Substituted nucleosides, nucleotides and analogs thereof

Abstract

Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.

Description

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

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

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SEQLISTING_065C8-Substitute.TXT, created Feb. 20, 2020, which is 2 Kb in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

BACKGROUND

Field

The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are nucleotide analogs, pharmaceutical compositions that include one or more nucleotide analogs and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a nucleotide analog, alone or in combination therapy with one or more other agents.

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. 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 a method of ameliorating and/or treating a hepatitis C viral (HCV) infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a HCV infection. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a HCV infection.

Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, in the manufacture of a medicament for inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof, that can be used for inhibiting replication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments disclosed herein relate to a method of inhibiting replication of a hepatitis C virus that can include administering to a subject identified as suffering from a HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, another antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the agent can be a compound, or a pharmaceutically acceptable salt thereof, selected from Compound 1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5012, 6001-6078, 7000-7027 and 8000-8016, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the method can include administering a second agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the foregoing.

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.

FIG. 6 shows example compounds of Formula (CC) and alpha-thiotriphosphates thereof, wherein Formula (CC) and alpha-thiotriphosphates thereof are described herein.

FIG. 7 shows example compounds of Formula (AA), wherein Formula (AA) is described herein.

FIG. 8 shows example compounds of Formula (BB), wherein Formula (BB) is described herein.

FIG. 9 shows example compounds of Formula (I), wherein Formula (I) is described herein.

FIG. 10 shows the gels from the assessment of incorporation of several compound with a uracil base by the human mitochondrial RNA polymerase.

FIG. 11 shows the gels from the assessment of incorporation of several compounds with a guanine base by the human mitochondrial RNA polymerase.

FIGS. 12A-D shows the results of the inhibition of mitochondrial protein synthesis assays.

DETAILED DESCRIPTION

Definitions

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, R³, R⁴, R^5A, R^5B, R^6A, R^6B, R^6C, R^6D, R^6E, R^6F, R^6G, R^6H, R^7A, R^7B, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R^A1, R^A2, R^A3 and R^A4 represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R^a and R^b of an NR^a R^b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:

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

Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

As used herein, “C_a to C_b” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.

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 can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted.

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, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

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, pyrrolidone, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.

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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

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

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

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

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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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 each X is a halogen.

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

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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)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.

The term “nucleotide” is used herein in its ordinary sense as understood by those skilled in the art, and refers to a nucleoside having a phosphate ester bound to the pentose moiety, for example, at the 5′-position.

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

The term “—O-linked amino acid” refers to an amino acid that is attached to the indicated moiety via the hydroxy from its main-chain carboxylic acid group. When the amino acid is attached in an —O-linked amino acid, the hydrogen that is part of the hydroxy from its main-chain carboxylic acid group is not present and the amino acid is attached via the oxygen. O-linked amino acids can be substituted or unsubstituted.

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.

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

its protonated forms (for example,

and its tautomers (such as

As used herein, the term “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example,

As used herein, the terms “monophosphate,” “diphosphate,” and “triphosphate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms.

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-propyl silyloxymethyl, [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).

The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

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

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 a phosphate and a phosphorothioate groups are intended to be included. Examples of tautomers of a phosphorothioate include the following:

Furthermore, all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases.

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.

Compounds

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

wherein: B¹ can be selected from an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

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

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

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

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

R^5B can be selected from O⁻, OH, an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, an —O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester derivative,

R^6A can be an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl; R^6B and R^6C can be independently selected from hydrogen, an unsubstituted C_1-6 alkyl, an unsubstituted C_3-6 alkenyl, an unsubstituted C_3-6 alkynyl and an unsubstituted C_3-6 cycloalkyl; R^6D can be NHR^6G; R^6E can be hydrogen, halogen or NHR^6H; R^6F can be NHR^6I; R^6G can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A1 and —C(═O)OR^A2; R^6H can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A3 and —C(═O)OR^A4; R^6I can be selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_3-6 alkenyl, an optionally substituted C_3-6 cycloalkyl, —C(═O)R^A5 and —C(═O)OR^A6; X¹ can be N (nitrogen) or —CR^6J, R^6J can be selected from hydrogen, halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl and an optionally substituted C_2-6 alkynyl; R^A1, R^A2, R^A3, R^A4, R^A5 and R^A6 can be independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_6-10 aryl, heteroaryl, heterocyclyl, aryl(C_1-6 alkyl), heteroaryl(C_1-6 alkyl) and heterocyclyl(C_1-6 alkyl); R^7A can be hydrogen or —C(═O)R¹²; R^7B and R^7C can be independently hydrogen or an optionally substituted C_1-6 alkyl; R⁸ and R¹² can be independently an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl; R⁹, R¹⁰ and R¹¹ can be independently absent or hydrogen; R^8A, R^9A, R^11A, R^12A, R^8B, R^9B, R^11B, R^12B, R^p2, R^p3, R^p5 and R^p6 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl and an optionally substituted aryl; R^10A, R^10B, R^13A, R^13B, R^p4 and R^p7 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl; R^14A, R^14B, R^15A, R^15B, R^p8 and R^p9 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl and an optionally substituted aryl; n can be 0 or 1; p, q, and r can be independently 1 or 2; s, t and u can be independently 3, 4 or 5; Z¹, Z^1A, Z^1B and Z^p1 can be independently O (oxygen) or S (sulfur); and provided that when R⁴ is

and R^5A is O⁻ or OH, then R^5B is O⁻, OH,

an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

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

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

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

In some embodiments, R¹ can be an optionally substituted C_1-6 alkyl. In some embodiments, R¹ can be an unsubstituted C_1-6 alkyl. For example, R¹ can be unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstituted isobutyl, unsubstituted tert-butyl, unsubstituted pentyl (branched and straight-chained) or unsubstituted hexyl (branched and straight-chained). In some embodiments, R¹ can be a substituted C_1-6 alkyl. Suitable substitutions are described herein. As an example, R¹ can be a halo-substituted C_1-6 alkyl (such as —CF₃ or —CH₂CH₂F). In other embodiments, R¹ can be an optionally substituted C_2-6 alkenyl. Suitable alkenyl groups include, but are not limited to optionally substituted variants of the following: ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, pentenyl (branched and straight-chained), hexenyl (branched and straight-chained), vinyl and allenyl. In still other embodiments, R¹ can be an optionally substituted C_2-6 alkynyl. In yet still other embodiments, R¹ can be an optionally substituted C_3-6 cycloalkyl, such as those described herein.

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

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

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

In some embodiments, the compound of Formula (I) can be a monophosphate. In other embodiments, the compound of Formula (I) can be a thiomonophosphate. In some embodiments, the compound of Formula (I) can be a diphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiodiphosphate. In some embodiments, the compound of Formula (I) can be a triphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiotriphosphate. In some embodiments, R⁴ can be

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

R^5A can be O⁻ or OH; R^5B can be

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

R^5A can be O⁻ or OH; R^5B can be

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

In some embodiments, R^5A can be an optionally substituted N-linked amino acid. Various amino acids are suitable, including those described herein. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. In other embodiments, R^5A can be an optionally substituted N-linked amino acid ester derivative. Examples of N-linked amino acid ester derivatives include, but are not limited to, ester derivatives of any of the following amino acids: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of N-linked amino acid ester derivatives include, but are not limited to, an ester derivative of any of the following amino acids: alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine. In some embodiments, the N-linked amino acid ester derivative can be a C_1-6 alkyl ester derivative, for example, an isopropyl ester of alanine. In other embodiments, the N-linked amino acid ester derivative can be a C_3-6 cycloalkyl ester derivative, such as a cyclohexyl ester of alanine.

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

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

When R¹⁴ is substituted, R¹⁴ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R¹⁴ can be an unsubstituted C_1-6-alkyl, such as those described herein. In some embodiments, R¹⁴ can be hydrogen. In other embodiments, R¹⁴ can be methyl. In some embodiments, R¹³ can be an optionally substituted C_1-6 alkyl. Examples of optionally substituted C_1-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In some embodiments, R¹³ can be methyl or isopropyl. In some embodiments, R¹³ can be ethyl or neopentyl. In other embodiments, R¹³ can be an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R¹³ can be an optionally substituted cyclohexyl. In still other embodiments, R¹³ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹³ can be an optionally substituted aryl(C_1-6 alkyl). In some embodiments, R¹³ can be an optionally substituted benzyl. In some embodiments, R¹³ can be an optionally substituted C_1-6 haloalkyl, for example, CF₃. In some embodiments, R¹⁵ can be hydrogen. In other embodiments, R¹⁵ can be an optionally substituted C_1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R¹⁵ can be methyl. In some embodiments, R¹⁴ and R¹⁵ can be taken together to form an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R¹⁴ and R¹⁵, the carbon to which R¹⁴ and R¹⁵ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁴ and R¹⁵ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R¹⁴ and R¹⁵ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^5B can be an —O-optionally substituted aryl. For example, R^5B can be an —O-optionally substituted phenyl. When the phenyl is substituted, the ring can be substituted 1, 2, 3 or more than 3 times. Suitable mono-substituted phenyl groups include, ortho-substituted phenyl, meta-substituted phenyl and para-substituted phenyl. In other embodiments, R^5B can be an —O-unsubstituted aryl. Alternatively, R^5B can be an —O-optionally substituted naphthyl. In other embodiments, R^5B can be an —O-optionally substituted heteroaryl. For example, R^5B can be an —O-optionally substituted quinolinyl. In still other embodiments, R^5B can be an —O-optionally substituted heterocyclyl.

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

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

When R¹⁷ is substituted, R¹⁷ can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R¹⁷ can be an unsubstituted C_1-6-alkyl, such as those described herein. In some embodiments, R¹⁷ can be hydrogen. In other embodiments, R¹⁷ can be methyl. In some embodiments, R¹⁶ can be an optionally substituted C_1-6 alkyl. Examples of optionally substituted C_1-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained). In some embodiments, R¹⁶ can be methyl or isopropyl. In some embodiments, R¹⁶ can be ethyl or neopentyl. In other embodiments, R¹⁶ can be an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R¹⁶ can be an optionally substituted cyclohexyl. In still other embodiments, R¹⁶ can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R¹⁶ can be an optionally substituted aryl(C_1-6 alkyl). In some embodiments, R¹⁶ can be an optionally substituted benzyl. In some embodiments, R¹⁶ can be an optionally substituted C_1-6 haloalkyl, for example, CF₃. In some embodiments, R¹⁸ can be hydrogen. In other embodiments, R¹⁸ can be an optionally substituted C_1-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R¹⁸ can be methyl. In some embodiments, R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C_3-6 cycloalkyl. Examples of optionally substituted C_3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R¹⁷ and R¹⁸, the carbon to which R¹⁷ and R¹⁸ are attached may be a chiral center. In some embodiment, the carbon to which R¹⁷ and R¹⁸ are attached may be a (R)-chiral center. In other embodiments, the carbon to which R⁷ and R⁸ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R^5B can be an —O-optionally substituted aryl. In other embodiments, R^5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R^5B can be an —O-optionally substituted heteroaryl. In some embodiments, R^5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative and R^5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

In some embodiments, R^5A can be

When R^5A is

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

In some embodiments, R^5B can be

When R^5B is

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

and R^5B can be

In some embodiments, R^5A can be

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

In some embodiments, R^5B can be

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

and R^5B can be

In some embodiments, R^5A can be

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

In some embodiments, R^5B can be

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

and R^5B can be

In some embodiments, R^5A can be

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

In some embodiments, R^5B can be

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

and R^5B can be

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

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

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

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

In some embodiments, R^p1 can be O⁻. In other embodiments, R^p1 can be OH. In other embodiments, R^p1 can be an —O-optionally substituted C_1-6 alkyl. For example, R^p1 can be a substituted or an unsubstituted version of the following: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched or straight chained) and hexoxy (branched or straight chained).

In some embodiments, R^p1 can be

wherein R^p2 and R^p3 can be independently selected from hydrogen, an optionally substituted C_1-24 alkyl and an optionally substituted aryl; and R^p4 can be selected from hydrogen, an optionally substituted C_1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^p2 and R^p3 can be hydrogen. In other embodiments, at least one of R^p2 and R^p3 can be an optionally substituted C_1-24 alkyl or an optionally substituted aryl. In some embodiments, R^p4 can be an optionally substituted C_1-24 alkyl. In some embodiments, R^p4 can be an unsubstituted C_1-4 alkyl. In other embodiments, R^p4 can be an optionally substituted aryl. In still other embodiments, R^p4 can be an optionally substituted —O—C_1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl. In some embodiments, R^p4 can be an unsubstituted —O—C_1-4 alkyl.

In some embodiments, R^p1 can be

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

In some embodiments, R^p1 can be

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

In some embodiments, R^p1 can be

In some embodiments, R^p9 can be hydrogen. In other embodiments, R^p9 can be an optionally substituted C_1-24 alkyl. In still other embodiments, R^p9 can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, R^p9 can be an optionally substituted C_1-6 alkyl. In some embodiments, R^p9 can be an unsubstituted C_1-6 alkyl. In some embodiments, u can be 3. In other embodiments, u can be 4. In still other embodiments, u can be 5. In some embodiments, R^p1 can be a S-acylthioethyl (SATE) group and form a SATE ester prodrug.

