the reaction was complete. The reaction mixture was cooled, and diluted with EA, washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/MeOH; 95:5) to give 5′-O-(t-butyldimethylsilyl)-2′-O,5′(R)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C18) (101 mg, 59%) as a white solid.

Step 2. Preparation of 5′-O-(t-butyldimethylsilyl)-2′-O,5′(R)—C-dimethyl-3′-O-(4-methoxytrityl)cytidine (C19)

To a solution of compound C18 (160 mg, 0.24 mmol) in anhydrous CH₃CN (2.0 mL), TEA (0.105 mL, 0.72 mmol), N-methylpiperidine (49 μL, 0.48 mmol), TsCl (139 mg, 0.72 mmol) were added successively. The resulting mixture was stirred at RT for 2 h. After cooling the reaction to 0° C., 29% NH₄OH (1.5 mL) was then added. The resulting mixture was stirred for 2 h at RT and evaporated. The residue was purified by silica gel column chromatography (DCM/MeOH; 95:5-93:7) to give 5′-O-(t-butyldimethylsilyl)-2′-O,5′(R)—C-dimethyl-3′-O-(4-methoxytrityl)cytidine (C19) (131 mg, 82%) as a white solid.

Step 3. Preparation of 3′-O,N4-di(4-methoxytrityl)-2′-O,5′(R)—C-dimethylcytidine (C21)

MMTrCl (184 mg, 0.6 mmol) was added to a solution of compound C19 (131 mg, 0.2 mmol) in anhydrous DCM (4 mL). AgNO₃ (102 mg, 0.6 mmol) and collidine (73 μL, 0.6 mmol) were added. The reaction mixture was stirred at RT overnight under N₂. The reaction was monitored by TLC. The reaction mixture was filtered and washed with saturated NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel DCM/MeOH; 95:5) to give 5′-O-(t-butyldimethylsilyl)-3′-O,N⁴-di(4-methoxytrityl)-2′-O,5′(R)—C-dimethylcytidine (C20) (180 mg, 97%).

TBAF (1.0M solution in THF) (0.6 ml, 0.6 mmol) was added to a solution of compound C20 (180 mg, 0.19 mmol) in anhydrous THF (2 mL) and stirred at RT overnight. TLC showed the reaction was complete. EA was added to the reaction mixture and washed with water, followed by brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the residue which was purified by silica gel (DCM/MeOH=95:5) to give 3′-O,N⁴-di(4-methoxytrityl)-2′-O,5′(R)—C-dimethylcytidine (C21) (100.4 mg, 65%).

Step 4. Preparation of 2′-O,5′(R)—C-dimethylcytidine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (C16)

According to the procedure described for Example 41, 4.7 mg of 2′-O,5′(R)—C-dimethylcytidine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (C16) was prepared from 100 mg (0.12 mmol) of 3′-O, N⁴-di(4-methoxytrityl)-2′-O,5′(R)—C-dimethylcytidine (C21). ¹H NMR (CD₃OD, two isomers) δ 1.18-1.37 (m, 9H), 1.47 (d, J=6.8 Hz, 3H), 3.46, 3.49 (2s, 3H), 3.71-3.94 (m, 3H), 4.28, 4.37 (each t, J=5.6, 6.0 Hz, 1H), 4.91-4.96 (m, 1H), 5.78-5.91 (m, 1H), 5.95, 5.98 (2d, J=4.4, 4.4 Hz, 1H), 7.16-7.26 (m, 3H), 7.33-7.37 (m, 2H), 7.53, 7.79 (2d, J=7.2, 7.6 Hz, 1H); ³¹P NMR (CD₃OD, two isomer) δ 2.95 (s), 3.11 (s). MS m/z 670.5 (MH⁺+diisopropylethylamine).

Example 51

Preparation of 5′(R)—C-methylarabinocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C22)

According to the procedure described for Example 41, 5.8 mg of 5′ (R)—C-methylarabinocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (C22) was prepared from 100 mg (0.09 mmol) of 5′(R)—C-methyl-2′,3′-O,N⁴-tri(4-methoxytrityl)arabinocytidine (P10). ¹H NMR (CD₃OD, two isomers) δ 1.28, 1.33 (2d, J=each 7.2 Hz, 3H), 1.43, 1.47 (2d, J=6.4, 6.8 Hz, 3H), 3.65, 3.66 (2s, 3H), 3.74-3.77 (m, 1H), 3.92-3.97 (m, 1H), 4.13-4.18 (m, 1H), 4.28-4.29 (m, 1H), 5.77, 5.82 (2d, J=7.6, 7.2 Hz, 1H), 6.15, 6.17 (2d, J=3.6, 4.0 Hz, 1H), 7.16-7.25 (m, 3H), 7.32-7.37 (m, 2H), 7.71 (d, J=7.6 Hz, 1H); ³¹P NMR (CD₃OD, major isomer) δ 2.38 (s), 2.65 (s). MS m/z 497.3 (MH⁺).

Example 52

Preparation of 5′(R)—C-methylarabinouridine 5′-[phenylmethoxy-L-alaninyl)]phosphate (D1)

Following the general procedure for 2′-deoxy-2′-β-C-,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate, 24.7 mg (two isomers) of 5′(R)—C-methylarabinouridine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (D1) was obtained as white solid from 160 mg (0.2 mmol) of 2′,3′-O-di(4-methoxytrityl)-5′(R)—C-methylarabinouridine (P6). ¹H NMR (DMSO-d₆, major isomer) δ 1.22 (d, J=6.8, Hz, 3H), 1.28 (d, J=6.0 Hz, 3H), 3.6 (s, 3H), 3.66 (dd, J=7.2, 3.2 Hz, 1H), 3.81-3.94 (m, 2H), 3.97-4.01 (m, 1H), 4.61-4.70 (m, 1H), 5.40 (d, J=8.0 Hz, 1H), 5.58 (d, J=4.8 Hz, 1H, OH), 5.66 (d, J=4.4 Hz, 1H, OH), 5.85 (dd, J=12.4, 10.0 Hz, 1H, NH), 7.15-7.23 (m, 3H), 7.35-7.40 (m, 2H), 7.3 (d, J=8.0 Hz, 1H); ³¹P NMR (DMSO-d₆, major isomer) δ 3.54 (s). MS m/z 629.4 (MH⁺+6-methyl-2-heptylamine).

Example 53

Preparation of 5′(S)—C-methylarabinouridine 5′-[phenylmethoxy-L-alaninyl)]phosphate (D2)

Following the general procedure for 2′-deoxy-2′-β-C-,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate, 3.1 mg (two isomers) of 5′ (S)—C-methylarabinouridine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (D2) was obtained as white solid from 160 mg (0.2 mmol) of 2′,3′-O-di(4-methoxytrityl)-5′(S)—C-methylarabinouridine (P7). ¹H NMR (CD₃OD, two isomers) δ 1.29, 1.31 (2dd, J=7.2, 1.2/0.8 Hz, 3H), 1.45, 1.49 (2d, J=6.4/6.0 Hz, 3H), 3.65, 3.66 (2s, 3H), 3.73-3.78 (m, 1H), 4.12, 4.17 (2dd, J=4.0, 2.0 Hz, 1H), 4.26, 4.30 (2dd, J=3.6/4.0, 2.4 Hz, 1H), 4.78-4.90 (m, 1H), 5.57, 6.20 (2d, J=8.0 Hz, 1H), 6.12, 6.14 (2d, J=4.0/4.4 Hz, 1H), 7.16-7.26 (m, 3H), 7.33-7.38 (m, 2H), 7.69, 7.70 (2d, J=8.0 Hz, 1H); ³¹P NMR (CD₃OD, two isomers) δ 2.41 (s), 2.62 (s). MS m/z 629.4 (MH⁺+6-methyl-2-heptylamine).

Example 54

Preparation of 5′(S)—C-methyluridine 5′-[1-phenylmethoxy-L-alaninyl)]phosphate (D3)

To a solution of 2′,3′-O-methoxymethylidene-5′(S)-methyluridine (P6) (106.2 mg) in 2 mL THF under argon at 0° C. was added t-BuMgCl (0.88 mL, 1 M in THF) dropwise over 5 min. After 15 min, a solution of phenyl(methoxy-L-alaninyl) phosphorochloridate (1.0 mL, 1.0 M in THF) was added. The reaction was allowed to warm to ambient temperature and was stirred for 2 days. After cooling to 0° C., the reaction was quenched with saturated NH₄Cl, and the desired product extracted with ethyl acetate. The solvents were removed, and the resultant intermediate taken up in 80% aqueous formic acid and warmed briefly to 60° C. The solvent was evaporated. The residue was co-evaporated with MeOH/toluene three times. The resultant material was subjected to silica gel chromatography, eluting with a gradient of 3% to 10% methanol in methylene chloride. 40 mg of 5′(S)—C-methyluridine 5′-[1-phenyl(methyl-L-alaninyl)]phosphate (D3) was obtained. ³¹P NMR (CDCl₃, two isomers) δ 2.30 (s), 2.52 (s). MS m/z 498.3 (M−1)⁻.