In some embodiments, R^p1 can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. For example, R^p1 can be optionally substituted version of the following: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof. In some embodiments, R^p1 can be selected from N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester and N-leucine isopropyl ester. In some embodiments, R^p1 can have the structure

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

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

Examples of suitable

groups include the following:

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

In some embodiments, B¹ can be unsubstituted

In other embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In some embodiments, R^6A can be an optionally substituted C_1-6 alkyl. For example, R^6A can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In other embodiments, R^6A can be an optionally substituted C_3-6 cycloalkyl, for example, optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

In other embodiments, B¹ can be an optionally substituted

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

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

In some embodiments, B¹ can be an optionally substituted

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

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

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

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

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

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

In some embodiments, Z¹ can be O (oxygen). In other embodiments, Z¹ can be S (sulfur).

In some embodiments, R² is not halo. In some embodiments, R² is not fluoro. In some embodiments, R^5B is not an —O-optionally substituted aryl. In some embodiments, R^5B is not an —O-unsubstituted aryl. In some embodiments, R^5A is not N-alanine isopropyl ester. In some embodiments, R¹ is not an optionally substituted C_1-6 alkyl. For example, R¹ is not an unsubstituted C_1-6 alkyl, such as methyl. In some embodiments, B¹ is not an optionally substituted uracil, for example, a halo-substituted uracil. In some embodiment, when both -------- are each absent; R^P is absent; R³ is OH or —OC(═O)R⁸; R² is F; and R¹ is methyl, ethyl or ethenyl; then R⁴ cannot be selected from H and

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

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

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

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

Examples of compounds of Formula (I) include the following:

pharmaceutically acceptable salt of the foregoing.

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

or a pharmaceutically acceptable salt of the foregoing.

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

or a pharmaceutically acceptable salt of the foregoing.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

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

or a pharmaceutically acceptable salt of the foregoing.

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

or a pharmaceutically acceptable salt of the foregoing.

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

or a pharmaceutically acceptable salt of the foregoing.

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

or a pharmaceutically acceptable salt of the foregoing.

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

R^5A being an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; and R^5B being an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, an —O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. By neutralizing the charge on the phosphate or thiophosphate, penetration of the cell membrane may be facilitated as a result of the increased lipophilicity of the compound. Once absorbed and taken inside the cell, the groups attached to the phosphorus can be easily removed by esterases, proteases and/or other enzymes. In some embodiments, the groups attached to the phosphorus can be removed by simple hydrolysis. Inside the cell, the phosphate thus released may then be metabolized by cellular enzymes to the diphosphate or the active triphosphate. Likewise, the thio-phosphate may be metabolized to the alpha-thiodiphosphate or the alpha-thiotriphosphate. Furthermore, in some embodiments, varying the substituents on a compound described herein, such as compound of Formula (I), can help maintain the efficacy of such the compound by reducing undesirable effects, such as isomerization.

In some embodiments, the phosphorylation of a thio-monophosphate of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can be stereoselective. For example, a thio-monophosphate of a compound of Formula (I) can be phosphorylated to give an alpha-thiodiphosphate and/or an alpha-thiotriphosphate compound that can be enriched in the (R) or (S) diastereomer with respect to the 5′-O-phosphorous atom. For example, one of the (R) and (S) configuration with respect to the 5′-O-phosphorous atom of the alpha-thiodiphosphate and/or the alpha-thiotriphosphate compound can be present in an amount >50%, ≥75%, ≥90%, ≥95% or ≥99% compared to the amount of the other of the (R) or (S) configuration with respect to the 5′-O-phosphorous atom. In some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can result in the formation of a compound that has the (R)-configuration at the 5′-O-phosphorous atom. In some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable salt thereof, can result in formation of a compound that has the (S)-configuration at the 5′-O-phosphorous atom.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can act as a chain terminator of HCV replication. For example, compounds of Formula (I) can contain a moiety at the 2′-carbon position such that once the compound is incorporated into an RNA chain of HCV no further elongation is observed to occur. For example, a compound of Formula (I) can contain a 2′-carbon modification wherein R¹ is a non-hydrogen group selected from an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl and an optionally substituted C_3-6 cycloalkyl.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be more resistant to hydrolysis and/or more resistant to enzymatic transformations. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have increased metabolic stability, increased plasma stability, can be more resistant to hydrolysis and/or can be more resistant to enzymatic transformations compared to a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4′-position. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have improved properties. A non-limiting list of example properties include, but are not limited to, increased biological half-life, increased bioavailability, increase potency, a sustained in vivo response, increased dosing intervals, decreased dosing amounts, decreased cytotoxicity, reduction in required amounts for treating disease conditions, reduction in viral load, reduction in time to seroconversion (i.e., the virus becomes undetectable in patient serum), increased sustained viral response, a reduction of morbidity or mortality in clinical outcomes, increased subject compliance, decreased liver conditions (such as liver fibrosis, liver cirrhosis and/or liver cancer), and compatibility with other medications. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have a biological half-life of greater than 24 hours. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have a biological half-life greater than a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4′-position. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have more potent antiviral activity (for example, a lower EC₅₀ in an HCV replicon assay) as compared to the current standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, does not significantly inhibit mitochondrial function of the mitochondrial RNA polymerase. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is incorporated in the human mitochondrial RNA polymerase less than 10% compared to the natural 5′-triphosphate nucleotide with the same B¹.

Additionally, in some embodiments, the presence of a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate in a compound of Formula (I) can increase the stability of the compound by inhibiting its degradation. Also, in some embodiments, the presence of a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can make the compound more resistant to cleavage in vivo and provide sustained, extended efficacy. In some embodiments, a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can facilitate the penetration of the cell membrane by a compound of Formula (I) by making the compound more lipophilic. In some embodiments, a thiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate or phosphorbisamidate can have improved oral bioavailability, improved aqueous stability and/or reduced risk of byproduct-related toxicity. In some embodiments, for comparison purposes, a compound of Formula (I) can be compared to a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4′-position.

Synthesis

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

Compounds of Formula (I) can be prepared using various methods known to those skilled in the art. Examples of methods are shown in Schemes 1 and 2. Suitable phosphorus containing precursors can be commercially obtained or prepared by synthetic methods known to those skilled in the art. Examples of general structures of phosphorus containing precursors are shown in Schemes 1 and 2, and include phosphorochloridates and thiophosphorochloridates. Suitable phosphorochloridates and thiophosphorochloridates are commercially available and/or can be synthetically prepared.

One method for forming a compound of Formula (I) is shown in Scheme 1. In Scheme 1, R^1a, R^2a, R^3a and B^1a can be the same as R¹, R², R³ and B¹ as described herein for Formula (I). In some embodiments, a compound of Formula (I) can be generated from a compound of Formula (A) and a compound of Formula (B) or a compound of Formula (A) and a compound of Formula (C) using an organometallic reagent, such as a Grignard reagent. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnesium bromides. In other embodiments, an appropriate base can be used to form a compound of Formula (I). Examples of suitable bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole)).

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

Alternatively, one of the oxygens attached to the phosphorus can be exchanged with a sulfur using a sulfurization reagent. Suitable sulfurization agents are known to those skilled in the art, and include, but are not limited to, elemental sulfur, Lawesson's reagent, cyclooctasulfur, 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage's reagent), 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

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

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

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

To reduce the formation of side products, one or more the groups attached to the pentose ring can be protected with one or more suitable protecting groups. As an example, if R² and/or R³ is/are hydroxy group(s), the hydroxy group(s) can be protected with suitable protecting groups, such as triarylmethyl and/or silyl groups. Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy) trityl (TBTr), 4,4′,4″-tris (4,5-dichlorophthalimido) trityl (CPTr), 4,4′,4″-tris (levulinyloxy) trityl (TLTr), p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl, p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl, 9-(4-octadecyloxyphenyl) xanthen-9-yl, 1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl, 4,4′,4″-tris-(tert-butylphenyl) methyl (TTTr) and 4,4′-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups are described herein and include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. Alternatively, R² and/or R³ can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2-oxacyclopentylidene orthoester, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylidene orthoester, and alpha-methoxybenzylidene orthoester; suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3-(benzyloxy)propyl acetal, benzylidene acetal, 3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; and suitable cyclic ketals include 1-t-butylethylidene ketal, 1-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal and 1-(4-methoxyphenyl)ethylidene ketal.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, the pharmaceutical composition can include a single diastereomer of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (for example, a single diastereomer is present in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the other diastereomers). In other embodiments, the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition can include a concentration of one diastereomer of >50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, or ≥98%, as compared to the total concentration of the other diastereomers. In some embodiments, the pharmaceutical composition includes a 1:1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. A pharmaceutical composition is suitable for human and/or veterinary applications.

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

Some embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject an effective amount of one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof. Other embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject identified as suffering from the disease or condition an effective amount of one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relates to a method of ameliorating or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein (for example, a compound of Formula (I)), or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein. Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a HCV infection by administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein.

Some embodiments disclosed herein relate to methods of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to methods of inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for inhibiting replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for inhibiting replication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).

In some embodiments, the compound can be a compound of Formula (I), or a pharmaceutical acceptable salt thereof, wherein R⁴ is hydrogen. In other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is a mono, di, or triphosphate, or a pharmaceutically acceptable salt of the foregoing. In still other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is a thiomonophosphate, alpha-thiodiphosphate, or alpha-thiotriphosphate, or a pharmaceutically acceptable salt of the foregoing. In yet still other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is phosphoroamidate or phosphorbisamidate, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is thiophosphoroamidate or thiophosphorbisamidate, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutical acceptable salt thereof, that can be used for ameliorating and/or treating a viral infection (for example, a HCV infection) and/or inhibit replication of a virus (such as a HCV virus) can be any of the embodiments provided in any of the embodiments described above beginning at the first paragraph after the section heading entitled “Compounds” and ending with the sentence: “In some embodiments, a compound of Formula (I) cannot be selected from:

or a pharmaceutically acceptable salt of the foregoing.”

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 that can include contacting a cell infected with hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof. Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include administering to a subject infected with hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit a RNA dependent RNA polymerase, and thus, inhibit the replication of HCV RNA. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can inhibit a HCV polymerase (for example, NS5B polymerase).

Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrhosis and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof), wherein the liver condition is caused by a HCV infection. Some embodiments described herein relate to a method of increasing liver function in a subject having a HCV infection that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof). Also contemplated is a method for reducing or eliminating further virus-caused liver damage in a subject having an HCV infection by administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof). In some embodiments, this method can include slowing or halting the progression of liver disease. In other embodiments, the course of the disease can be reversed, and stasis or improvement in liver function is contemplated. In some embodiments, liver fibrosis, liver cirrhosis and/or liver cancer can be treated; liver function can be increased; virus-caused liver damage can be reduced or eliminated; progression of liver disease can be slowed or halted; the course of the liver disease can be reversed and/or liver function can be improved or maintained by contacting a cell infected with hepatitis C virus with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.)

There are a variety of genotypes of HCV, and a variety of subtypes within each genotype. For example, at present it is known that there are eleven (numbered 1 through 11) main genotypes of HCV, although others have classified the genotypes as 6 main genotypes. Each of these genotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formula (I), or a pharmaceutical acceptable salt thereof, can be effective to treat at least one genotype of HCV. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can be effective to treat all 11 genotypes of HCV. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can be effective to treat 3 or more, 5 or more, 7 or more, or 9 or more genotypes of HCV. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable salt thereof can be more effective against a larger number of HCV genotypes than the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable salt thereof, can be more effective against a particular HCV genotype than the standard of care (such as genotype 1, 2, 3, 4, 5 and/or 6).

Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, a reduction in the rate of liver function decrease; stasis in liver function; improvement in liver function; reduction in one or more markers of liver dysfunction, including alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase and/or other indicator of disease response. Similarly, successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I), or a pharmaceutical acceptable salt thereof) can reduce the incidence of liver cancer in HCV infected subjects.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce HCV viral titers to undetectable levels, for example, to about 100 to about 500, to about 50 to about 100, to about 10 to about 50, or to about 15 to about 25 international units/mL serum. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce HCV viral load compared to the HCV viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, wherein the HCV viral load is measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be an amount that is effective to reduce HCV viral load to lower than about 25 international units/mL serum. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a reduction in HCV viral titer in the serum of the subject in the range of about 1.5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5-log reduction compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the HCV viral load can be measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after completion of the treatment regime with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 1 month after completion).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of the hepatitis C virus relative to pre-treatment levels in a subject, as determined after completion of the treatment regime (for example, 1 month after completion). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of the replication of the hepatitis C virus relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of the hepatitis C virus replication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of the hepatitis C virus replication compared to the reduction of the hepatitis C virus reduction achieved by pegylated interferon in combination with ribavirin, administered according to the standard of care, or may achieve the same reduction as that standard of care therapy in a shorter period of time, for example, in one month, two months, or three months, as compared to the reduction achieved after six months of standard of care therapy with ribavirin and pegylated interferon.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 200, less than about 100, less than about 25, or less than about 15 international units per milliliter serum) is found in the subject's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can reduce a level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated subject, or to a placebo-treated subject. Methods of measuring serum markers are known to those skilled in the art and include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker. A non-limiting list of examples of markers includes measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) using known methods. In general, an ALT level of less than about 45 IU/L (international units/liter), an AST in the range of 10-34 IU/L, ALP in the range of 44-147 IU/L, GGT in the range of 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with what is considered a normal level.

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 (for example, an agent used in a conventional standard of care). In some embodiments, development of resistant HCV strains is delayed when a subject is treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of HCV strains resistant to other HCV drugs (such as an agent used in a conventional standard of care).

In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject for whom other anti-HCV medications are contraindicated. For example, administration of pegylated interferon alpha in combination with ribavirin is contraindicated in subjects with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) and other subjects at risk from the hematologic side effects of current therapy. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided to a subject that is hypersensitive to interferon and/or ribavirin.

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), or a pharmaceutically acceptable salt thereof, can decrease the number and/or severity of side effects that can be observed in HCV patients being treated with ribavirin and pegylated interferon according to the standard of care. Examples of side effects include, but are not limited to fever, malaise, tachycardia, chills, headache, arthralgias, myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritability, confusion, depression, severe depression, suicidal ideation, anemia, low white blood cell counts, and thinning of hair. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided to a subject that discontinued a HCV therapy because of one or more adverse effects or side effects associated with one or more other HCV agents (for example, an agent used in a conventional standard of care).

Table 1 provides some embodiments of the percentage improvement obtained using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to the standard of care. Examples include the following: in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a percentage of non-responders that is 10% less than the percentage of non-responders receiving the standard of care; in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving the standard of care; and in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving the standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art.

TABLE 1
Percentage		Percentage	Percentage
of non-	Percentage	of	of viral load	Number of	Severity of
responders	of relapsers	resistance	rebound	side effects	side effects
10% less	10% less	10% less	10% less	10% less	10% less
25% less	25% less	25% less	25% less	25% less	25% less
40% less	40% less	40% less	40% less	40% less	40% less
50% less	50% less	50% less	50% less	50% less	50% less
60% less	60% less	60% less	60% less	60% less	60% less
70% less	70% less	70% less	70% less	70% less	70% less
80% less	80% less	80% less	80% less	80% less	80% less
90% less	90% less	90% less	90% less	90% less	90% less
about 10%	about 10%	about 10%	about 10% to	about 10% to	about 10% to
to about	to about	to about	about 30%	about 30%	about 30%
30% less	30% less	30% less	less	less	less
about 20%	about 20%	about 20%	about 20% to	about 20% to	about 20% to
to about	to about	to about	about 50%	about 50%	about 50%
50% less	50% less	50% less	less	less	less
about 30%	about 30%	about 30%	about 30% to	about 30% to	about 30% to
to about	to about	to about	about 70%	about 70%	about 70%
70% less	70% less	70% less	less	less	less
about 20%	about 20%	about 20%	about 20% to	about 20% to	about 20% to
to about	to about	to about	about 80%	about 80%	about 80%
80% less	80% less	80% less	less	less	less

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 terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

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), or a pharmaceutically acceptable salt thereof, can be administered less frequently compared to the frequency of administration of an agent within the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one time per day. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one time per day to a subject suffering from a HCV infection. In some embodiments, the total time of the treatment regime with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can less compared to the total time of the treatment regime with the standard of care.

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), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable salt thereof, can be used in combination with one or more additional agent(s). Examples of additional agents that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include, but are not limited to, agents currently used in a conventional standard of care for treating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of Formula (AA), (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (AA), or a pharmaceutically acceptable salt thereof), compounds of Formula (BB) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (BB), or a pharmaceutically acceptable salt thereof), compounds of Formula (CC) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (CC), or a pharmaceutically acceptable salt thereof), and/or combinations thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used with one, two, three or more additional agents described herein. A non-limiting list of examples of combinations of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in Tables A, B, C, D and E.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with an agent(s) currently used in a conventional standard of care therapy. For example, for the treatment of HCV, a compound disclosed herein can be used in combination with Pegylated interferon-alpha-2a (brand name PEGASYS®) and ribavirin, Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin, Pegylated interferon-alpha-2a, Pegylated interferon-alpha-2b, or ribavirin.

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. Additional HCV protease inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include VP-19744, PSI-879, VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479, R-1626, R-7182, MK-0608, INX-8014, INX-8018, A-848837, A-837093, BILB-1941, VCH-916, VCH-716, GSK-71185, GSK-625433, XTL-2125 and those disclosed in PCT Publication No. WO 2012/142085, which is hereby incorporated by reference for the limited purpose of its disclosure of HCV protease inhibitors, HCV polymerase inhibitors and NS5A inhibitors. A non-limiting list of example HCV protease inhibitors includes the compounds numbered 1001-1016 in FIG. 1.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189, PSI-352938, PSI-661, 4′-azidouridine (including known prodrugs of 4′-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinations thereof. A non-limiting list of example nucleoside inhibitors includes compounds numbered 2001-2012 in FIG. 2. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof. A non-limiting list of example non-nucleoside inhibitors includes the compounds numbered 3001-3014 in FIG. 3. Further HCV polymerase inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include VX-500, VX-813, VBY-376, TMC-435350, EZ-058, EZ-063, GS-9132, ACH-1095, IDX-136, IDX-316, ITMN-8356, ITMN-8347, ITMN-8096, ITMN-7587, VX-985, and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a NS5A inhibitor. Examples of NS5A inhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A non-limiting list of example NS5A inhibitors includes the compounds numbered 4001-4012 in FIG. 4. Additional NS5A inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, include A-832, PPI-1301 and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122, cyclosporin A and/or combinations thereof. A non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5012 in FIG. 5.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (AA), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (AA), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2013/0164261, published Jun. 27, 2013, the contents of which are incorporated by reference in its entirety):

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

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

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

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (BB), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0165286, published Jun. 28, 2012, the contents of which are incorporated by reference in their entireties):

wherein B^BB1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; X^BB can be O (oxygen) or S (sulfur); R^BB1 can be selected from —Z^BB—R^BB9, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; Z^BB can be selected from O (oxygen), S (sulfur) and N(R^BB10); R^BB2 and R^BB3 can be independently selected from hydrogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl, an optionally substituted C_1-6 haloalkyl and an optionally substituted aryl(C_1-6 alkyl); or R^BB2 and R^BB3 can be taken together to form a group selected from an optionally substituted C_3-6 cycloalkyl, an optionally substituted C_3-6 cycloalkenyl, an optionally substituted C_3-6 aryl and an optionally substituted C_3-6 heteroaryl; R^BB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl, an optionally substituted C_2-6 alkynyl and an optionally substituted allenyl; R^BB5 can be hydrogen or an optionally substituted C_1-6 alkyl; R^BB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C_1-6 alkyl, —OR^BB11 and —OC(═O)R^BB12; R^BB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^BB13 and —OC(═O)R^BB14; R^BB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C_1-6 alkyl, —OR^BB15 and —OC(═O)R^BB16; R^BB9 can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C_1-6alkyl), an optionally substituted heteroaryl(C_1-6alkyl) and an optionally substituted heterocyclyl(C_1-6alkyl); R^BB10 can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C_1-6alkyl), an optionally substituted heteroaryl(C_1-6alkyl) and an optionally substituted heterocyclyl(C_1-6alkyl); R^BB11, R^BB13 and R^BB15 can be independently hydrogen or an optionally substituted C_1-6 alkyl; and R^BB12, R^BB14 and R^BB16 can be independently an optionally substituted C_1-6 alkyl or an optionally substituted C_3-6 cycloalkyl. In some embodiments, at least one of R^BB2 and R^BB3 is not hydrogen. A non-limiting list of example compounds of Formula (BB) includes the compound numbered 8000-8016 in FIG. 8.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (CC), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (CC), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0071434, published Mar. 22, 2012, the contents of which are incorporated by reference in its entirety):

wherein B^CC1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^CC1 can be selected from O⁻, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^CC2 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and

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

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

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

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

Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include administering to a subject suffering from the HCV infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting the replication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting the replication of a hepatitis C virus that can include administering to a subject infected with the hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt the thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.

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

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

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. 1-8 (including pharmaceutically acceptable salts thereof) may be a reduction in the required amount(s) of one or more compounds of FIGS. 1-8 (including pharmaceutically acceptable salts thereof) that is effective in treating a disease condition disclosed herein (for example, HCV), as compared to the amount required to achieve same therapeutic result when one or more compounds of FIGS. 1-8 (including pharmaceutically acceptable salts thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound in FIGS. 1-8 (including a pharmaceutically acceptable salt thereof), can be less compared to the amount of the compound in FIGS. 1-8 (including a pharmaceutically acceptable salt thereof), needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof) thereof; different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof); little to no significant effects on cytochrome P450; little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 1-8 (including pharmaceutically acceptable salts thereof); greater percentage of subjects achieving a sustained viral response compared to when a compound is administered as monotherapy and/or a decrease in treatment time to achieve a sustained viral response compared to when a compound is administered as monotherapy.

A non-limiting list of example combination of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, with one or more additional agent(s) are provided in Tables A, B, C, D and E. Each numbered X and Y compound in Tables A, B, C, D and E has a corresponding name and/or structure provided in FIGS. 1-8. The numbered compounds in Tables A, B, C, D and E includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions containing the compounds or a pharmaceutically acceptable salt thereof. For example, 1001 includes the compound corresponding to 1001, pharmaceutically acceptable salts thereof, and pharmaceutical compositions that include compound 1001 and/or a pharmaceutically acceptable salt thereof. The combinations exemplified in Tables A, B, C, D and E are designated by the formula X:Y, which represents a combination of a compound X with a compound Y. For example, the combination designated as 1001:9004 in Table A represents a combination of compound 1001 with compound 9004, including pharmaceutically acceptable salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004). Thus, the combination designated as 1001:9004 in Table A represents the combination of Telaprevir (compound 1001, as shown in FIG. 1) and

(compound 9004, as shown in FIG. 9), including pharmaceutically acceptable salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004). Each of the combinations provided in Tables A, B, C, D and E can be used with one, two, three or more additional agents described herein. In some embodiments described herein, the combination of agents can be used to treat, ameliorate and/or inhibit a virus and/or a viral infection, wherein the virus can be HCV and the viral infection can be an HCV viral infection.