Example 55

Preparation of 2′-deoxy-2′,2′-difluoro-5′(S)—C-methyluridine 5′-[phenylmethoxy-L-alaninyl)]phosphate (D4)

2′-Deoxy-2′,2′-difluoro-5′(S)—C-methyluridine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (D4) (7.5 mg) was prepared from 55 mg of 2′-deoxy-2′,2′-difluoro-3′-(4-O-methoxytrityl)-5′(S)—C-methyluridine using procedure for synthesis of 2′-deoxy-2′-β-C-,5′(S)—C-dimethyl-2′-α-fluorocytidine 5′-[phenyl(methoxy-L-alaninyl)]phosphate described above. ³¹P NMR (CD₃OD, two isomers): δ 3.09, 3.08 (1:1). ¹H NMR (CD₃OD, two isomers): δ 7.57-7.48 (1H, two d); 7.32-7.26 (2H, m); 7.19-7.11 (3H, m); 6.08-6.03 (1H, m); 5.68-5.63 (1H, two d); 4.25-4.15 (1H, m); 3.98-3.86 (1H, m); 3.82-3.80 (1H, m); 3.60-3.58 (3H, two s), 1.54-1.38 (3H, two d), 1.30-1.20 (3H, m). MS: m/z 518.4 (M−1).

Example 56

Preparation of 2′-deoxy-2′-C-β-5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine 5′-[phenylmethoxy-L-alaninyl)]phosphate (D7)

Step 1. Preparation of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-3′-O-(4-methoxytrity)-2′-C-β-methyluridine (D8)

TBSCl (1.39 g, 8.84 mmol) was added to a solution of 2′-deoxy-2′-(β/α˜9:1)—C-methyluridine (D8) (prepared according to a published procedure: Journal of Organic Chemistry, 2003, 68, 6799) (1.78 g, 7.37 mmol) in anhydrous pyridine (30 mL) at 0° C. under N₂. The reaction mixture was stirred at RT overnight, and the progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure. The residue was diluted with EA, washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/MeOH; 95:5) to give 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′-C-(β/α˜9:1)-methyluridine (1.6 g, 60%) as a white solid.

MMTrCl (407 mg, 1.32 mmol) was added to a solution of (314 mg, 0.88 mmol) 5′-O-(t-butyldimethylsilyl)-2′-deoxy-2′(β/α)-C-methyluridine in anhydrous DCM (4 mL). AgNO₃ (225.0 mg, 1.32 mmol) and collidine (0.21 ml, 1.76 mmol) were added. The reaction mixture was stirred at RT overnight under N₂. TLC showed the reaction was complete. The reaction mixture was filtered and washed with saturated NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel DCM/MeOH; 95:5) to give 5′-O-(t-butyldimethylsilyl)-2′-deoxy-3′-O-(4-methoxytrity)-2′-C-β/α(9:1)-methyluridine (D9) (542 mg, 98%).

Step 2. Preparation of 2′-deoxy-3′-O-4-methoxytrity-2′-C-(β)-methyluridine (D10)

TEA-3HF (0.28 ml, 1.72 mmol)/TEA (0.25 ml, 1.72 mmol) was added dropwise to a solution of 5′-O-(t-butyldimethylsilyl)-2′-deoxy-3′-O-(4-methoxytrity)-2′-C-β/α-methyluridine (D9) (542 mg, 0.86 mmol) in anhydrous THF (13 mL). The reaction mixture was stirred at RT overnight. The reaction was monitored by TLC. The reaction was showed to be incomplete by TLF. TEA.3HF (0.54 ml, 3.3 mmol) and TEA (0.6 ml, 4.15 mmol) were added until the reaction was showed to be complete by TLC. The solvent was removed in vacuo at RT. DCM was added. The residue and washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (Hexanes/EA=1:9) to give 2′-deoxy-3′-O-(4-methoxytrity)-2′-C-β-methyluridine (D10) (347 mg, 78%).

Step 3. Preparation of 2′-deoxy-5-C,5′-O-didehydro-3′-O-(4-methoxytrityl)-2′-C-β-methyl-uridine (D11)

Pyridine (0.68 mL, 8.55 mmol) and Dess-Martin (324 mg, 0.76 mmol) were added to a solution of 2′-deoxy-3′-O-4-(methoxytrity)-2′-C-β-methyluridine (D10) (295 mg, 0.57 mmol) in anhydrous CH₂Cl₂ (7 mL) at 0° C. under N₂. The reaction mixture was stirred at RT for 4 h. The reaction was monitored by TLC. The reaction mixture was diluted with EA. The organic layer was washed with 10% Na₂S₂O₃ twice, followed by water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/EA=1/1) to give 2′-deoxy-5-C,5′-O-didehydro-3′-O-(4-methoxytrityl)-2′-C-β-methyl-uridine (D11) (273 mg, 94%).

Step 4. Preparation of 2′-deoxy-2′-C-β-5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C11)

MeMgBr (1.52 mL, 2.13 mmol) was added dropwise to a solution of 2′-deoxy-5-C,5′-O-didehydro-3′-O-(4-methoxytrityl)-2′-C-β-methyl-uridine (D11) (273 mg, 0.53 mmol) in anhydrous THF (10 mL). The reaction mixture was cooled by an ice-EtOH bath under N₂. The reaction mixture was stirred at RT for 6 h. The reaction was monitored by TLC. The reaction mixture was quenched with saturated NH₄Cl. EA was added, and the organic layer was washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (hexanes/EA=1/1 to 1/1) to give 2′-deoxy-2′-C-β-5′ (R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine (C11) (116 mg, 41%).

Step 5. Preparation of 2′-deoxy-2′-C-β-5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (D 7)

According to the procedure described for Example 41, 22.1 mg of 2′-deoxy-2′-C-β-5′(R/S)—C-dimethyl-3′-O-(4-methoxytrityl)uridine 5′-[phenyl(methoxy-L-alaninyl)]phosphate (D7) was prepared from 60.0 mg (0.11 mmol) of 2′-deoxy-3′-O-(4-methoxytrityl)-2′-C-(β)-methyl-5′(R/S)—C-methyluridine (C11). ¹H NMR (DMSO-d₆) 0.75, 0.82 (2d, each J=7.2 Hz, 3H), 1.19, 1.24 (2d, each J=7.2 Hz, 3H), 1.35, 1.39, 1.44 (3d, J=6.4, 6.8, 6.4 Hz, 3H), 2.43-2.47 (m, 1H), 3.54, 3.56 (2s, 3H), 3.59 (m, 1H), 3.75-3.81 (m, 1H), 3.86-3.90 (m, 1H), 4.67-4.72 (m, 1H), 5.44 (d, J=5.6 Hz, 1H), 5.48, 5.52 (2d, J=8.4, 8.0 Hz, 1H), 5.86 (t, J=12.0 Hz, 1H), 6.11 (d, J=7.6 Hz, 1H), 7.16-7.23 (m, 1H), 7.34-7.40 (m, 1H), 7.62 (d, J=8.0 Hz, 1H), 11.34 (s, 1H); ³¹P NMR (DMSO-d₆, four isomers) δ 3.33 (s), 3.59 (s), 3.64 (s), 3.70 (s); MS m/z 496.4 (M−H⁺).

Example 57

Preparation of 2′O,5′(R)—C-dimethyluridine-5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate (D12)

Step 1. Preparation of 5′-O-(t-butyldimethylsilyl)-3′-O-(4-methoxytrityl)-2′-O-methyluridine (D15)

TBSCl (7.0 g, 46.5 mmol), and DMAP (0.95 g, 7.76 mmol) were added to a solution of commercially available 2′-O-methyl uridine (D13) (10.0 g, 38.8 mmol) in anhydrous pyridine (100 mL) at 0° C. under N₂. The reaction mixture was stirred at RT overnight. TLC was used to monitor the reaction. The solvent was evaporated under reduced pressure. The residue was diluted with EA, washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The desired product, 5′-O-(t-butyldimethylsilyl)-2′-O-methyluridine (D14) (12.6 g), was obtained as white solid, which was used in next step without further purification.

MMTrCl (7.5 g, 24.5 mmol) was added to a solution of 5′-O-(t-butyldimethylsilyl)-2′-O-methyluridine (D14) (7.0 g, 18.8 mmol) in anhydrous DCM (50 mL). AgNO₃ (4.2 g, 24.5 mmol) and collidine (3.4 ml, 37.6 mmol) was added. The reaction mixture was stirred at RT overnight under N₂. The reaction was monitored by TLC. The reaction mixture was filtered and washed with saturated NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel DCM/MeOH; 97:3) to give 5′-O-(t-butyldimethylsilyl)-3′-O-(4-methoxytrityl)-2′-O-methyl uridine (D15) (9.5 g, 78%).