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

TABLE B
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
3001:9000	3001:9001	3001:9002	3001:9003	3001:9004	3001:9005
3002:9000	3002:9001	3002:9002	3002:9003	3002:9004	3002:9005
3003:9000	3003:9001	3003:9002	3003:9003	3003:9004	3003:9005
3004:9000	3004:9001	3004:9002	3004:9003	3004:9004	3004:9005
3005:9000	3005:9001	3005:9002	3005:9003	3005:9004	3005:9005
3006:9000	3006:9001	3006:9002	3006:9003	3006:9004	3006:9005
3007:9000	3007:9001	3007:9002	3007:9003	3007:9004	3007:9005
3008:9000	3008:9001	3008:9002	3008:9003	3008:9004	3008:9005
3009:9000	3009:9001	3009:9002	3009:9003	3009:9004	3009:9005
3010:9000	3010:9001	3010:9002	3010:9003	3010:9004	3010:9005
3011:9000	3011:9001	3011:9002	3011:9003	3011:9004	3011:9005
3012:9000	3012:9001	3012:9002	3012:9003	3012:9004	3012:9005
3013:9000	3013:9001	3013:9002	3013:9003	3013:9004	3013:9005
3014:9000	3014:9001	3014:9002	3014:9003	3014:9004	3014:9005
4001:9000	4001:9001	4001:9002	4001:9003	4001:9004	4001:9005
4002:9000	4002:9001	4002:9002	4002:9003	4002:9004	4002:9005
4003:9000	4003:9001	4003:9002	4003:9003	4003:9004	4003:9005
4004:9000	4004:9001	4004:9002	4004:9003	4004:9004	4004:9005
4005:9000	4005:9001	4005:9002	4005:9003	4005:9004	4005:9005
4006:9000	4006:9001	4006:9002	4006:9003	4006:9004	4006:9005
4007:9000	4007:9001	4007:9002	4007:9003	4007:9004	4007:9005
4008:9000	4008:9001	4008:9002	4008:9003	4008:9004	4008:9005
4009:9000	4009:9001	4009:9002	4009:9003	4009:9004	4009:9005
4010:9000	4010:9001	4010:9002	4010:9003	4010:9004	4010:9005
4011:9000	4011:9001	4011:9002	4011:9003	4011:9004	4011:9005
4012:9000	4012:9001	4012:9002	4012:9003	4012:9004	4012:9005
5001:9000	5001:9001	5001:9002	5001:9003	5001:9004	5001:9005
5002:9000	5002:9001	5002:9002	5002:9003	5002:9004	5002:9005
5003:9000	5003:9001	5003:9002	5003:9003	5003:9004	5003:9005
5004:9000	5004:9001	5004:9002	5004:9003	5004:9004	5004:9005
5005:9000	5005:9001	5005:9002	5005:9003	5005:9004	5005:9005
5006:9000	5006:9001	5006:9002	5006:9003	5006:9004	5006:9005
5007:9000	5007:9001	5007:9002	5007:9003	5007:9004	5007:9005
5008:9000	5008:9001	5008:9002	5008:9003	5008:9004	5008:9005
5009:9000	5009:9001	5009:9002	5009:9003	5009:9004	5009:9005
5010:9000	5010:9001	5010:9002	5010:9003	5010:9004	5010:9005
5011:9000	5011:9001	5011:9002	5011:9003	5011:9004	5011:9005
5012:9000	5012:9001	5012:9002	5012:9003	5012:9004	5012:9005
3001:9006	3001:9007	3001:9008	3001:9009	3001:9010	3001:9011
3002:9006	3002:9007	3002:9008	3002:9009	3002:9010	3002:9011
3003:9006	3003:9007	3003:9008	3003:9009	3003:9010	3003:9011
3004:9006	3004:9007	3004:9008	3004:9009	3004:9010	3004:9011
3005:9006	3005:9007	3005:9008	3005:9009	3005:9010	3005:9011
3006:9006	3006:9007	3006:9008	3006:9009	3006:9010	3006:9011
3007:9006	3007:9007	3007:9008	3007:9009	3007:9010	3007:9011
3008:9006	3008:9007	3008:9008	3008:9009	3008:9010	3008:9011
3009:9006	3009:9007	3009:9008	3009:9009	3009:9010	3009:9011
3010:9006	3010:9007	3010:9008	3010:9009	3010:9010	3010:9011
3011:9006	3011:9007	3011:9008	3011:9009	3011:9010	3011:9011
3012:9006	3012:9007	3012:9008	3012:9009	3012:9010	3012:9011
3013:9006	3013:9007	3013:9008	3013:9009	3013:9010	3013:9011
3014:9006	3014:9007	3014:9008	3014:9009	3014:9010	3014:9011
4001:9006	4001:9007	4001:9008	4001:9009	4001:9010	4001:9011
4002:9006	4002:9007	4002:9008	4002:9009	4002:9010	4002:9011
4003:9006	4003:9007	4003:9008	4003:9009	4003:9010	4003:9011
4004:9006	4004:9007	4004:9008	4004:9009	4004:9010	4004:9011
4005:9006	4005:9007	4005:9008	4005:9009	4005:9010	4005:9011
4006:9006	4006:9007	4006:9008	4006:9009	4006:9010	4006:9011
4007:9006	4007:9007	4007:9008	4007:9009	4007:9010	4007:9011
4008:9006	4008:9007	4008:9008	4008:9009	4008:9010	4008:9011
4009:9006	4009:9007	4009:9008	4009:9009	4009:9010	4009:9011
4010:9006	4010:9007	4010:9008	4010:9009	4010:9010	4010:9011
4011:9006	4011:9007	4011:9008	4011:9009	4011:9010	4011:9011
4012:9006	4012:9007	4012:9008	4012:9009	4012:9010	4012:9011
5001:9006	5001:9007	5001:9008	5001:9009	5001:9010	5001:9011
5002:9006	5002:9007	5002:9008	5002:9009	5002:9010	5002:9011
5003:9006	5003:9007	5003:9008	5003:9009	5003:9010	5003:9011
5004:9006	5004:9007	5004:9008	5004:9009	5004:9010	5004:9011
5005:9006	5005:9007	5005:9008	5005:9009	5005:9010	5005:9011
5006:9006	5006:9007	5006:9008	5006:9009	5006:9010	5006:9011
5007:9006	5007:9007	5007:9008	5007:9009	5007:9010	5007:9011
5008:9006	5008:9007	5008:9008	5008:9009	5008:9010	5008:9011
5009:9006	5009:9007	5009:9008	5009:9009	5009:9010	5009:9011
5010:9006	5010:9007	5010:9008	5010:9009	5010:9010	5010:9011
5011:9006	5011:9007	5011:9008	5011:9009	5011:9010	5011:9011
5012:9006	5012:9007	5012:9008	5012:9009	5012:9010	5012:9011
3001:9012	3001:9013	3001:9014	3001:9015	3001:9016	3001:9017
3002:9012	3002:9013	3002:9014	3002:9015	3002:9016	3002:9017
3003:9012	3003:9013	3003:9014	3003:9015	3003:9016	3003:9017
3004:9012	3004:9013	3004:9014	3004:9015	3004:9016	3004:9017
3005:9012	3005:9013	3005:9014	3005:9015	3005:9016	3005:9017
3006:9012	3006:9013	3006:9014	3006:9015	3006:9016	3006:9017
3007:9012	3007:9013	3007:9014	3007:9015	3007:9016	3007:9017
3008:9012	3008:9013	3008:9014	3008:9015	3008:9016	3008:9017
3009:9012	3009:9013	3009:9014	3009:9015	3009:9016	3009:9017
3010:9012	3010:9013	3010:9014	3010:9015	3010:9016	3010:9017
3011:9012	3011:9013	3011:9014	3011:9015	3011:9016	3011:9017
3012:9012	3012:9013	3012:9014	3012:9015	3012:9016	3012:9017
3013:9012	3013:9013	3013:9014	3013:9015	3013:9016	3013:9017
3014:9012	3014:9013	3014:9014	3014:9015	3014:9016	3014:9017
4001:9012	4001:9013	4001:9014	4001:9015	4001:9016	4001:9017
4002:9012	4002:9013	4002:9014	4002:9015	4002:9016	4002:9017
4003:9012	4003:9013	4003:9014	4003:9015	4003:9016	4003:9017
4004:9012	4004:9013	4004:9014	4004:9015	4004:9016	4004:9017
4005:9012	4005:9013	4005:9014	4005:9015	4005:9016	4005:9017
4006:9012	4006:9013	4006:9014	4006:9015	4006:9016	4006:9017
4007:9012	4007:9013	4007:9014	4007:9015	4007:9016	4007:9017
4008:9012	4008:9013	4008:9014	4008:9015	4008:9016	4008:9017
4009:9012	4009:9013	4009:9014	4009:9015	4009:9016	4009:9017
4010:9012	4010:9013	4010:9014	4010:9015	4010:9016	4010:9017
4011:9012	4011:9013	4011:9014	4011:9015	4011:9016	4011:9017
4012:9012	4012:9013	4012:9014	4012:9015	4012:9016	4012:9017
5001:9012	5001:9013	5001:9014	5001:9015	5001:9016	5001:9017
5002:9012	5002:9013	5002:9014	5002:9015	5002:9016	5002:9017
5003:9012	5003:9013	5003:9014	5003:9015	5003:9016	5003:9017
5004:9012	5004:9013	5004:9014	5004:9015	5004:9016	5004:9017
5005:9012	5005:9013	5005:9014	5005:9015	5005:9016	5005:9017
5006:9012	5006:9013	5006:9014	5006:9015	5006:9016	5006:9017
5007:9012	5007:9013	5007:9014	5007:9015	5007:9016	5007:9017
5008:9012	5008:9013	5008:9014	5008:9015	5008:9016	5008:9017
5009:9012	5009:9013	5009:9014	5009:9015	5009:9016	5009:9017
5010:9012	5010:9013	5010:9014	5010:9015	5010:9016	5010:9017
5011:9012	5011:9013	5011:9014	5011:9015	5011:9016	5011:9017
5012:9012	5012:9013	5012:9014	5012:9015	5012:9016	5012:9017
3001:9018	3001:9019	3001:9020	3001:9021	3001:9022	3001:9023
3002:9018	3002:9019	3002:9020	3002:9021	3002:9022	3002:9023
3003:9018	3003:9019	3003:9020	3003:9021	3003:9022	3003:9023
3004:9018	3004:9019	3004:9020	3004:9021	3004:9022	3004:9023
3005:9018	3005:9019	3005:9020	3005:9021	3005:9022	3005:9023
3006:9018	3006:9019	3006:9020	3006:9021	3006:9022	3006:9023
3007:9018	3007:9019	3007:9020	3007:9021	3007:9022	3007:9023
3008:9018	3008:9019	3008:9020	3008:9021	3008:9022	3008:9023
3009:9018	3009:9019	3009:9020	3009:9021	3009:9022	3009:9023
3010:9018	3010:9019	3010:9020	3010:9021	3010:9022	3010:9023
3011:9018	3011:9019	3011:9020	3011:9021	3011:9022	3011:9023
3012:9018	3012:9019	3012:9020	3012:9021	3012:9022	3012:9023
3013:9018	3013:9019	3013:9020	3013:9021	3013:9022	3013:9023
3014:9018	3014:9019	3014:9020	3014:9021	3014:9022	3014:9023
4001:9018	4001:9019	4001:9020	4001:9021	4001:9022	4001:9023
4002:9018	4002:9019	4002:9020	4002:9021	4002:9022	4002:9023
4003:9018	4003:9019	4003:9020	4003:9021	4003:9022	4003:9023
4004:9018	4004:9019	4004:9020	4004:9021	4004:9022	4004:9023
4005:9018	4005:9019	4005:9020	4005:9021	4005:9022	4005:9023
4006:9018	4006:9019	4006:9020	4006:9021	4006:9022	4006:9023
4007:9018	4007:9019	4007:9020	4007:9021	4007:9022	4007:9023
4008:9018	4008:9019	4008:9020	4008:9021	4008:9022	4008:9023
4009:9018	4009:9019	4009:9020	4009:9021	4009:9022	4009:9023
4010:9018	4010:9019	4010:9020	4010:9021	4010:9022	4010:9023
4011:9018	4011:9019	4011:9020	4011:9021	4011:9022	4011:9023
4012:9018	4012:9019	4012:9020	4012:9021	4012:9022	4012:9023
5001:9018	5001:9019	5001:9020	5001:9021	5001:9022	5001:9023
5002:9018	5002:9019	5002:9020	5002:9021	5002:9022	5002:9023
5003:9018	5003:9019	5003:9020	5003:9021	5003:9022	5003:9023
5004:9018	5004:9019	5004:9020	5004:9021	5004:9022	5004:9023
5005:9018	5005:9019	5005:9020	5005:9021	5005:9022	5005:9023
5006:9018	5006:9019	5006:9020	5006:9021	5006:9022	5006:9023
5007:9018	5007:9019	5007:9020	5007:9021	5007:9022	5007:9023
5008:9018	5008:9019	5008:9020	5008:9021	5008:9022	5008:9023
5009:9018	5009:9019	5009:9020	5009:9021	5009:9022	5009:9023
5010:9018	5010:9019	5010:9020	5010:9021	5010:9022	5010:9023
5011:9018	5011:9019	5011:9020	5011:9021	5011:9022	5011:9023
5012:9018	5012:9019	5012:9020	5012:9021	5012:9022	5012:9023
3001:9024	3001:9025	3001:9026	3001:9027	3001:9028	3001:9029
3002:9024	3002:9025	3002:9026	3002:9027	3002:9028	3002:9029
3003:9024	3003:9025	3003:9026	3003:9027	3003:9028	3003:9029
3004:9024	3004:9025	3004:9026	3004:9027	3004:9028	3004:9029
3005:9024	3005:9025	3005:9026	3005:9027	3005:9028	3005:9029
3006:9024	3006:9025	3006:9026	3006:9027	3006:9028	3006:9029
3007:9024	3007:9025	3007:9026	3007:9027	3007:9028	3007:9029
3008:9024	3008:9025	3008:9026	3008:9027	3008:9028	3008:9029
3009:9024	3009:9025	3009:9026	3009:9027	3009:9028	3009:9029
3010:9024	3010:9025	3010:9026	3010:9027	3010:9028	3010:9029
3011:9024	3011:9025	3011:9026	3011:9027	3011:9028	3011:9029
3012:9024	3012:9025	3012:9026	3012:9027	3012:9028	3012:9029
3013:9024	3013:9025	3013:9026	3013:9027	3013:9028	3013:9029
3014:9024	3014:9025	3014:9026	3014:9027	3014:9028	3014:9029