Step 2. Preparation of 3′-O-(4-methoxytrityl)-2′O-methyluridine (D16)

TEA-3HF (7.1 ml, 44.3 mmol) and TEA (10.6 ml, 73.8 mmol) was added dropwise to a solution of 5′-O-(t-butyldimethylsilyl)-3′-O-(4-methoxytrityl)-2′-O-methyluridine (D15) (9.5 g, 14.8 mmol) in anhydrous THF (90 mL). The reaction mixture was stirred at RT overnight. TLC showed the reaction was incomplete. Additional TEA-3HF (0.54 ml, 3.3 mmol) and TEA (0.6 ml, 4.15 mmol), were added. TLC showed the reaction went to completion. The solvent was removed in vacuo at RT. EA was added. The mixture were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel DCM/MeOH; 95:5) to give 3′-O-(4-methoxytrityl)-2′O-methyluridine (D16) as white solid (7.01 g, 90%).

Step 3. Preparation of 3′-O-(4-methoxytrityl)-5-C,5′-O-didehydro-2′-O-methyl uridine (D17)

Pyridine (15.4 mL) and Dess-Martin (6.7 g, 15.8 mmol) were added to a solution of 3′-O-(4-methoxytrityl)-2′-O-methyl uridine (D16) (7.01 g, 13.2 mmol) in anhydrous CH₂Cl₂ (100 mL) at 0° C. under N₂. The reaction mixture was stirred at RT for 4 h. TLC showed the reaction went to completion. The reaction mixture was diluted with EA. The organic layer was washed with 10% Na₂S₂O₃ twice, followed by water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/EA=1/1) to give 3′-O-(4-methoxytrityl)-5-C,5′-O-didehydro-2′-O-methyl uridine (D17) (7.6 g).

Step 4. Preparation of 2′-O-methyl-3′-O-(4-methoxytrityl)-5′-(S)—C-methyluridine (D18), and 2′-O-methyl-3′-O-(4-methoxytrityl)-5′-(R)—C-methyluridine (D19)

MeMgBr (31 mL, 43.2 mmol; 1.4M solution in hexanes) was added dropwise to a solution of 3′-O-(4-methoxytrityl)-5-C,5′-O-didehydro-2′-O-methyl uridine (D17) (7.6 g, 14.4 mmol) in anhydrous THF (120 mL) which was cooled by an ice-EtOH bath under N₂. The reaction mixture was stirred at RT for 4 h. TLC showed the reaction went to completion. The reaction mixture was quenched with saturated NH₄Cl. EA was added. The organic layer was washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel (DCM/EA=1:1) to give 2′-O-methyl-3′-O-(4-methoxytrityl)-5-(S)—C-methyluridine (D18) (3.04 g, 39%) and 2′O-methyl-3′-O-(4-methoxytrityl)-5′(R/S)—C-methyluridine (1.54 g, 20%) (D18+D19). Further purification on silica gel column (DCM/EA=1:1) gave 2′O-methyl-3′-O-(4-methoxytrityl)-5′(R)—C-methyluridine (D19) (140 mg, 2%) as white solid.

Step 5. Preparation of 2′O-methoxy-5′-(R)—C-methyluridine-5′-[1-naphthyl(isopropoxy-L alaninyl)]phosphate (D12)

According to the procedure described for Example 41, 25.1 mg of 2′-β-methoxy-5′-(R)—C-methyluridine-5′-[1-naphthyl(isopropoxy-L-alaninyl)]phosphate was prepared from 100 mg (0.18 mmol) of 2′-O-methyl-3′-O-(4-methoxytrityl)-5(R/S)—C-methyluridine. ¹H NMR (CD₃OD, two isomers) δ 1.14-1.32 (m, 9H), 1.44 (2d, J=6.4, 1.55 Hz, 3H), 3.47, 3.49 (2s, 3H), 3.76-3.78 (m, 2H), 3.90-3.98 (m, 2H), 4.17, 4.26 (each t, J=5.2, 6.0 Hz, 1H), 4.8-5.01 (m, 1H), 5.39, 5.51 (2d, J=8.0 Hz, 1H), 5.85, 5.89 (2d, J=4.8, 3.6 Hz, 1H), 7.39-7.44 (m, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.53-7.55 (m, 3H), 7.64 (d, J=8.0 Hz, 1H), 7.71 (t, 1H), 7.87-7.91 (m, 1H), 8.16-8.19 (m, 1H); ³¹P NMR (CD₃OD, two isomer) δ 3.39 (s), 3.74 (s). MS m/z 721.2 (MH⁺+diisopropylethylamine).

Example 58

Preparation of 5′(R)—C-methyluridine-5′-[phenyl(methoxy-L-alaninyl)]phosphate

According to the procedure described for Example 54, 16.7 mg of 5′ (R)—C-methyluridine 5′-[phenyl(methoxy-L-alaninyl)]phosphate was prepared from 60 mg (0.2 mmol) of 2′,3′-O-methoxymethylidene-5′(R)-methyluridine (P7). ¹H NMR (CD₃OD, major isomers) δ ¹H NMR (CD₃OD, major isomer) δ 1.31, (d, J=7.2, Hz, 3H), 1.44 (d, J=6.4, Hz, 3H), 3.64 (s, 3H), 3.90-3.91 (m, 2H), 4.03 (t, J=4.0, Hz, 1H), 4.23 (t, J=4.0, Hz, 1H), 4.75 (m, 1H), 4.24 (dd, J=5.2, 4.0 Hz, 1H), 4.33 (t, J=5.2 Hz, 1H), 4.70-4.78 (m, 1H), 5.55 (d, J=8.4 Hz, 1H), 5.85 (d, J=6.0 Hz, 1H), 7.18-7.24 (m, 3H), 7.33-7.37 (m, 2H), 7.69 (d, J=8.0 Hz, 1H); ³¹P NMR (CD₃OD, major isomer) δ 2.88 (s, major), 2.96 (s, minor). MS m/z 498.0 (M−H⁺); ³¹P NMR (CD₃OD, major isomer) δ 2.38 (s), 2.65 (s). MS m/z 497.3 (M−H).

Example 59

Preparation of 2′-deoxy-2′-β-C-methyl-5′(S)—C-methyl-2′-α-fluorouridine-[phenyl(methoxy-L-alaninyl)]phosphate

According to the procedure described for Example 41, 6.0 mg of 2′-deoxy-2′-β-C-methyl-5′(S)—C-methyl-2′-α-fluorouridine-5′-[phenyl(methoxy-L-alaninyl)]phosphate (D21) was prepared from 60 mg (0.11 mmol) of 2′-deoxy-3′-O,N⁴-di(4′-methoxytrityl)-2′-β-C-methyl-5′(S)—C-methyl-2′-α-fluorouridine (P9). ¹H NMR (CD₃OD, major isomer) δ 1.32-1.38 (m, 6H), 1.47 (d, J=6.8 Hz, 3H), 3.63 (s, 3H), 3.90-3.40 (m, 2H), 4.80 (m, 1H), 5.69 (d, J=8.0 Hz, 1H), 6.01 (brs, 1H), 7.16-7.38 (m, 5H), 7.64 (d, J=8.0 Hz, 1H); ³¹P NMR (CD₃OD, major isomer) δ 2.93 (s). MS m/z 514.0 (M−H).

Example 60

Preparation of 1-(2,6-diaminopurin-9-yl)-5(S)—C-methyl-β-D-ribofuranose 5-[phenyl(isopropoxy-L-alaninyl)]phosphate (E1)

Step 1. Preparation of P16—To a stirred suspension of P15 (4.5 g, 7.99 mmol) and 6-chloroguanine (1.35 g, 7.99 mmol) in anhydrous MeCN (50 mL) was added DBU (3.84 g, 24 mmol) at 0° C. The mixture was stirred at 0° C. for 5 minutes and then TMSOTf (7.1 mL, 32 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 20 minutes and then was stirred at 70° C. for 3 hours. The reaction was cooled to RT and diluted with EA. The solution was washed with saturated NaHCO₃ and brine in sequence. The organic layer was dried over Na₂SO₄ and then concentrated. The residue was purified on a silica gel column (PE: EA=4:1 to 3:1) to give P16 (4.6 g, 86%) as light yellow foam.

Step 2. Preparation of P17—Compound P16 (7.74 g, 11.2 mmol) was dissolved in a minimum of 1,4-dioxane and then saturated aqueous ammonia was added (100 mL). The mixture was stirred at 100° C. in a sealed vessel for 10 hours. The mixture was cooled to RT and diluted with MeOH. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (MeOH: DCM=1:20 to 1:8) to give P17 (2.47 g, 79%) as a white solid. ¹H NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 6.78 (brs, 2H), 5.78 (d, J=7.2 Hz, 1H), 4.70-4.73 (m, 1H), 4.22-4.24 (m, 1H), 3.91-3.97 (m, 1H), 3.99 (t, J=2.0 Hz, 1H), 1.24 (d, J=6.4 Hz, 3H).