4001:9024	4001:9025	4001:9026	4001:9027	4001:9028	4001:9029
4002:9024	4002:9025	4002:9026	4002:9027	4002:9028	4002:9029
4003:9024	4003:9025	4003:9026	4003:9027	4003:9028	4003:9029
4004:9024	4004:9025	4004:9026	4004:9027	4004:9028	4004:9029
4005:9024	4005:9025	4005:9026	4005:9027	4005:9028	4005:9029
4006:9024	4006:9025	4006:9026	4006:9027	4006:9028	4006:9029
4007:9024	4007:9025	4007:9026	4007:9027	4007:9028	4007:9029
4008:9024	4008:9025	4008:9026	4008:9027	4008:9028	4008:9029
4009:9024	4009:9025	4009:9026	4009:9027	4009:9028	4009:9029
4010:9024	4010:9025	4010:9026	4010:9027	4010:9028	4010:9029
4011:9024	4011:9025	4011:9026	4011:9027	4011:9028	4011:9029
4012:9024	4012:9025	4012:9026	4012:9027	4012:9028	4012:9029
5001:9024	5001:9025	5001:9026	5001:9027	5001:9028	5001:9029
5002:9024	5002:9025	5002:9026	5002:9027	5002:9028	5002:9029
5003:9024	5003:9025	5003:9026	5003:9027	5003:9028	5003:9029
5004:9024	5004:9025	5004:9026	5004:9027	5004:9028	5004:9029
5005:9024	5005:9025	5005:9026	5005:9027	5005:9028	5005:9029
5006:9024	5006:9025	5006:9026	5006:9027	5006:9028	5006:9029
5007:9024	5007:9025	5007:9026	5007:9027	5007:9028	5007:9029
5008:9024	5008:9025	5008:9026	5008:9027	5008:9028	5008:9029
5009:9024	5009:9025	5009:9026	5009:9027	5009:9028	5009:9029
5010:9024	5010:9025	5010:9026	5010:9027	5010:9028	5010:9029
5011:9024	5011:9025	5011:9026	5011:9027	5011:9028	5011:9029
5012:9024	5012:9025	5012:9026	5012:9027	5012:9028	5012:9029
3001:9030	3001:9031	3001:9032	3001:9033	3001:9034	3001:9035
3002:9030	3002:9031	3002:9032	3002:9033	3002:9034	3002:9035
3003:9030	3003:9031	3003:9032	3003:9033	3003:9034	3003:9035
3004:9030	3004:9031	3004:9032	3004:9033	3004:9034	3004:9035
3005:9030	3005:9031	3005:9032	3005:9033	3005:9034	3005:9035
3006:9030	3006:9031	3006:9032	3006:9033	3006:9034	3006:9035
3007:9030	3007:9031	3007:9032	3007:9033	3007:9034	3007:9035
3008:9030	3008:9031	3008:9032	3008:9033	3008:9034	3008:9035
3009:9030	3009:9031	3009:9032	3009:9033	3009:9034	3009:9035
3010:9030	3010:9031	3010:9032	3010:9033	3010:9034	3010:9035
3011:9030	3011:9031	3011:9032	3011:9033	3011:9034	3011:9035
3012:9030	3012:9031	3012:9032	3012:9033	3012:9034	3012:9035
3013:9030	3013:9031	3013:9032	3013:9033	3013:9034	3013:9035
3014:9030	3014:9031	3014:9032	3014:9033	3014:9034	3014:9035
4001:9030	4001:9031	4001:9032	4001:9033	4001:9034	4001:9035
4002:9030	4002:9031	4002:9032	4002:9033	4002:9034	4002:9035
4003:9030	4003:9031	4003:9032	4003:9033	4003:9034	4003:9035
4004:9030	4004:9031	4004:9032	4004:9033	4004:9034	4004:9035
4005:9030	4005:9031	4005:9032	4005:9033	4005:9034	4005:9035
4006:9030	4006:9031	4006:9032	4006:9033	4006:9034	4006:9035
4007:9030	4007:9031	4007:9032	4007:9033	4007:9034	4007:9035
4008:9030	4008:9031	4008:9032	4008:9033	4008:9034	4008:9035
4009:9030	4009:9031	4009:9032	4009:9033	4009:9034	4009:9035
4010:9030	4010:9031	4010:9032	4010:9033	4010:9034	4010:9035
4011:9030	4011:9031	4011:9032	4011:9033	4011:9034	4011:9035
4012:9030	4012:9031	4012:9032	4012:9033	4012:9034	4012:9035
5001:9030	5001:9031	5001:9032	5001:9033	5001:9034	5001:9035
5002:9030	5002:9031	5002:9032	5002:9033	5002:9034	5002:9035
5003:9030	5003:9031	5003:9032	5003:9033	5003:9034	5003:9035
5004:9030	5004:9031	5004:9032	5004:9033	5004:9034	5004:9035
5005:9030	5005:9031	5005:9032	5005:9033	5005:9034	5005:9035
5006:9030	5006:9031	5006:9032	5006:9033	5006:9034	5006:9035
5007:9030	5007:9031	5007:9032	5007:9033	5007:9034	5007:9035
5008:9030	5008:9031	5008:9032	5008:9033	5008:9034	5008:9035
5009:9030	5009:9031	5009:9032	5009:9033	5009:9034	5009:9035
5010:9030	5010:9031	5010:9032	5010:9033	5010:9034	5010:9035
5011:9030	5011:9031	5011:9032	5011:9033	5011:9034	5011:9035
5012:9030	5012:9031	5012:9032	5012:9033	5012:9034	5012:9035
3001:9036	3001:9037	3001:9038	3001:9039	3001:9040	3001:9041
3002:9036	3002:9037	3002:9038	3002:9039	3002:9040	3002:9041
3003:9036	3003:9037	3003:9038	3003:9039	3003:9040	3003:9041
3004:9036	3004:9037	3004:9038	3004:9039	3004:9040	3004:9041
3005:9036	3005:9037	3005:9038	3005:9039	3005:9040	3005:9041
3006:9036	3006:9037	3006:9038	3006:9039	3006:9040	3006:9041
3007:9036	3007:9037	3007:9038	3007:9039	3007:9040	3007:9041
3008:9036	3008:9037	3008:9038	3008:9039	3008:9040	3008:9041
3009:9036	3009:9037	3009:9038	3009:9039	3009:9040	3009:9041
3010:9036	3010:9037	3010:9038	3010:9039	3010:9040	3010:9041
3011:9036	3011:9037	3011:9038	3011:9039	3011:9040	3011:9041
3012:9036	3012:9037	3012:9038	3012:9039	3012:9040	3012:9041
3013:9036	3013:9037	3013:9038	3013:9039	3013:9040	3013:9041
3014:9036	3014:9037	3014:9038	3014:9039	3014:9040	3014:9041
4001:9036	4001:9037	4001:9038	4001:9039	4001:9040	4001:9041
4002:9036	4002:9037	4002:9038	4002:9039	4002:9040	4002:9041
4003:9036	4003:9037	4003:9038	4003:9039	4003:9040	4003:9041
4004:9036	4004:9037	4004:9038	4004:9039	4004:9040	4004:9041
4005:9036	4005:9037	4005:9038	4005:9039	4005:9040	4005:9041
4006:9036	4006:9037	4006:9038	4006:9039	4006:9040	4006:9041
4007:9036	4007:9037	4007:9038	4007:9039	4007:9040	4007:9041
4008:9036	4008:9037	4008:9038	4008:9039	4008:9040	4008:9041
4009:9036	4009:9037	4009:9038	4009:9039	4009:9040	4009:9041
4010:9036	4010:9037	4010:9038	4010:9039	4010:9040	4010:9041
4011:9036	4011:9037	4011:9038	4011:9039	4011:9040	4011:9041
4012:9036	4012:9037	4012:9038	4012:9039	4012:9040	4012:9041
5001:9036	5001:9037	5001:9038	5001:9039	5001:9040	5001:9041
5002:9036	5002:9037	5002:9038	5002:9039	5002:9040	5002:9041
5003:9036	5003:9037	5003:9038	5003:9039	5003:9040	5003:9041
5004:9036	5004:9037	5004:9038	5004:9039	5004:9040	5004:9041
5005:9036	5005:9037	5005:9038	5005:9039	5005:9040	5005:9041
5006:9036	5006:9037	5006:9038	5006:9039	5006:9040	5006:9041
5007:9036	5007:9037	5007:9038	5007:9039	5007:9040	5007:9041
5008:9036	5008:9037	5008:9038	5008:9039	5008:9040	5008:9041
5009:9036	5009:9037	5009:9038	5009:9039	5009:9040	5009:9041
5010:9036	5010:9037	5010:9038	5010:9039	5010:9040	5010:9041
5011:9036	5011:9037	5011:9038	5011:9039	5011:9040	5011:9041
5012:9036	5012:9037	5012:9038	5012:9039	5012:9040	5012:9041
3001:9042	3001:9043	3001:9044	3001:9045	3001:9046	3001:9047
3002:9042	3002:9043	3002:9044	3002:9045	3002:9046	3002:9047
3003:9042	3003:9043	3003:9044	3003:9045	3003:9046	3003:9047
3004:9042	3004:9043	3004:9044	3004:9045	3004:9046	3004:9047
3005:9042	3005:9043	3005:9044	3005:9045	3005:9046	3005:9047
3006:9042	3006:9043	3006:9044	3006:9045	3006:9046	3006:9047
3007:9042	3007:9043	3007:9044	3007:9045	3007:9046	3007:9047
3008:9042	3008:9043	3008:9044	3008:9045	3008:9046	3008:9047
3009:9042	3009:9043	3009:9044	3009:9045	3009:9046	3009:9047
3010:9042	3010:9043	3010:9044	3010:9045	3010:9046	3010:9047
3011:9042	3011:9043	3011:9044	3011:9045	3011:9046	3011:9047
3012:9042	3012:9043	3012:9044	3012:9045	3012:9046	3012:9047
3013:9042	3013:9043	3013:9044	3013:9045	3013:9046	3013:9047
3014:9042	3014:9043	3014:9044	3014:9045	3014:9046	3014:9047
4001:9042	4001:9043	4001:9044	4001:9045	4001:9046	4001:9047
4002:9042	4002:9043	4002:9044	4002:9045	4002:9046	4002:9047
4003:9042	4003:9043	4003:9044	4003:9045	4003:9046	4003:9047
4004:9042	4004:9043	4004:9044	4004:9045	4004:9046	4004:9047
4005:9042	4005:9043	4005:9044	4005:9045	4005:9046	4005:9047
4006:9042	4006:9043	4006:9044	4006:9045	4006:9046	4006:9047
4007:9042	4007:9043	4007:9044	4007:9045	4007:9046	4007:9047
4008:9042	4008:9043	4008:9044	4008:9045	4008:9046	4008:9047
4009:9042	4009:9043	4009:9044	4009:9045	4009:9046	4009:9047
4010:9042	4010:9043	4010:9044	4010:9045	4010:9046	4010:9047
4011:9042	4011:9043	4011:9044	4011:9045	4011:9046	4011:9047
4012:9042	4012:9043	4012:9044	4012:9045	4012:9046	4012:9047
5001:9042	5001:9043	5001:9044	5001:9045	5001:9046	5001:9047
5002:9042	5002:9043	5002:9044	5002:9045	5002:9046	5002:9047
5003:9042	5003:9043	5003:9044	5003:9045	5003:9046	5003:9047
5004:9042	5004:9043	5004:9044	5004:9045	5004:9046	5004:9047
5005:9042	5005:9043	5005:9044	5005:9045	5005:9046	5005:9047
5006:9042	5006:9043	5006:9044	5006:9045	5006:9046	5006:9047
5007:9042	5007:9043	5007:9044	5007:9045	5007:9046	5007:9047
5008:9042	5008:9043	5008:9044	5008:9045	5008:9046	5008:9047
5009:9042	5009:9043	5009:9044	5009:9045	5009:9046	5009:9047
5010:9042	5010:9043	5010:9044	5010:9045	5010:9046	5010:9047
5011:9042	5011:9043	5011:9044	5011:9045	5011:9046	5011:9047
5012:9042	5012:9043	5012:9044	5012:9045	5012:9046	5012:9047
3001:9048	3001:9049	3001:9050	3001:9051	3001:9052	3001:9053
3002:9048	3002:9049	3002:9050	3002:9051	3002:9052	3002:9053
3003:9048	3003:9049	3003:9050	3003:9051	3003:9052	3003:9053
3004:9048	3004:9049	3004:9050	3004:9051	3004:9052	3004:9053
3005:9048	3005:9049	3005:9050	3005:9051	3005:9052	3005:9053
3006:9048	3006:9049	3006:9050	3006:9051	3006:9052	3006:9053
3007:9048	3007:9049	3007:9050	3007:9051	3007:9052	3007:9053
3008:9048	3008:9049	3008:9050	3008:9051	3008:9052	3008:9053
3009:9048	3009:9049	3009:9050	3009:9051	3009:9052	3009:9053
3010:9048	3010:9049	3010:9050	3010:9051	3010:9052	3010:9053
3011:9048	3011:9049	3011:9050	3011:9051	3011:9052	3011:9053
3012:9048	3012:9049	3012:9050	3012:9051	3012:9052	3012:9053
3013:9048	3013:9049	3013:9050	3013:9051	3013:9052	3013:9053
3014:9048	3014:9049	3014:9050	3014:9051	3014:9052	3014:9053
4001:9048	4001:9049	4001:9050	4001:9051	4001:9052	4001:9053
4002:9048	4002:9049	4002:9050	4002:9051	4002:9052	4002:9053
4003:9048	4003:9049	4003:9050	4003:9051	4003:9052	4003:9053
4004:9048	4004:9049	4004:9050	4004:9051	4004:9052	4004:9053
4005:9048	4005:9049	4005:9050	4005:9051	4005:9052	4005:9053
4006:9048	4006:9049	4006:9050	4006:9051	4006:9052	4006:9053
4007:9048	4007:9049	4007:9050	4007:9051	4007:9052	4007:9053
4008:9048	4008:9049	4008:9050	4008:9051	4008:9052	4008:9053
4009:9048	4009:9049	4009:9050	4009:9051	4009:9052	4009:9053
4010:9048	4010:9049	4010:9050	4010:9051	4010:9052	4010:9053
4011:9048	4011:9049	4011:9050	4011:9051	4011:9052	4011:9053
4012:9048	4012:9049	4012:9050	4012:9051	4012:9052	4012:9053
5001:9048	5001:9049	5001:9050	5001:9051	5001:9052	5001:9053
5002:9048	5002:9049	5002:9050	5002:9051	5002:9052	5002:9053
5003:9048	5003:9049	5003:9050	5003:9051	5003:9052	5003:9053
5004:9048	5004:9049	5004:9050	5004:9051	5004:9052	5004:9053
5005:9048	5005:9049	5005:9050	5005:9051	5005:9052	5005:9053