Step 3. Preparation of P18—To a suspension of P17 (600 mg, 2.0 mmol) in 10 mL of anhydrous THF was added trimethyl orthoformate (1.06 g, 10.0 mmol) and TsOH.H₂O (510 mg, 3.0 mmol). The mixture was stirred at RT for 16 hours. The reaction was quenched by NaHCO₃ and concentrated. The residue was purified by on a silica gel column (MeOH: DCM=1:20 to 1:10) to give P18 (410 mg, 60.6%) as white foam.

Step 4. Preparation of E1—Compound P18 (310 mg, 0.92 mmol) was dissolved in DMF-dimethylacetamide (10 mL) and the mixture was refluxed for 16 hours. The solvent was removed to give the crude fully blocked nucleoside (410 mg, 100%). To the solution of the crude nucleoside (410 mg, 0.92 mmol) in THF (3 mL) was added a solution of t-BuMgCl in THF (2.75 mL, 2.75 mmol) at 0° C. followed by a solution of phenyl(isopropoxy-L-alaninyl) phosphorochloridate (564 mg, 1.84 mmol in 2 mL THF). The mixture was stirred at RT for 16 hours and then quenched with water. The solvent was removed in vacuum. The residue was purified on a silica gel column (5% MeOH in DCM) to give the crude product (crude 280 mg) which was treated with 60% aqueous HCOOH solution at RT for 16 hours. The solvent was removed and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound E1 (single stereomer, 9.08 mg, 1.6%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.86 (s, 1H), 7.42 (t, J=8.0 Hz, 2H), 7.20-7.35 (m, 3H), 6.88 (bs, 1H), 6.01-6.07 (m, 1H), 5.97 (bs, 1H), 5.85 (d, J=6.4 Hz, 1H), 5.54 (d, J=6.0 Hz, 1H), 5.31 (d, J=5.2 Hz, 1H), 4.94-4.97 (m, 1H), 4.73-4.80 (m, 1H), 4.37-4.44 (m, 1H), 4.25-4.30 (m, 1H), 3.96-3.98 (m, 1H), 3.83-3.91 (m, 1H), 1.46 (d, J=6.4 Hz, 3H), 1.24-1.29 (m, 9H); ³¹P NMR (DMSO-d₆, 162 MHz) δ 3.44; ESI-LCMS: m/z 566 [M+H]⁺.

Example 61

Preparation of 5′(S)—C-ethyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A24)

Step 1. Preparation of P20—To a suspension of P19 (50.0 g, 187 mmol) in anhydrous pyridine (500 mL) was added TBSCl (30.0 g, 200 mmol) at 0° C. The mixture was stirred at RT for 5 hours and then concentrated to dryness. The residue was dissolved in anhydrous DCM (500 mL). A mixture of sym-collidine (24.2 g, 200 mmol) and AgNO₃ (30.4 g, 200 mmol) was added followed by MMTrCl (283.0 g, 935 mmol). The mixture was stirred at RT for 24 hours, quenched by MeOH, filtered and the filtrate was concentrated. The residues was purified on a silica gel column (20% EA in PE) to give the crude product, which was dissolved in 1M TBAF in THF (200 mL) and stirred at RT for 2 hours. The solvent was removed and the residue was purified on a silica gel column (40% EA in PE) to give P20 (155.0 g, 77%) as a light yellow solid.

Step 2. Preparation of P21—To a suspension of P20 (2.0 g, 1.8 mmol) in anhydrous DCM (50 mL) was added DMP (1.27 g, 3.0 mmol) under N₂. The mixture was stirred at RT for 2 hours before quenched by saturated aqueous Na₂SO₃ and NaHCO₃. The mixture was extracted with DCM. The organic layer was dried and concentrated to give the crude product P2-3 (1.8 g, 90%) used for the next step without further purification.

Step 3. Preparation of P22—To an ice-EtOH cold solution of P21 (1.8 g, 1.65 mmol) in anhydrous THF (10 mL) was added with EtMgBr (1.0 M solution in THF, 10 mL, 10 mmol) dropwise under N₂. The reaction mixture was stirred at RT overnight. The mixture was cooled to 0° C. and quenched by saturated NH₄Cl. The solution was extracted with EA. The organic layer was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified on a silica gel column (PE/EA=3/1 to 1/1) to give compound P22 (1.18 g, 44%) as a single stereomer.

Step 4. Preparation of P23—Compound P22 (200 mg, 0.18 mmol) was dissolved in 15 mL AcOH/H₂O (v/v=4:1). The mixture was stirred at 50° C. overnight. The solvent was removed under vacuum and the residue was purified on a silica gel column (DCM: MeOH=100:1 to 8:1) to give P23 (13 mg, 25%). ¹H NMR (DMSO-d₆,400 Hz) 8.31 (s, 1H), 8.08 (s, 1H), 7.34 (s, 2H), 5.82 (d, J=6.4 Hz, 1H), 5.44 (d, J=4.0 Hz, 1H), 5.37 (d, J=6.8 Hz, 1H), 5.08 (d, J=4.0 Hz, 1H), 4.51-4.53 (m, 1H), 4.07-4.10 (m, 1H), 3.87-3.88 (m, 1H), 3.41-3.47 (m, 1H), 1.37-1.44 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).

Step 5. Preparation of P24—To a suspension of P23 (200 mg, 0.68 mmol) in 10 mL of anhydrous THF was added trimethyl orthoformate (1.06 g, 10.0 mmol) and TsOH.H₂O (171 mg, 1.0 mmol). The mixture was stirred at RT for 16 hours. The reaction was quenched by NaHCO₃ and then concentrated. The residue was purified on a column on silica gel (eluting with MeOH:DCM=1:20 to 1:10) to give the intermediate (180 mg) as white foam. The intermediate (180 mg, 0.53 mmol) was dissolved in anhydrous pyridine (10 mL) and cooled to 0° C. TMSCl (215 mg, 2.0 mmol) was added in dropwise. The mixture was stirred at RT for 3 hours before MMTrCl (400 mg, 1.3 mmol) was added. The mixture was stirred at 50° C. for 16 hours. The reaction was quenched by NH₄OH, the mixture was concentrated and purified by column on silica gel (1% MeOH in DCM) to give P24 (220 mg, 53%) as white foam.

Step 6. Preparation of A24—To a stirred solution of P24 (220 mg, 0.36 mmol) in anhydrous THF (4 mL) was added a solution of t-BuMgCl (0.72 mL, 1M in THF) dropwise at 40° C. The mixture was then stirred at 40° C. for 40 minutes. A solution of phenyl (isopropoxy-L-alaninyl) phosphorochloridate (219 mg, 0.72 mmol) in THF (1 mL) was added dropwise. After addition, the mixture was stirred at 40° C. for 16 hours. Then the reaction was quenched with H₂O and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on a column on silica gel (PE: EA=2:1 to 1:1) to give protected form of the prodrug (52 mg) as white solid. The product was dissolved in 60% HCOOH aqueous solution and the mixture was stirred at 25° C. for 16 hours. The solvent was removed and the residue was purified on a silica gel column (CH₃OH:DCM=1:100 to 1:20) to give the crude product which was further purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound A24 (9.24 mg, 9.5%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.35, 8.29 (2s, 1H), 8.22, 8.20 (2s, 1H), 7.15-7.36 (m, 5H), 6.04 (s, 1H), 4.51-4.77 (m, 3H), 4.40 (s, 1H), 4.23, 4.65 (2d, J=4.0 Hz, 1H), 3.82-3.87 (m, 1H), 1.91-1.95 (m, 1H), 1.82-1.85 (m, 1H), 1.21 (s, 6H), 1.05-1.09 (m, 3H), 0.99-1.03 (m, 3.2H); ³¹P NMR (DMSO-d₆, 162 MHz) δ 1.71, 1.43; ESI-LCMS: m/z 565 [M+H]⁺.

Example 62

Preparation of 5′(R)—C-ethyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A25)

Step 1. Preparation of P25—To an ice-cold suspension of CrO₃ (135 mg, 1.35 mmol) in anhydrous DCM (5 mL) was added anhydrous pyridine (0.25 mL, 2.7 mmol) and Ac₂O (0.13 mL, 1.13 mmol) under N₂. The mixture was stirred at RT for about 10 min until the mixture became homogeneous. The mixture was cooled to 0° C. and a solution of P22 (500 mg, 0.45 mmol) in anhydrous DCM (5 mL) was added. The resultant mixture was stirred at RT for 1 h. The mixture was diluted with DCM (50 mL) and washed with aqueous NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give P25 (406 mg, 81%).