5006:9048	5006:9049	5006:9050	5006:9051	5006:9052	5006:9053
5007:9048	5007:9049	5007:9050	5007:9051	5007:9052	5007:9053
5008:9048	5008:9049	5008:9050	5008:9051	5008:9052	5008:9053
5009:9048	5009:9049	5009:9050	5009:9051	5009:9052	5009:9053
5010:9048	5010:9049	5010:9050	5010:9051	5010:9052	5010:9053
5011:9048	5011:9049	5011:9050	5011:9051	5011:9052	5011:9053
5012:9048	5012:9049	5012:9050	5012:9051	5012:9051	5012:9053
3001:9054	3001:9055	3001:9056	3001:9057	3001:9058	3001:9059
3002:9054	3002:9055	3002:9056	3002:9057	3002:9058	3002:9059
3003:9054	3003:9055	3003:9056	3003:9057	3003:9058	3003:9059
3004:9054	3004:9055	3004:9056	3004:9057	3004:9058	3004:9059
3005:9054	3005:9055	3005:9056	3005:9057	3005:9058	3005:9059
3006:9054	3006:9055	3006:9056	3006:9057	3006:9058	3006:9059
3007:9054	3007:9055	3007:9056	3007:9057	3007:9058	3007:9059
3008:9054	3008:9055	3008:9056	3008:9057	3008:9058	3008:9059
3009:9054	3009:9055	3009:9056	3009:9057	3009:9058	3009:9059
3010:9054	3010:9055	3010:9056	3010:9057	3010:9058	3010:9059
3011:9054	3011:9055	3011:9056	3011:9057	3011:9058	3011:9059
3012:9054	3012:9055	3012:9056	3012:9057	3012:9058	3012:9059
3013:9054	3013:9055	3013:9056	3013:9057	3013:9058	3013:9059
3014:9054	3014:9055	3014:9056	3014:9057	3014:9058	3014:9059
4001:9054	4001:9055	4001:9056	4001:9057	4001:9058	4001:9059
4002:9054	4002:9055	4002:9056	4002:9057	4002:9058	4002:9059
4003:9054	4003:9055	4003:9056	4003:9057	4003:9058	4003:9059
4004:9054	4004:9055	4004:9056	4004:9057	4004:9058	4004:9059
4005:9054	4005:9055	4005:9056	4005:9057	4005:9058	4005:9059
4006:9054	4006:9055	4006:9056	4006:9057	4006:9058	4006:9059
4007:9054	4007:9055	4007:9056	4007:9057	4007:9058	4007:9059
4008:9054	4008:9055	4008:9056	4008:9057	4008:9058	4008:9059
4009:9054	4009:9055	4009:9056	4009:9057	4009:9058	4009:9059
4010:9054	4010:9055	4010:9056	4010:9057	4010:9058	4010:9059
4011:9054	4011:9055	4011:9056	4011:9057	4011:9058	4011:9059
4012:9054	4012:9055	4012:9056	4012:9057	4012:9058	4012:9059
5001:9054	5001:9055	5001:9056	5001:9057	5001:9058	5001:9059
5002:9054	5002:9055	5002:9056	5002:9057	5002:9058	5002:9059
5003:9054	5003:9055	5003:9056	5003:9057	5003:9058	5003:9059
5004:9054	5004:9055	5004:9056	5004:9057	5004:9058	5004:9059
5005:9054	5005:9055	5005:9056	5005:9057	5005:9058	5005:9059
5006:9054	5006:9055	5006:9056	5006:9057	5006:9058	5006:9059
5007:9054	5007:9055	5007:9056	5007:9057	5007:9058	5007:9059
5008:9054	5008:9055	5008:9056	5008:9057	5008:9058	5008:9059
5009:9054	5009:9055	5009:9056	5009:9057	5009:9058	5009:9059
5010:9054	5010:9055	5010:9056	5010:9057	5010:9058	5010:9059
5011:9054	5011:9055	5011:9056	5011:9057	5011:9058	5011:9059
5012:9054	5012:9055	5012:9056	5012:9057	5012:9058	5012:9059
3001:9060	3001:9061	3001:9062	3001:9063	3001:9064	3001:9065
3002:9060	3002:9061	3002:9062	3002:9063	3002:9064	3002:9065
3003:9060	3003:9061	3003:9062	3003:9063	3003:9064	3003:9065
3004:9060	3004:9061	3004:9062	3004:9063	3004:9064	3004:9065
3005:9060	3005:9061	3005:9062	3005:9063	3005:9064	3005:9065
3006:9060	3006:9061	3006:9062	3006:9063	3006:9064	3006:9065
3007:9060	3007:9061	3007:9062	3007:9063	3007:9064	3007:9065
3008:9060	3008:9061	3008:9062	3008:9063	3008:9064	3008:9065
3009:9060	3009:9061	3009:9062	3009:9063	3009:9064	3009:9065
3010:9060	3010:9061	3010:9062	3010:9063	3010:9064	3010:9065
3011:9060	3011:9061	3011:9062	3011:9063	3011:9064	3011:9065
3012:9060	3012:9061	3012:9062	3012:9063	3012:9064	3012:9065
3013:9060	3013:9061	3013:9062	3013:9063	3013:9064	3013:9065
3014:9060	3014:9061	3014:9062	3014:9063	3014:9064	3014:9065
4001:9060	4001:9061	4001:9062	4001:9063	4001:9064	4001:9065
4002:9060	4002:9061	4002:9062	4002:9063	4002:9064	4002:9065
4003:9060	4003:9061	4003:9062	4003:9063	4003:9064	4003:9065
4004:9060	4004:9061	4004:9062	4004:9063	4004:9064	4004:9065
4005:9060	4005:9061	4005:9062	4005:9063	4005:9064	4005:9065
4006:9060	4006:9061	4006:9062	4006:9063	4006:9064	4006:9065
4007:9060	4007:9061	4007:9062	4007:9063	4007:9064	4007:9065
4008:9060	4008:9061	4008:9062	4008:9063	4008:9064	4008:9065
4009:9060	4009:9061	4009:9062	4009:9063	4009:9064	4009:9065
4010:9060	4010:9061	4010:9062	4010:9063	4010:9064	4010:9065
4011:9060	4011:9061	4011:9062	4011:9063	4011:9064	4011:9065
4012:9060	4012:9061	4012:9062	4012:9063	4012:9064	4012:9065
5001:9060	5001:9061	5001:9062	5001:9063	5001:9064	5001:9065
5002:9060	5002:9061	5002:9062	5002:9063	5002:9064	5002:9065
5003:9060	5003:9061	5003:9062	5003:9063	5003:9064	5003:9065
5004:9060	5004:9061	5004:9062	5004:9063	5004:9064	5004:9065
5005:9060	5005:9061	5005:9062	5005:9063	5005:9064	5005:9065
5006:9060	5006:9061	5006:9062	5006:9063	5006:9064	5006:9065
5007:9060	5007:9061	5007:9062	5007:9063	5007:9064	5007:9065
5008:9060	5008:9061	5008:9062	5008:9063	5008:9064	5008:9065
5009:9060	5009:9061	5009:9062	5009:9063	5009:9064	5009:9065
5010:9060	5010:9061	5010:9062	5010:9063	5010:9064	5010:9065
5011:9060	5011:9061	5011:9062	5011:9063	5011:9064	5011:9065
5012:9060	5012:9061	5012:9062	5012:9063	5012:9064	5012:9065
3001:9066	3001:9067	3001:9068	3001:9069	3001:9070	3001:9071
3002:9066	3002:9067	3002:9068	3002:9069	3002:9070	3002:9071
3003:9066	3003:9067	3003:9068	3003:9069	3003:9070	3003:9071
3004:9066	3004:9067	3004:9068	3004:9069	3004:9070	3004:9071
3005:9066	3005:9067	3005:9068	3005:9069	3005:9070	3005:9071
3006:9066	3006:9067	3006:9068	3006:9069	3006:9070	3006:9071
3007:9066	3007:9067	3007:9068	3007:9069	3007:9070	3007:9071
3008:9066	3008:9067	3008:9068	3008:9069	3008:9070	3008:9071
3009:9066	3009:9067	3009:9068	3009:9069	3009:9070	3009:9071
3010:9066	3010:9067	3010:9068	3010:9069	3010:9070	3010:9071
3011:9066	3011:9067	3011:9068	3011:9069	3011:9070	3011:9071
3012:9066	3012:9067	3012:9068	3012:9069	3012:9070	3012:9071
3013:9066	3013:9067	3013:9068	3013:9069	3013:9070	3013:9071
3014:9066	3014:9067	3014:9068	3014:9069	3014:9070	3014:9071
4001:9066	4001:9067	4001:9068	4001:9069	4001:9070	4001:9071
4002:9066	4002:9067	4002:9068	4002:9069	4002:9070	4002:9071
4003:9066	4003:9067	4003:9068	4003:9069	4003:9070	4003:9071
4004:9066	4004:9067	4004:9068	4004:9069	4004:9070	4004:9071
4005:9066	4005:9067	4005:9068	4005:9069	4005:9070	4005:9071
4006:9066	4006:9067	4006:9068	4006:9069	4006:9070	4006:9071
4007:9066	4007:9067	4007:9068	4007:9069	4007:9070	4007:9071
4008:9066	4008:9067	4008:9068	4008:9069	4008:9070	4008:9071
4009:9066	4009:9067	4009:9068	4009:9069	4009:9070	4009:9071
4010:9066	4010:9067	4010:9068	4010:9069	4010:9070	4010:9071
4011:9066	4011:9067	4011:9068	4011:9069	4011:9070	4011:9071
4012:9066	4012:9067	4012:9068	4012:9069	4012:9070	4012:9071
5001:9066	5001:9067	5001:9068	5001:9069	5001:9070	5001:9071
5002:9066	5002:9067	5002:9068	5002:9069	5002:9070	5002:9071
5003:9066	5003:9067	5003:9068	5003:9069	5003:9070	5003:9071
5004:9066	5004:9067	5004:9068	5004:9069	5004:9070	5004:9071
5005:9066	5005:9067	5005:9068	5005:9069	5005:9070	5005:9071
5006:9066	5006:9067	5006:9068	5006:9069	5006:9070	5006:9071
5007:9066	5007:9067	5007:9068	5007:9069	5007:9070	5007:9071
5008:9066	5008:9067	5008:9068	5008:9069	5008:9070	5008:9071
5009:9066	5009:9067	5009:9068	5009:9069	5009:9070	5009:9071
5010:9066	5010:9067	5010:9068	5010:9069	5010:9070	5010:9071
5011:9066	5011:9067	5011:9068	5011:9069	5011:9070	5011:9071
5012:9066	5012:9067	5012:9068	5012:9069	5012:9070	5012:9071
3001:9072	3001:9073	3001:9074	3001:9075	3001:9076	3001:9077
3002:9072	3002:9073	3002:9074	3002:9075	3002:9076	3002:9077
3003:9072	3003:9073	3003:9074	3003:9075	3003:9076	3003:9077
3004:9072	3004:9073	3004:9074	3004:9075	3004:9076	3004:9077
3005:9072	3005:9073	3005:9074	3005:9075	3005:9076	3005:9077
3006:9072	3006:9073	3006:9074	3006:9075	3006:9076	3006:9077
3007:9072	3007:9073	3007:9074	3007:9075	3007:9076	3007:9077
3008:9072	3008:9073	3008:9074	3008:9075	3008:9076	3008:9077
3009:9072	3009:9073	3009:9074	3009:9075	3009:9076	3009:9077
3010:9072	3010:9073	3010:9074	3010:9075	3010:9076	3010:9077
3011:9072	3011:9073	3011:9074	3011:9075	3011:9076	3011:9077
3012:9072	3012:9073	3012:9074	3012:9075	3012:9076	3012:9077
3013:9072	3013:9073	3013:9074	3013:9075	3013:9076	3013:9077
3014:9072	3014:9073	3014:9074	3014:9075	3014:9076	3014:9077
4001:9072	4001:9073	4001:9074	4001:9075	4001:9076	4001:9077
4002:9072	4002:9073	4002:9074	4002:9075	4002:9076	4002:9077
4003:9072	4003:9073	4003:9074	4003:9075	4003:9076	4003:9077
4004:9072	4004:9073	4004:9074	4004:9075	4004:9076	4004:9077
4005:9072	4005:9073	4005:9074	4005:9075	4005:9076	4005:9077
4006:9072	4006:9073	4006:9074	4006:9075	4006:9076	4006:9077
4007:9072	4007:9073	4007:9074	4007:9075	4007:9076	4007:9077
4008:9072	4008:9073	4008:9074	4008:9075	4008:9076	4008:9077
4009:9072	4009:9073	4009:9074	4009:9075	4009:9076	4009:9077
4010:9072	4010:9073	4010:9074	4010:9075	4010:9076	4010:9077
4011:9072	4011:9073	4011:9074	4011:9075	4011:9076	4011:9077
4012:9072	4012:9073	4012:9074	4012:9075	4012:9076	4012:9077
5001:9072	5001:9073	5001:9074	5001:9075	5001:9076	5001:9077
5002:9072	5002:9073	5002:9074	5002:9075	5002:9076	5002:9077
5003:9072	5003:9073	5003:9074	5003:9075	5003:9076	5003:9077
5004:9072	5004:9073	5004:9074	5004:9075	5004:9076	5004:9077
5005:9072	5005:9073	5005:9074	5005:9075	5005:9076	5005:9077
5006:9072	5006:9073	5006:9074	5006:9075	5006:9076	5006:9077
5007:9072	5007:9073	5007:9074	5007:9075	5007:9076	5007:9077
5008:9072	5008:9073	5008:9074	5008:9075	5008:9076	5008:9077
5009:9072	5009:9073	5009:9074	5009:9075	5009:9076	5009:9077
5010:9072	5010:9073	5010:9074	5010:9075	5010:9076	5010:9077
5011:9072	5011:9073	5011:9074	5011:9075	5011:9076	5011:9077
5012:9072	5012:9073	5012:9074	5012:9075	5012:9076	5012:9077
3001:9078	3001:9079	3001:9080	3001:9081	3001:9082	3001:9083
3002:9078	3002:9079	3002:9080	3002:9081	3002:9082	3002:9083
3003:9078	3003:9079	3003:9080	3003:9081	3003:9082	3003:9083
3004:9078	3004:9079	3004:9080	3004:9081	3004:9082	3004:9083
3005:9078	3005:9079	3005:9080	3005:9081	3005:9082	3005:9083
3006:9078	3006:9079	3006:9080	3006:9081	3006:9082	3006:9083
3007:9078	3007:9079	3007:9080	3007:9081	3007:9082	3007:9083
3008:9078	3008:9079	3008:9080	3008:9081	3008:9082	3008:9083
3009:9078	3009:9079	3009:9080	3009:9081	3009:9082	3009:9083