Step 2. Preparation of P26—To an ice-cold solution of P25 (400 mg, 0.36 mmol) in 95% EtOH (10 mL) was added NaBH₄ (126 mg, 3.6 mmol) under N₂. The reaction was stirred at RT overnight. The solvent was evaporated. The residue was diluted with EA (30 mL), washed with saturated NaHCO₃ aq. and brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by prep-TLC to give P26 (398 mg, 98%) as a yellow solid.

Step 3. Preparation of P27—Compound P26 (220 mg, 0.2 mmol) was dissolved in 15 mL AcOH/H2O (v/v=4:1). The mixture was stirred at 50° C. overnight. The solvent was removed under vacuum and the residue was purified by silica gel column (DCM:MeOH=100:1 to 8:1) to give P27 (35 mg, 59%). ¹H NMR (DMSO-d6, 400 MHz) δ 8.31 (s, 1H), 8.11 (s, 1H), 7.38 (s, 2H), 5.82 (d, J=8.0 Hz, 1H), 5.72 (d, J=4.0 Hz, 1H), 5.36 (d, J=6.8 Hz, 1H), 5.14 (d, J=4.0 Hz, 1H), 4.64-4.67 (m, 1H), 4.12-4.13 (m, 1H), 3.82-3.83 (m, 1H), 3.56-3.59 (m, 1H), 1.31-1.36 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

Step 4. Preparation of P28—To a suspension of P27 (400 mg, 1.1 mmol) in 10 mL of anhydrous THF was added trimethyl orthoformate (636 mg, 6.0 mmol) and TsOH.H₂O (200 mg, 1.2 mmol). The mixture was stirred at RT for 16 hours. The reaction was quenched by NaHCO₃ and concentrated. The residue was purified on a silica gel column (MeOH:DCM=1:20 to 1:10) to give the intermediate (340 mg, 73%) as white foam. The product (340 mg, 0.91 mmol) was dissolved in anhydrous pyridine (10 mL) and cooled to 0° C. TMSCl (260 mg, 2.4 mmol) was added in dropwise and the mixture was stirred at RT for 3 hours before MMTrCl (480 mg, 1.6 mmol) was added. The mixture was stirred at 50° C. for 16 hours. The reaction was quenched by NH₄OH and concentrated. The residue was purified on silica gel column (1% MeOH in DCM) to give P28 (410 mg, 53%) as white foam.

Step 5. Preparation of A25—To a stirred solution of P28 (190 mg, 0.29 mmol) in anhydrous THF (5 mL) was added a solution of t-BuMgCl (0.9 mL, 1M in THF) dropwise at 40° C. The mixture was then stirred at 40° C. for 40 minutes. A solution of phenyl (isopropoxy-L-alaninyl) phosphorochloridate (270 mg, 0.885 mmol) in THF (1 mL) was added dropwise. After addition, the mixture was stirred at 40° C. for 16 hours. Then the reaction was quenched with H₂O and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on a silica gel column (PE:EA=2:1 to 1:1) to give crude protected prodrug (170 mg) which was treated with 60% HCOOH aqueous solution for 16 hours. The solvent was removed and the residue was purified by column on silica gel (MeOH:DCM=1:100 to 1:20) to give the crude product which was purified by RP HPLC separation (MeCN and 0.1% HCOOH in water) to give compound A25 (18.73 mg, 12.5%) as a white solid. ¹H NMR (DMSO-d6, 400 MHz) δ 8.30, 8.27 (2s, 1H), 8.12-8.18 (m, 1H), 7.28 (t, J=8.4 Hz, 2H), 7.10-7.15 (m, 3H), 6.04, 5.95 (2d, J=4.8 Hz, 1H), 4.44-4.95 (m, 1H), 4.71-4.74 (m, 2H), 4.45-4.49 (m, 1H), 4.11-4.15 (m, 1H), 3.84-3.86 (m, 1H), 1.84-1.86 (m, 2H), 1.26 (d, J=7.2 Hz, 3H), 1.17-1.23 (m, 7H), 0.96-1.09 (m, 3H); ³¹P NMR (DMSO-d6, 162 MHz) δ 3.19, 2.82; ESI-LCMS: m/z 565 [M+H]⁺.

Example 63

Preparation of 5′(S)—C-trifluoromethyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A26)

Step 1. Preparation of P30—To a solution of D-ribose (30.0 g, 1.33 mol) in acetone (285 mL) and MeOH (15 mL) was added concentrated H₂SO₄ (1.2 mL). The solution was refluxed for 24 hours. The reaction was cooled and neutralized with aqueous ammonia. The mixture was poured into H₂O (500 mL) and extracted with EA. The combined organic layers were dried with MgSO₄. The solvent was and the residue was purified on a silica gel column (PE:EA=4:1 to 2:1) to give P30 as colorless oil (25.5 g, 62.5%).

Step 2. Preparation of P31—To a solution of P30 (25.5 g, 125 mmol) in anhydrous DCM (800 mL) was added Dess-Martin preiodinane (78.2 g, 0.18 mol) at 0° C. under N₂. The resultant mixture was stirred at 15° C. overnight. The mixture was washed with saturated aqueous Na₂SO₃ and NaHCO₃ solution. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give compound P31 as a syrup which was used for the next step without further purification (16.5 g, 66%).

Step 3. Preparation of P32—To a solution of P31 (4.6 g, 22.8 mmol) and tetrabutylammonium acetate (TBAA) (345 mg, 1.15 mmol) in anhydrous THF (150 mL) was added a solution of TMSCF₃ (65.2 g, 459 mmol) at −50° C. under N₂. After the addition, the reaction mixture was warmed to 0° C. and stirred for 4 hours. The mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue (4.7 g). The residue was dissolved in 150 mL THF and then was added TBAF (3.99 g, 13.7 mmol). The reaction mixture was stirred for 2 hours and then quenched with water, extracted with EtOAc, dried over anhydrous MgSO₄, filtered and concentrated to give syrup which was used for the next step without further purification

Step 4. Preparation of P33—To an ice-cooled solution of crude P32 in anhydrous pyridine (70 mL) was added BzCl (5.8 g, 38 mmol) dropwise under N₂. The reaction mixture was stirred at RT overnight. EA (300 mL) was added to the mixture and then washed with water (200 mL) and saturated aqueous NaHCO₃ (200 mL). The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue which was purified by on a silica gel column (PE/EA=20/1) to give P33 as syrup (3.6 g, 9.6 mmol).

Step 5. Preparation of P34—To a solution of Compound P33 (3.6 g, 9.6 mmol) in MeOH (200 mL) was added with concentrated aqueous HCl (2 mL). The resultant mixture was refluxed for 16 hours. The solvent was removed under vacuum. The residue was dissolved in DCM (200 mL) and washed with saturated aqueous NaHCO₃. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give syrup which was purified on a silica gel column (PE/EA=3/1) to give crude compound as syrup (2.73 g). The crude (2.73 g, 8.12 mmol) was dissolved in anhydrous pyridine (80 mL) and BzCl (6.8 g, 44.9 mmol) was added dropwise. The reaction mixture was stirred at RT overnight. EA (200 mL) was added to the mixture and then washed with water (100 mL) and saturated aqueous NaHCO₃ (100 mL). The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give the residue (4.3 g). The residue was dissolved in HOAc (30 mL) and Ac₂O (3.3 mL) and the solution was cooled to 10° C. Concentrated H₂SO₄ was added dropwise The resultant mixture was stirred at RT for 5 h and then poured onto ice-water. The precipitate was collected by filtration. The collected solid was dissolved in EA (60 mL) and washed with saturated aqueous NaHCO₃ (50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum and the residue was purified on a silica gel column (PE/EA=20/1 to 20/1) to give P34 as foam (3.8 g, 68%).

Step 6. Preparation of P35—To an ice-cooled solution of P34 (1.14 g, 2.0 mmol) and 6-chloro-9H-purine (508 mg, 3.0 mmol) in anhydrous MeCN (20 mL) was added DBU (912 mg, 6 mmol). The mixture was stirred at for 30 minutes before TMSOTf (1.44 mL, 8.0 mmol) was added dropwise under N₂. The mixture was stirred at 70° C. overnight and then cooled to RT. The solution was diluted with EA and washed with aqueous NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue which was purified on a silica gel column (PE/EA=4/1 to 3/1) to give the mixture of two isomers (1.1 g, 80.6%). Further purification by prep-TLC gave pure P35 (660 mg, 60%).

Step 7. Preparation of P36—Compound P35 (1.1 g, 1.6 mmol.) in 1,4-dioxane (10 mL) and NH₃.MeOH (30 mL) was added to a sealed heavy-wall pressure tube and the mixture was stirred at 100° C. overnight. Then concentrated and purified by silica gel column to give compound P36 (503 mg, 94%). ¹H NMR (CD₃OD, 400 MHz) δ 8.31 (s, 1H), 8.17 (s, 1H), 5.99 (d, J=6.4 Hz, 1H), 4.69 (t, J=4.8 Hz, 1H), 4.31-4.36 (m, 2H), 4.22-4.24 (m, 1H).