3010:9078	3010:9079	3010:9080	3010:9081	3010:9082	3010:9083
3011:9078	3011:9079	3011:9080	3011:9081	3011:9082	3011:9083
3012:9078	3012:9079	3012:9080	3012:9081	3012:9082	3012:9083
3013:9078	3013:9079	3013:9080	3013:9081	3013:9082	3013:9083
3014:9078	3014:9079	3014:9080	3014:9081	3014:9082	3014:9083
4001:9078	4001:9079	4001:9080	4001:9081	4001:9082	4001:9083
4002:9078	4002:9079	4002:9080	4002:9081	4002:9082	4002:9083
4003:9078	4003:9079	4003:9080	4003:9081	4003:9082	4003:9083
4004:9078	4004:9079	4004:9080	4004:9081	4004:9082	4004:9083
4005:9078	4005:9079	4005:9080	4005:9081	4005:9082	4005:9083
4006:9078	4006:9079	4006:9080	4006:9081	4006:9082	4006:9083
4007:9078	4007:9079	4007:9080	4007:9081	4007:9082	4007:9083
4008:9078	4008:9079	4008:9080	4008:9081	4008:9082	4008:9083
4009:9078	4009:9079	4009:9080	4009:9081	4009:9082	4009:9083
4010:9078	4010:9079	4010:9080	4010:9081	4010:9082	4010:9083
4011:9078	4011:9079	4011:9080	4011:9081	4011:9082	4011:9083
4012:9078	4012:9079	4012:9080	4012:9081	4012:9082	4012:9083
5001:9078	5001:9079	5001:9080	5001:9081	5001:9082	5001:9083
5002:9078	5002:9079	5002:9080	5002:9081	5002:9082	5002:9083
5003:9078	5003:9079	5003:9080	5003:9081	5003:9082	5003:9083
5004:9078	5004:9079	5004:9080	5004:9081	5004:9082	5004:9083
5005:9078	5005:9079	5005:9080	5005:9081	5005:9082	5005:9083
5006:9078	5006:9079	5006:9080	5006:9081	5006:9082	5006:9083
5007:9078	5007:9079	5007:9080	5007:9081	5007:9082	5007:9083
5008:9078	5008:9079	5008:9080	5008:9081	5008:9082	5008:9083
5009:9078	5009:9079	5009:9080	5009:9081	5009:9082	5009:9083
5010:9078	5010:9079	5010:9080	5010:9081	5010:9082	5010:9083
5011:9078	5011:9079	5011:9080	5011:9081	5011:9082	5011:9083
5012:9078	5012:9079	5012:9080	5012:9081	5012:9082	5012:9083
3001:9084	3001:9085	3001:9086	3001:9087	3001:9088	3001:9089
3002:9084	3002:9085	3002:9086	3002:9087	3002:9088	3002:9089
3003:9084	3003:9085	3003:9086	3003:9087	3003:9088	3003:9089
3004:9084	3004:9085	3004:9086	3004:9087	3004:9088	3004:9089
3005:9084	3005:9085	3005:9086	3005:9087	3005:9088	3005:9089
3006:9084	3006:9085	3006:9086	3006:9087	3006:9088	3006:9089
3007:9084	3007:9085	3007:9086	3007:9087	3007:9088	3007:9089
3008:9084	3008:9085	3008:9086	3008:9087	3008:9088	3008:9089
3009:9084	3009:9085	3009:9086	3009:9087	3009:9088	3009:9089
3010:9084	3010:9085	3010:9086	3010:9087	3010:9088	3010:9089
3011:9084	3011:9085	3011:9086	3011:9087	3011:9088	3011:9089
3012:9084	3012:9085	3012:9086	3012:9087	3012:9088	3012:9089
3013:9084	3013:9085	3013:9086	3013:9087	3013:9088	3013:9089
3014:9084	3014:9085	3014:9086	3014:9087	3014:9088	3014:9089
4001:9084	4001:9085	4001:9086	4001:9087	4001:9088	4001:9089
4002:9084	4002:9085	4002:9086	4002:9087	4002:9088	4002:9089
4003:9084	4003:9085	4003:9086	4003:9087	4003:9088	4003:9089
4004:9084	4004:9085	4004:9086	4004:9087	4004:9088	4004:9089
4005:9084	4005:9085	4005:9086	4005:9087	4005:9088	4005:9089
4006:9084	4006:9085	4006:9086	4006:9087	4006:9088	4006:9089
4007:9084	4007:9085	4007:9086	4007:9087	4007:9088	4007:9089
4008:9084	4008:9085	4008:9086	4008:9087	4008:9088	4008:9089
4009:9084	4009:9085	4009:9086	4009:9087	4009:9088	4009:9089
4010:9084	4010:9085	4010:9086	4010:9087	4010:9088	4010:9089
4011:9084	4011:9085	4011:9086	4011:9087	4011:9088	4011:9089
4012:9084	4012:9085	4012:9086	4012:9087	4012:9088	4012:9089
5001:9084	5001:9085	5001:9086	5001:9087	5001:9088	5001:9089
5002:9084	5002:9085	5002:9086	5002:9087	5002:9088	5002:9089
5003:9084	5003:9085	5003:9086	5003:9087	5003:9088	5003:9089
5004:9084	5004:9085	5004:9086	5004:9087	5004:9088	5004:9089
5005:9084	5005:9085	5005:9086	5005:9087	5005:9088	5005:9089
5006:9084	5006:9085	5006:9086	5006:9087	5006:9088	5006:9089
5007:9084	5007:9085	5007:9086	5007:9087	5007:9088	5007:9089
5008:9084	5008:9085	5008:9086	5008:9087	5008:9088	5008:9089
5009:9084	5009:9085	5009:9086	5009:9087	5009:9088	5009:9089
5010:9084	5010:9085	5010:9086	5010:9087	5010:9088	5010:9089
5011:9084	5011:9085	5011:9086	5011:9087	5011:9088	5011:9089
5012:9084	5012:9085	5012:9086	5012:9087	5012:9088	5012:9089
3001:9090	3001:9091	3001:9092	3001:9093	3001:9094	3001:9095
3002:9090	3002:9091	3002:9092	3002:9093	3002:9094	3002:9095
3003:9090	3003:9091	3003:9092	3003:9093	3003:9094	3003:9095
3004:9090	3004:9091	3004:9092	3004:9093	3004:9094	3004:9095
3005:9090	3005:9091	3005:9092	3005:9093	3005:9094	3005:9095
3006:9090	3006:9091	3006:9092	3006:9093	3006:9094	3006:9095
3007:9090	3007:9091	3007:9092	3007:9093	3007:9094	3007:9095
3008:9090	3008:9091	3008:9092	3008:9093	3008:9094	3008:9095
3009:9090	3009:9091	3009:9092	3009:9093	3009:9094	3009:9095
3010:9090	3010:9091	3010:9092	3010:9093	3010:9094	3010:9095
3011:9090	3011:9091	3011:9092	3011:9093	3011:9094	3011:9095
3012:9090	3012:9091	3012:9092	3012:9093	3012:9094	3012:9095
3013:9090	3013:9091	3013:9092	3013:9093	3013:9094	3013:9095
3014:9090	3014:9091	3014:9092	3014:9093	3014:9094	3014:9095
4001:9090	4001:9091	4001:9092	4001:9093	4001:9094	4001:9095
4002:9090	4002:9091	4002:9092	4002:9093	4002:9094	4002:9095
4003:9090	4003:9091	4003:9092	4003:9093	4003:9094	4003:9095
4004:9090	4004:9091	4004:9092	4004:9093	4004:9094	4004:9095
4005:9090	4005:9091	4005:9092	4005:9093	4005:9094	4005:9095
4006:9090	4006:9091	4006:9092	4006:9093	4006:9094	4006:9095
4007:9090	4007:9091	4007:9092	4007:9093	4007:9094	4007:9095
4008:9090	4008:9091	4008:9092	4008:9093	4008:9094	4008:9095
4009:9090	4009:9091	4009:9092	4009:9093	4009:9094	4009:9095
4010:9090	4010:9091	4010:9092	4010:9093	4010:9094	4010:9095
4011:9090	4011:9091	4011:9092	4011:9093	4011:9094	4011:9095
4012:9090	4012:9091	4012:9092	4012:9093	4012:9094	4012:9095
5001:9090	5001:9091	5001:9092	5001:9093	5001:9094	5001:9095
5002:9090	5002:9091	5002:9092	5002:9093	5002:9094	5002:9095
5003:9090	5003:9091	5003:9092	5003:9093	5003:9094	5003:9095
5004:9090	5004:9091	5004:9092	5004:9093	5004:9094	5004:9095
5005:9090	5005:9091	5005:9092	5005:9093	5005:9094	5005:9095
5006:9090	5006:9091	5006:9092	5006:9093	5006:9094	5006:9095
5007:9090	5007:9091	5007:9092	5007:9093	5007:9094	5007:9095
5008:9090	5008:9091	5008:9092	5008:9093	5008:9094	5008:9095
5009:9090	5009:9091	5009:9092	5009:9093	5009:9094	5009:9095
5010:9090	5010:9091	5010:9092	5010:9093	5010:9094	5010:9095
5011:9090	5011:9091	5011:9092	5011:9093	5011:9094	5011:9095
5012:9090	5012:9091	5012:9092	5012:9093	5012:9094	5012:9095
3001:9096	3001:9097	3001:9098	3001:9099	3001:9100	3001:9101
3002:9096	3002:9097	3002:9098	3002:9099	3002:9100	3002:9101
3003:9096	3003:9097	3003:9098	3003:9099	3003:9100	3003:9101
3004:9096	3004:9097	3004:9098	3004:9099	3004:9100	3004:9101
3005:9096	3005:9097	3005:9098	3005:9099	3005:9100	3005:9101
3006:9096	3006:9097	3006:9098	3006:9099	3006:9100	3006:9101
3007:9096	3007:9097	3007:9098	3007:9099	3007:9100	3007:9101
3008:9096	3008:9097	3008:9098	3008:9099	3008:9100	3008:9101
3009:9096	3009:9097	3009:9098	3009:9099	3009:9100	3009:9101
3010:9096	3010:9097	3010:9098	3010:9099	3010:9100	3010:9101
3011:9096	3011:9097	3011:9098	3011:9099	3011:9100	3011:9101
3012:9096	3012:9097	3012:9098	3012:9099	3012:9100	3012:9101
3013:9096	3013:9097	3013:9098	3013:9099	3013:9100	3013:9101
3014:9096	3014:9097	3014:9098	3014:9099	3014:9100	3014:9101
4001:9096	4001:9097	4001:9098	4001:9099	4001:9100	4001:9101
4002:9096	4002:9097	4002:9098	4002:9099	4002:9100	4002:9101
4003:9096	4003:9097	4003:9098	4003:9099	4003:9100	4003:9101
4004:9096	4004:9097	4004:9098	4004:9099	4004:9100	4004:9101
4005:9096	4005:9097	4005:9098	4005:9099	4005:9100	4005:9101
4006:9096	4006:9097	4006:9098	4006:9099	4006:9100	4006:9101
4007:9096	4007:9097	4007:9098	4007:9099	4007:9100	4007:9101
4008:9096	4008:9097	4008:9098	4008:9099	4008:9100	4008:9101
4009:9096	4009:9097	4009:9098	4009:9099	4009:9100	4009:9101
4010:9096	4010:9097	4010:9098	4010:9099	4010:9100	4010:9101
4011:9096	4011:9097	4011:9098	4011:9099	4011:9100	4011:9101
4012:9096	4012:9097	4012:9098	4012:9099	4012:9100	4012:9101
5001:9096	5001:9097	5001:9098	5001:9099	5001:9100	5001:9101
5002:9096	5002:9097	5002:9098	5002:9099	5002:9100	5002:9101
5003:9096	5003:9097	5003:9098	5003:9099	5003:9100	5003:9101
5004:9096	5004:9097	5004:9098	5004:9099	5004:9100	5004:9101
5005:9096	5005:9097	5005:9098	5005:9099	5005:9100	5005:9101
5006:9096	5006:9097	5006:9098	5006:9099	5006:9100	5006:9101
5007:9096	5007:9097	5007:9098	5007:9099	5007:9100	5007:9101
5008:9096	5008:9097	5008:9098	5008:9099	5008:9100	5008:9101
5009:9096	5009:9097	5009:9098	5009:9099	5009:9100	5009:9101
5010:9096	5010:9097	5010:9098	5010:9099	5010:9100	5010:9101
5011:9096	5011:9097	5011:9098	5011:9099	5011:9100	5011:9101
5012:9096	5012:9097	5012:9098	5012:9099	5012:9100	5012:9101
3001:9102	3001:9103	3001:9104	3001:9105	—	—
3002:9102	3002:9103	3002:9104	3002:9105
3003:9102	3003:9103	3003:9104	3003:9105
3004:9102	3004:9103	3004:9104	3004:9105
3005:9102	3005:9103	3005:9104	3005:9105
3006:9102	3006:9103	3006:9104	3006:9105
3007:9102	3007:9103	3007:9104	3007:9105
3008:9102	3008:9103	3008:9104	3008:9105
3009:9102	3009:9103	3009:9104	3009:9105
3010:9102	3010:9103	3010:9104	3010:9105
3011:9102	3011:9103	3011:9104	3011:9105
3012:9102	3012:9103	3012:9104	3012:9105
3013:9102	3013:9103	3013:9104	3013:9105
3014:9102	3014:9103	3014:9104	3014:9105
4001:9102	4001:9103	4001:9104	4001:9105
4002:9102	4002:9103	4002:9104	4002:9105
4003:9102	4003:9103	4003:9104	4003:9105
4004:9102	4004:9103	4004:9104	4004:9105
4005:9102	4005:9103	4005:9104	4005:9105
4006:9102	4006:9103	4006:9104	4006:9105
4007:9102	4007:9103	4007:9104	4007:9105
4008:9102	4008:9103	4008:9104	4008:9105
4009:9102	4009:9103	4009:9104	4009:9105
4010:9102	4010:9103	4010:9104	4010:9105
4011:9102	4011:9103	4011:9104	4011:9105
4012:9102	4012:9103	4012:9104	4012:9105
5001:9102	5001:9103	5001:9104	5001:9105
5002:9102	5002:9103	5002:9104	5002:9105
5003:9102	5003:9103	5003:9104	5003:9105
5004:9102	5004:9103	5004:9104	5004:9105
5005:9102	5005:9103	5005:9104	5005:9105
5006:9102	5006:9103	5006:9104	5006:9105
5007:9102	5007:9103	5007:9104	5007:9105
5008:9102	5008:9103	5008:9104	5008:9105
5009:9102	5009:9103	5009:9104	5009:9105
5010:9102	5010:9103	5010:9104	5010:9105
5011:9102	5011:9103	5011:9104	5011:9105
5012:9102	5012:9103	5012:9104	5012:9105