Step 8. Preparation of P37—To a suspension of P36 (670 mg, 2.0 mmol) in 20 mL of anhydrous THF was added trimethyl orthoformate (1.27 g, 12.0 mmol) and TsOH monohydrate (400 mg, 2.4 mmol). The mixture was stirred at RT for 16 hours. The reaction was quenched by NaHCO₃ and concentrated. The residue was purified on a silica gel column (MeOH:DCM=1:20 to 1:10) to give the crude (540 mg) as white foam. The crude was dissolved in anhydrous pyridine (10 mL) and cooled to 0° C. TMSCl (520 mg, 4.8 mmol) was added in dropwise. The mixture was stirred at RT for 3 hours, before MMTrCl (960 mg, 3.2 mmol) was added. The mixture was stirred at 50° C. for 16 hours. The reaction was quenched by NH₄OH, the mixture was concentrated and purified on a silica gel column (1% MeOH in DCM) to give P37 (610 mg, 48%) as white foam.

Step 9. Preparation of A26—To a mixture of compound P37 (323 mg, 0.5 mmol), N,N-Diisopropylethylamine (2 mL) and CH₃CN (20 mL) was added a solution of phenyl(isopropoxy-L-alaninyl) phosphorochloridate (610 mg, 2.0 mmol in THF). After addition, the mixture was refluxed for 16 hours. Then the solvent was removed in vacuum. The residue was purified on a silica gel column (PE:EA=2:1 to 1:1) to give the protected prodrug (220 mg, 48%) which was treated with 60% HCOOH for 16 hours at RT. The solvent was removed and the residue was purified on a silica gel column (MeOH:DCM=1:100 to 1:20) to give the crude product which was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound A26 (17.44 mg, 6.2%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.23 (s, 1H), 8.19 (s, 1H), 7.28 (t, J=8.0 Hz, 2H), 7.08-7.15 (m, 3H), 6.06 (d, J=3.2 Hz, 1H), 5.29 (d, J=7.2 Hz, 1H), 4.95 (brs, 1H), 4.49-4.53 (m, 2H), 4.41 (d, J=4.4 Hz, 1H), 3.81-3.88 (m, 1H), 1.26 (d, J=7.2 Hz, 3H), 1.15-1.19 (m, 6H); ³¹P NMR (DMSO-d₆, 162 MHz) δ 2.32; ESI-LCMS: m/z 605 [M+H]⁺.

Example 64

Preparation of 5′(R)—C-trifluoromethyladenosine 5′-[phenyl(isopropoxy-L-alaninyl)]phosphate (A27)

Step 1. Preparation of P38—To an ice-cooled solution of P34 (1.14 g, 2.0 mmol) and 6-chloro-9H-purine (508 mg, 3.0 mmol) in anhydrous MeCN (20 mL) was added DBU (912 mg, 6 mmol). The mixture was stirred at for 30 minutes before TMSOTf (1.44 mL, 8.0 mmol) was added dropwise under N₂. The mixture was stirred at 70° C. overnight and then cooled to RT. The solution was diluted with EA and washed with aqueous NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue which was purified on a silica gel column (PE/EA=4/1 to 3/1) to give the mixture of two isomers (1.1 g, 80.6%). Further purification by prep-TLC gave pure P38 (230 mg, 21%).

Step 2. Preparation of P39—A suspension of P38 (230 mg, 0.35 mmol.) in 1,4-dioxane (2 mL) and conc. aqueous ammonia (10 mL, 28%) was stirred at 100° C. in a sealed vessel overnight. The solvent was removed and the residue was purified by on a silica gel column to give compound P39 (41.5 mg, 35.4%). ¹H NMR (CD₃OD, 400 MHz) δ 8.24 (s, 1H), 8.18 (s, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.79-4.82 (m, 1H), 4.43-4.47 (d, J=5.6 Hz, 1H), 4.27-4.30 (m, 2H).

Step 3. Preparation of P40—To a suspension of P39 (90 mg, 0.27 mmol) in 10 mL of anhydrous THF was added trimethyl orthoformate (320 mg, 3.0 mmol) and TsOH.H₂O (51 mg, 0.3 mmol). The mixture was stirred at RT for 16 hours. The reaction was quenched by NaHCO₃ (to pH>7), then concentrated and purified by column on silica gel (eluting with MeOH:DCM=1:20 to 1:10) to give the crude (99 mg, 97%) as white foam. The crude product was dissolved in anhydrous pyridine (5 mL) and cooled to 0° C. TMSCl (52 mg, 0.48 mmol) was added. The mixture was stirred at RT for 3 hours before MMTrCl (200 mg, 0.67 mmol) was added. The mixture was stirred at 50° C. for 16 hours. The reaction was quenched by NH₄OH and the mixture was concentrated and purified by column on silica gel (1% MeOH in DCM) to give P40 (110 mg, 65%) as white foam.

Step 4. Preparation of A27—To a solution of P40 (110 mg, 0.17 mmol) in N,N-Diisopropylethylamine (2 mL) and CH₃CN (10 mL) was added a solution of phenyl (isopropoxy-L-alaninyl) phosphorochloridate (122 mg, 0.4 mmol in THF). The mixture was refluxed for 16 hours. Then the solvent was removed under vacuum. The residue was purified by column on silica gel (PE: EA=2:1 to 1:1) to give the protected compound (100 mg, 64%) as white foam. The protected precursor (100 mg, 0.11 mmol) was dissolved in 60% HCOOH aqueous solution and the mixture was stirred at RT for 16 hours. The solvent was removed and the residue was purified by column chromatography on silica gel (CH₃OH:CH₂Cl₂=1:100 to 1:20) to give the crude product, which was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound A27 (17.5 mg, 26%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.35 (s, 1H), 8.23 (s, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.15-7.18 (m, 3H), 5.97 (d, J=7.2 Hz, 1H), 5.34-5.38 (m, 1H), 4.89-4.93 (m, 1H), 4.55-4.60 (m, 1H), 4.31-4.35 (m, 1H), 3.82-3.88 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.19 (br, 6H); ³¹P NMR (DMSO-d₆, 162 MHz) δ 3.53; ESI-LCMS: m/z 605 [M+H]⁺.

Example 65

Preparation of 5′(S)—C-methyladenosine 5′(S)-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A10a) and 5′(S)—C-methyladenosine 5′(R)-[phenyl(cyclohexoxy-L-alaninyl)]phosphate (A10b)

Compound P41 (1.2 g, 2.0 mmol) was dissolved in 80% HCOOH aqueous solution and the mixture was stirred at RT for 16 hours. The solvent was removed and the residue was purified by RP HPLC (column type: 150*21.5 mm, with organic phase gradient (28˜58% acetonitrile solution in neutral system)) to give A10a (22.7 mg, 1.9%) and A10b (189 mg, 16%).

¹H NMR for compound A10a (CD₃OD, 400 MHz) δ 8.34 (s, 1H), 8.24 (s, 1H), 7.20-7.38 (m, 5H), 6.06 (d, J=4.4 Hz, 1H), 4.79-4.84 (m, 1H), 4.62-4.66 (m, 1H), 4.56 (t, J=5.2 Hz, 1H), 4.49 (t, J=5.2 Hz, 1H), 4.04-4.07 (m, 1H), 3.85-3.93 (m, 1H), 1.26-1.76 (m, 16H); ³¹P NMR (CD₃OD, 162 MHz) δ3.13; ESI-LCMS: m/z 591 [M+H]⁺.

¹H NMR for compound A10b (CD₃OD, 400 MHz) δ 8.26 (s, 1H), 8.19 (s, 1H), 7.10-7.30 (m, 5H), 6.03 (d, J=5.2 Hz, 1H), 4.80-4.84 (m, 1H), 4.67-4.73 (m, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.33 (t, J=4.8 Hz, 1H), 4.04-4.06 (m, 1H), 3.85-3.93 (s, 1H), 1.24-1.78 (m, 16H); ³¹P NMR (CD₃OD, 162 MHz) δ3.14; ESI-LCMS: m/z 591 [M+H]⁺.

Example 66

Preparation of 5′(S)—C-methyladenosine 5′-[2-chlorophenyl(cyclohexoxy-L-alaninyl)]phosphate (A28)

Step 1: Preparation of P41—To a stirred solution of phosphoryl trichloride (3.06 g, 20 mmol) and 2-chlorophenol (2.56 g, 20 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (2.04 mL, 20 mmol) in DCM (20 mL) dropwise at −78° C. After addition, the mixture was warmed to RT gradually and stirred for 2 hours. Then the solution was re-cooled to −78° C. and (S)-cyclohexyl 2-aminopropanoate hydrochloride (3.73 g, 18 mmol) was added followed by TEA (3.67 g, 36 mmol) dropwise at −78° C. The mixture was warmed to RT gradually and stirred for 2 hours. Then the solvent was removed and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off and the filtrate was concentrated. The residue was purified on a silica gel column (pure DCM) to give the phosphorylchlorodate as colorless oil (3.1 g, 40.9%).

Step 2: Preparation of A28—To a stirred solution of P3 (595.6 mg, 1 mmol) in anhydrous THF (10 mL) was added a solution of t-BuMgCl (3 mL, 1M in THF) dropwise at −78° C. The mixture was then stirred at RT for 30 minutes and re-cooled to −78° C. A solution of P41 (3 mL, 1M in THF) was added dropwise and then the mixture was stirred at RT overnight. The reaction was quenched with H₂O and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on a silica gel column (PE:EA=1:1 to 1:3) to give protected prodrug (670 mg), which was treated with 65% HCOOH aqueous solution at RT overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel first and then by RP HPLC (0.1% HCOOH in water and MeCN) to give A28 as a white solid (191.8 mg, single stereomer, 30.7%). ¹H NMR (CD₃OD, 400 MHz) δ 8.28 (s, 1H), 8.19 (s, 1H), 7.39-7.46 (m, 2H), 7.07-7.20 (m, 2H), 6.03 (d, J=5.2 Hz, 1H), 4.90-4.95 (m, 1H), 4.67-4.73 (m, 1H), 4.51 (dd, J₁=J₂=5.6 Hz, 1H), 4.38 (dd, J₁=4.0 Hz, J₂=5.6 Hz, 1H), 4.05-4.08 (m, 1H), 3.91-3.99 (m, 1H), 1.66-1.82 (m, 4H), 1.54 (d, J=6.4 Hz, 3H), 1.28-1.51 (m, 9H); ³¹P NMR (CD₃OD, 162 MHz) δ: 2.91; ESI-LCMS: m/z 625 [M+H]⁺.

Example 67

Preparation of 5′-C—(S)-methyl adenosine 5′-phosphoramidates

By a similar procedure as described in Example 66, a number of 5′-C—(S)-methyladenosine 5′-phosphoramidates were prepared with the appropriate chlorophosphorylamino propanoate used in place of P41. The structures of the 5′-C—(S)-methyladenosine 5′-phosphoramidates, and corresponding characterization data, are listed in Table 6.

TABLE 6
Various 5′-C-(S)-methyladenosine 5′-phosphoramidates compounds
Compound		31P NMR	ESI-LCMS
No.	Structure	ppm	m/z
A29		3.12	643.1 (M + 1)+
A30		3.27	605.1 (M + 1)+
A31		6.04 6.03	609.3 (M + 1)+
A32		3.18 3.00	625.4 (M + 1)+
A33		3.56	621.3 (M + 1)+
A34		3.38	605.3 (M + 1)+
A35		3.59 3.12	642.0 (M + 1)+
A36		3.64 3.37	592.1 (M + 1)+
A37		3.23	605.2 (M + 1)+
A38		3.32 3.29	619.3 (M + 1)+
A39		3.85 3.78	619.3 (M + 1)+
A40		3.32 3.16	633.1 (M + 1)+
A41		3.22 3.18	651.1 (M + 1)+
A42		2.92 2.58	667.1 (M + 1)+
A43		4.52 3.98	577.3 (M + 1)+

TABLE 7
Additional nucleosides/nucleotides/nucleotide
derivatives/compounds
Structure

Example 68

5′-alkylated nucleoside 5′-triphosphates

The following 5′-alkylated nucleoside 5′-triphosphates were prepared according to the procedure described in U.S. Publication No. 2010-0249068, which is hereby incorporated by reference:

MS: 534.1 (M − 1) 31P NMR (D2O): −8.75 (d, 1P); −11.45 (d, 1P), −22.48 (t, 1P)
MS: 534.4 (M − 1) 31P NMR (D2O): −8.58 (bs, 1P); −11.09 (d, 1P), −22.15 (t, 1P)
MS: 526.2 (M − 1) 31P NMR (D2O): −9.58 (bs, 1P); −11.65 (d, 1P), −21.92 (bs, 1P)
MS: 529.9 (M − 1) 31P NMR (D2O): −10.15 (d, 1P); −11.20 (d, 1P), −22.45 (t, 1P)
MS: 496.0 (M − 1) 31P NMR (D2O): −10.15 (d, 1P); −11.30 (d, 1P), −22.54 (t, 1P)
MS: 520.1 (M − 1) 31P NMR (D2O): −9.75 (d, 1P); −11.41 (d, 1P), −22.54 (t, 1P)
MS: 516.0 (M − 1) 31P NMR (D2O): −9.50 (bs, 1P); −11.30 (d, 1P), −22.33 (t, 1P)

Example 69

HCV Replicon Assay

Cells

Huh-7 cells containing the self-replicating, subgenomic HCV replicon with a stable luciferase (LUC) reporter were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 2 mM L-glutamine and supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomyocin, 1% nonessential amino acids, and 0.5 mg/ml G418.

Determination of Anti-HCV Activity

Determination of 50% inhibitory concentration (EC₅₀) of compounds in HCV replicon cells were performed by the following procedure. On the first day, 5,000 HCV replicon cells were plated per well in a 96-well plate. On the following day, test compounds were solubilized in 100% DMSO to 100× the desired final testing concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. Compounds in 100% DMSO are reduced to 10% DMSO by diluting 1:10 in cell culture media. The compounds were diluted to 10% DMSO with cell culture media, which were used to dose the HCV replicon cells in 96-well format. The final DMSO concentration was 1%. The HCV replicon cells were incubated at 37° C. for 72 hours. At 72 hours, cells were processed when the cells are still subconfluent. Compounds that reduce the LUC signal are determined by Bright-Glo Luciferase Assay (Promega, Madison, Wis.). % Inhibition was determined for each compound concentration in relation to the control cells (untreated HCV replicon) to calculate the EC₅₀.

The antiviral activity of exemplary compounds is shown in Table 8, wherein ‘A’ represents an EC₅₀ of <1 μM, ‘B’ represents an EC₅₀ of <30 μM, ‘C’ represents an EC₅₀ of <100 μM and ‘D’ represents an EC₅₀ of <1000 μM. In Table 9 ‘A’ represents an EC₅₀ of <5 “B” represents an EC₅₀ of <30 μM, and ‘C’ represents an EC₅₀ of <200 μM.

TABLE 8
		HCV
		Replicon
Structure	Compound No.	Activity
	A15	B
		B
		D
		B
	A8	A
	A19	A
	A20	A
	A21	A
	A1	A
	A2	A
	A10	A
	A10a	A
	A10b	A
	A11	A
	A12	A
	A13	A
	A14	A
	A3	A
	A4	A
	A23	A
	A22	A
	A5	B
	A7	B
	A6	B
	A16	B
	A9	A
	A17	A
	A18	A
	A24	C
	A25	D
	A26	C
	A27	B
	A31	A
	A32	A
	A28	A
	A29	A
	A30	A
	A37	A
	A33	A
	A35	B
	A36	B
	A34	A
	A38	A
	A39	A
	A40	A
	A41	A
	A42	B
	A43	A
	B5	C
	B5	C
	C6	C
	C2	C
	C5	A
	C8	C
	C9	C
	C10	B
	D1	D
	D2	D
	D4	B
	D7	B
	E1	B

TABLE 9
Activity of Exemplary Compounds (C <200 μM, B <30 μM, A <5 μM)
          HCV
          Repli-
          con
          Activ-
Structure ity
          B
          B
          A
          B
          C
          C
          C
          B
          A
          A
          C
          B
          A
          A
          A
          A
          A
          A
          A
          C

Example 70

Combination of Compounds

Combination Testing

Two or more test compounds were tested in combination with each other using an HCV genotype 1b HCV replicon harbored in Huh7 cells with a stable luciferase (LUC) reporter. Cells were cultured under standard conditions in Dulbecco's modified Eagle's medium (DMEM; Mediatech Inc, Herndon, Va.) containing 10% heat-inactivated fetal bovine serum (FBS; Mediatech Inc, Herndon, Va.) 2 mM L-glutamine, and nonessential amino acids (JRH Biosciences). HCV replicon cells were plated in a 96-well plate at a density of 10⁴ cells per well in DMEM with 10% FBS. On the following day, the culture medium was replaced with DMEM containing either no compound as a control, the test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO, or a combination of compound A10 with one or more test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO. The cells were incubated with no compound as a control, with the test compounds, or the combination of compounds for 72 h. The direct effects of the combination of the test compounds were examined using a luciferase (LUC) based reporter as determined by the Bright-Glo Luciferase Assay (Promega, Madison, Wis.). Dose-response curves were determined for individual compounds and fixed ratio combinations of two or more test compounds.

The effects of test compound combinations were evaluated by two separate methods. In the Loewe additivity model, the experimental replicon data was analyzed by using CalcuSyn (Biosoft, Ferguson, Mo.), a computer program based on the method of Chou and Talalay. The program uses the experimental data to calculate a combination index (CI) value for each experimental combination tested. A CI value of <1 indicates a synergistic effect, a CI value of 1 indicates an additive effect, and a CI value of >1 indicates an antagonistic effect.

The second method utilized for evaluating combination effects used a program called MacSynergy II. MacSynergy II software was kindly provided by Dr. M. Prichard (University of Michigan). The Prichard Model allows for a three-dimensional examination of drug interactions and a calculation of the synergy volume (units: μM²%) generated from running the replicon assay using a checkerboard combination of two or more inhibitors. The volumes of synergy (positive volumes) or antagonism (negative volumes) represent the relative quantity of synergism or antagonism per change in the concentrations of the two drugs. Synergy and antagonism volumes are defined based on the Bliss independence model. In this model, synergy volumes of less than −25 indicate antagonistic interactions, volumes in the −25-25 range indicate additive behavior, volumes in the 25-100 range indicate synergistic behavior and volumes>100 indicate strong synergistic behavior. Determination of in vitro additive, synergistic and strongly synergistic behavior for combinations of compounds can be of utility in predicting therapeutic benefits for administering the combinations of compounds in vivo to infected patients.

The CI and synergy volume results for the combinations are provided in Table 10.

	TABLE 10
	Combination		Synergy Volume
	Compound	CI at EC50	(μM2 %)
	INX-189	0.67	31
	PSI-938	1	36
	PSI-6130	1	21
	PSI-7851	1.2	14
	GS-9190	0.45	112
	Filibuvir	0.46	38
	ANA-598	0.67	32
	VX-222	1.1	52
	VX-950	0.56	34
	ITMN-191	0.84	39
	TMC-435	0.85	104
	BMS-790052	0.48	25
	6002	0.01	127
	Ribavirin	0.88	0
	Pegylated	1	13
	Interferon
	Consensus	1.1	18
	Interferon
	Cyclosporin A	0.75	67
	BILN-2061	0.86	12
	HCV-796	0.39	35
	IFN-Lambda 1	0.64	43
	IFN-Lambda 2	0.56	31
	IFN-Lambda 3	0.87	33

Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein at least one of R3a and R3b is an optionally substituted C1-6-alkyl; and the other of R3a and R3b is hydrogen.

3. The compound of claim 2, wherein the optionally substituted C1-6-alkyl is methyl.

4. The compound of claim 1, wherein at least one of R3a and R3b is an optionally substituted C2-6-alkyl; and the other of R3a and R3b is hydrogen.

5. The compound of claim 1, wherein R2 is an optionally substituted aryl.

6. The compound of claim 5, wherein the optionally substituted aryl is an optionally substituted phenyl or an optionally substituted naphthyl.

7. The compound of claim 1, wherein R2 is an optionally substituted heteroaryl.

8. The compound of claim 1, wherein R1 is an optionally substituted N-linked α-amino acid.

9. The compound of claim 1, wherein R1 is an optionally substituted N-linked α-amino acid ester derivative.

10. The compound of claim 1, wherein R1 is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof.

11. The compound of claim 10, wherein R1 is selected from the group consisting of alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester, and leucine isopropyl ester.

12. The compound of claim 11, wherein R1 is alanine cyclohexyl ester.

13. The compound of claim 1, wherein R1 has the structure

14. The compound of claim 13, wherein R16 is an optionally substituted C1-6-alkyl.

15. The compound of claim 14, wherein the optionally substituted C1-6-alkyl is methyl.

16. The compound of claim 13, wherein R17 is hydrogen.

17. The compound of claim 13, wherein R15 is an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl.

18. The compound claim 13, wherein

19. The compound of claim 18, wherein

20. The compound of claim 1, wherein R7 is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6 alkyl, and —OH.

21. The compound of claim 1, wherein R5 is hydrogen.

22. The compound of claim 1, wherein R5 is —OR9.

23. The compound of claim 22, wherein R9 is hydrogen.

24. The compound of claim 22, wherein R9 is an optionally substituted C1-6 alkyl.

25. The compound of claim 1, wherein R5 is —OC(═O)R10.

26. The compound of claim 1, wherein R6 is —OR11 or —OC(═O)R12.

27. The compound of claim 1, wherein R5 and R6 are both oxygen atoms and linked together by a carbonyl group; or R5 and R6 are both hydrogen; or R5 is —OH, and R6 is —OH; or R5 is —OC(═O)R10 and R6 is —OC(═O)R12.

28. The compound of claim 1, wherein R6 and R7 are both halogen; or R6 is hydrogen, and R7 is selected from halogen, an optionally substituted C1-6 alkyl and —OR13; or R6 is halogen, and R7 is an optionally substituted C1-6 alkyl.

29. The compound of claim 1, wherein R8 is hydrogen.

30. The compound of claim 1, wherein R8 is an optionally substituted C1-6 alkyl.

31. The compound of claim 1, wherein B1 is selected from the group consisting of:

32. The compound of claim 31, wherein B1 is selected from the group consisting

33. The compound of claim 1, wherein when R2 is phenyl then R1 cannot be

34. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

35. The compound of claim 1, wherein the compound of Formula (I) is

36. The compound of claim 1, wherein the compound of Formula (I) is

37. The compound of claim 1, wherein the compound of Formula (I) is

38. The compound of claim 1, wherein the compound of Formula (I) is

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

40. A method of ameliorating or treating a viral infection comprising administering to a subject suffering from the viral infection a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein the viral infection is caused by a virus selected from the group consisting of an adenovirus, an Alphaviridae, an Arbovirus, an Astrovirus, a Bunyaviridae, a Coronaviridae, a Filoviridae, a Flaviviridae, a Hepadnaviridae, a Herpesviridae, an Alphaherpesvirinae, a Betaherpesvirinae, a Gammaherpesvirinae, a Norwalk Virus, an Astroviridae, a Caliciviridae, an Orthomyxoviridae, a Paramyxoviridae, a Paramyxoviruses, a Rubulavirus, a Morbillivirus, a Papovaviridae, a Parvoviridae, a Picornaviridae, an Aphthoviridae, a Cardioviridae, an Enteroviridae, a Coxsackie virus, a Polio Virus, a Rhinoviridae, a Phycodnaviridae, a Poxyiridae, a Reoviridae, a Rotavirus, a Retroviridae, an A-Type Retrovirus, an Immunodeficiency Virus, a Leukemia Viruses, an Avian Sarcoma Viruses, a Rhabdoviruses, a Rubiviridae and a Togaviridae.

42. A method for ameliorating or treating an HCV infection comprising administering to a subject suffering from an HCV infection a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

43. A method for inhibiting NS5B polymerase activity comprising contacting a cell with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

44. A method for inhibiting replication of a virus comprising contacting a cell infected with the virus with a compound of claim 1, or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the virus is HCV.

46. A method for ameliorating or treating a viral infection comprising contacting a cell infected with the virus with a compound of claim 1, or a pharmaceutically acceptable salt thereof.

47. The method of claim 46, wherein the viral infection is a HCV viral infection.

48. A method of ameliorating or treating a viral infection comprising contacting a cell infected with the viral infection with a therapeutically effective amount of a compound selected from a compound of claim 1, compound 7072, compound 7073, compound 7074, compound 7075, compound 7076, compound 7077, a monophosphate of any of the foregoing, a diphosphate of any of the foregoing, or a pharmaceutically acceptable salt the foregoing, in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

49. The method of claim 48, wherein the one or more agents are selected from the group consisting of Compounds 1001-1014, 2001-2010, 3001-3008, 4001-4005, 5001-5002, 6000-6078, 8000-8012 and 9000, or a pharmaceutically acceptable salt of any of the aforementioned compounds.

50. The method of claim 48, wherein the viral infection is a HCV viral infection.

51. A method of ameliorating or treating a viral infection comprising administering to a subject suffering from the viral infection a therapeutically effective amount of a compound selected from a compound of claim 1, compound 7072, compound 7073, compound 7074, compound 7075, compound 7076, and compound 7077, a monophosphate of any of the foregoing, a diphosphate of any of the foregoing, or a pharmaceutically acceptable salt the foregoing, in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB), a compound of Formula (CC) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

52. The method of claim 51, wherein the one or more agents are selected from the group consisting of Compounds 1001-1014, 2001-2010, 3001-3008, 4001-4005, 5001-5002, 6000-6078, 8000-8012 and 9000, or a pharmaceutically acceptable salt of any of the aforementioned compounds.

53. The method of claim 51, wherein the viral infection is a HCV viral infection.