TABLE C
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
9000:7000	9001:7000	9002:7000	9003:7000	9004:7000	9005:7000
9000:7001	9001:7001	9002:7001	9003:7001	9004:7001	9005:7001
9000:7002	9001:7002	9002:7002	9003:7002	9004:7002	9005:7002
9000:7003	9001:7003	9002:7003	9003:7003	9004:7003	9005:7003
9000:7004	9001:7004	9002:7004	9003:7004	9004:7004	9005:7004
9000:7005	9001:7005	9002:7005	9003:7005	9004:7005	9005:7005
9000:7006	9001:7006	9002:7006	9003:7006	9004:7006	9005:7006
9000:7007	9001:7007	9002:7007	9003:7007	9004:7007	9005:7007
9000:7008	9001:7008	9002:7008	9003:7008	9004:7008	9005:7008
9000:7009	9001:7009	9002:7009	9003:7009	9004:7009	9005:7009
9000:7010	9001:7010	9002:7010	9003:7010	9004:7010	9005:7010
9000:7011	9001:7011	9002:7011	9003:7011	9004:7011	9005:7011
9000:7012	9001:7012	9002:7012	9003:7012	9004:7012	9005:7012
9000:7013	9001:7013	9002:7013	9003:7013	9004:7013	9005:7013
9000:7014	9001:7014	9002:7014	9003:7014	9004:7014	9005:7014
9000:7015	9001:7015	9002:7015	9003:7015	9004:7015	9005:7015
9000:7016	9001:7016	9002:7016	9003:7016	9004:7016	9005:7016
9000:7017	9001:7017	9002:7017	9003:7017	9004:7017	9005:7017
9000:7018	9001:7018	9002:7018	9003:7018	9004:7018	9005:7018
9000:7019	9001:7019	9002:7019	9003:7019	9004:7019	9005:7019
9000:7020	9001:7020	9002:7020	9003:7020	9004:7020	9005:7020
9000:7021	9001:7021	9002:7021	9003:7021	9004:7021	9005:7021
9000:7022	9001:7022	9002:7022	9003:7022	9004:7022	9005:7022
9000:7023	9001:7023	9002:7023	9003:7023	9004:7023	9005:7023
9000:7024	9001:7024	9002:7024	9003:7024	9004:7024	9005:7024
9000:7025	9001:7025	9002:7025	9003:7025	9004:7025	9005:7025
9000:7026	9001:7026	9002:7026	9003:7026	9004:7026	9005:7026
9000:7027	9001:7027	9002:7027	9003:7027	9004:7027	9005:7027
9006:7000	9007:7000	9008:7000	9009:7000	9010:7000	9011:7000
9006:7001	9007:7001	9008:7001	9009:7001	9010:7001	9011:7001
9006:7002	9007:7002	9008:7002	9009:7002	9010:7002	9011:7002
9006:7003	9007:7003	9008:7003	9009:7003	9010:7003	9011:7003
9006:7004	9007:7004	9008:7004	9009:7004	9010:7004	9011:7004
9006:7005	9007:7005	9008:7005	9009:7005	9010:7005	9011:7005
9006:7006	9007:7006	9008:7006	9009:7006	9010:7006	9011:7006
9006:7007	9007:7007	9008:7007	9009:7007	9010:7007	9011:7007
9006:7008	9007:7008	9008:7008	9009:7008	9010:7008	9011:7008
9006:7009	9007:7009	9008:7009	9009:7009	9010:7009	9011:7009
9006:7010	9007:7010	9008:7010	9009:7010	9010:7010	9011:7010
9006:7011	9007:7011	9008:7011	9009:7011	9010:7011	9011:7011
9006:7012	9007:7012	9008:7012	9009:7012	9010:7012	9011:7012
9006:7013	9007:7013	9008:7013	9009:7013	9010:7013	9011:7013
9006:7014	9007:7014	9008:7014	9009:7014	9010:7014	9011:7014
9006:7015	9007:7015	9008:7015	9009:7015	9010:7015	9011:7015
9006:7016	9007:7016	9008:7016	9009:7016	9010:7016	9011:7016
9006:7017	9007:7017	9008:7017	9009:7017	9010:7017	9011:7017
9006:7018	9007:7018	9008:7018	9009:7018	9010:7018	9011:7018
9006:7019	9007:7019	9008:7019	9009:7019	9010:7019	9011:7019
9006:7020	9007:7020	9008:7020	9009:7020	9010:7020	9011:7020
9006:7021	9007:7021	9008:7021	9009:7021	9010:7021	9011:7021
9006:7022	9007:7022	9008:7022	9009:7022	9010:7022	9011:7022
9006:7023	9007:7023	9008:7023	9009:7023	9010:7023	9011:7023
9006:7024	9007:7024	9008:7024	9009:7024	9010:7024	9011:7024
9006:7025	9007:7025	9008:7025	9009:7025	9010:7025	9011:7025
9006:7026	9007:7026	9008:7026	9009:7026	9010:7026	9011:7026
9006:7027	9007:7027	9008:7027	9009:7027	9010:7027	9011:7027
9012:7000	9013:7000	9014:7000	9015:7000	9016:7000	9017:7000
9012:7001	9013:7001	9014:7001	9015:7001	9016:7001	9017:7001
9012:7002	9013:7002	9014:7002	9015:7002	9016:7002	9017:7002
9012:7003	9013:7003	9014:7003	9015:7003	9016:7003	9017:7003
9012:7004	9013:7004	9014:7004	9015:7004	9016:7004	9017:7004
9012:7005	9013:7005	9014:7005	9015:7005	9016:7005	9017:7005
9012:7006	9013:7006	9014:7006	9015:7006	9016:7006	9017:7006
9012:7007	9013:7007	9014:7007	9015:7007	9016:7007	9017:7007
9012:7008	9013:7008	9014:7008	9015:7008	9016:7008	9017:7008
9012:7009	9013:7009	9014:7009	9015:7009	9016:7009	9017:7009
9012:7010	9013:7010	9014:7010	9015:7010	9016:7010	9017:7010
9012:7011	9013:7011	9014:7011	9015:7011	9016:7011	9017:7011
9012:7012	9013:7012	9014:7012	9015:7012	9016:7012	9017:7012
9012:7013	9013:7013	9014:7013	9015:7013	9016:7013	9017:7013
9012:7014	9013:7014	9014:7014	9015:7014	9016:7014	9017:7014
9012:7015	9013:7015	9014:7015	9015:7015	9016:7015	9017:7015
9012:7016	9013:7016	9014:7016	9015:7016	9016:7016	9017:7016
9012:7017	9013:7017	9014:7017	9015:7017	9016:7017	9017:7017
9012:7018	9013:7018	9014:7018	9015:7018	9016:7018	9017:7018
9012:7019	9013:7019	9014:7019	9015:7019	9016:7019	9017:7019
9012:7020	9013:7020	9014:7020	9015:7020	9016:7020	9017:7020
9012:7021	9013:7021	9014:7021	9015:7021	9016:7021	9017:7021
9012:7022	9013:7022	9014:7022	9015:7022	9016:7022	9017:7022
9012:7023	9013:7023	9014:7023	9015:7023	9016:7023	9017:7023
9012:7024	9013:7024	9014:7024	9015:7024	9016:7024	9017:7024
9012:7025	9013:7025	9014:7025	9015:7025	9016:7025	9017:7025
9012:7026	9013:7026	9014:7026	9015:7026	9016:7026	9017:7026
9012:7027	9013:7027	9014:7027	9015:7027	9016:7027	9017:7027
9018:7000	9019:7000	9020:7000	9021:7000	9022:7000	9023:7000
9018:7001	9019:7001	9020:7001	9021:7001	9022:7001	9023:7001
9018:7002	9019:7002	9020:7002	9021:7002	9022:7002	9023:7002
9018:7003	9019:7003	9020:7003	9021:7003	9022:7003	9023:7003
9018:7004	9019:7004	9020:7004	9021:7004	9022:7004	9023:7004
9018:7005	9019:7005	9020:7005	9021:7005	9022:7005	9023:7005
9018:7006	9019:7006	9020:7006	9021:7006	9022:7006	9023:7006
9018:7007	9019:7007	9020:7007	9021:7007	9022:7007	9023:7007
9018:7008	9019:7008	9020:7008	9021:7008	9022:7008	9023:7008
9018:7009	9019:7009	9020:7009	9021:7009	9022:7009	9023:7009
9018:7010	9019:7010	9020:7010	9021:7010	9022:7010	9023:7010
9018:7011	9019:7011	9020:7011	9021:7011	9022:7011	9023:7011
9018:7012	9019:7012	9020:7012	9021:7012	9022:7012	9023:7012
9018:7013	9019:7013	9020:7013	9021:7013	9022:7013	9023:7013
9018:7014	9019:7014	9020:7014	9021:7014	9022:7014	9023:7014
9018:7015	9019:7015	9020:7015	9021:7015	9022:7015	9023:7015
9018:7016	9019:7016	9020:7016	9021:7016	9022:7016	9023:7016
9018:7017	9019:7017	9020:7017	9021:7017	9022:7017	9023:7017
9018:7018	9019:7018	9020:7018	9021:7018	9022:7018	9023:7018
9018:7019	9019:7019	9020:7019	9021:7019	9022:7019	9023:7019
9018:7020	9019:7020	9020:7020	9021:7020	9022:7020	9023:7020
9018:7021	9019:7021	9020:7021	9021:7021	9022:7021	9023:7021
9018:7022	9019:7022	9020:7022	9021:7022	9022:7022	9023:7022
9018:7023	9019:7023	9020:7023	9021:7023	9022:7023	9023:7023
9018:7024	9019:7024	9020:7024	9021:7024	9022:7024	9023:7024
9018:7025	9019:7025	9020:7025	9021:7025	9022:7025	9023:7025
9018:7026	9019:7026	9020:7026	9021:7026	9022:7026	9023:7026
9018:7027	9019:7027	9020:7027	9021:7027	9022:7027	9023:7027
9024:7000	9025:7000	9026:7000	9027:7000	9028:7000	9029:7000
9024:7001	9025:7001	9026:7001	9027:7001	9028:7001	9029:7001
9024:7002	9025:7002	9026:7002	9027:7002	9028:7002	9029:7002
9024:7003	9025:7003	9026:7003	9027:7003	9028:7003	9029:7003
9024:7004	9025:7004	9026:7004	9027:7004	9028:7004	9029:7004
9024:7005	9025:7005	9026:7005	9027:7005	9028:7005	9029:7005
9024:7006	9025:7006	9026:7006	9027:7006	9028:7006	9029:7006
9024:7007	9025:7007	9026:7007	9027:7007	9028:7007	9029:7007
9024:7008	9025:7008	9026:7008	9027:7008	9028:7008	9029:7008
9024:7009	9025:7009	9026:7009	9027:7009	9028:7009	9029:7009
9024:7010	9025:7010	9026:7010	9027:7010	9028:7010	9029:7010
9024:7011	9025:7011	9026:7011	9027:7011	9028:7011	9029:7011
9024:7012	9025:7012	9026:7012	9027:7012	9028:7012	9029:7012
9024:7013	9025:7013	9026:7013	9027:7013	9028:7013	9029:7013
9024:7014	9025:7014	9026:7014	9027:7014	9028:7014	9029:7014
9024:7015	9025:7015	9026:7015	9027:7015	9028:7015	9029:7015
9024:7016	9025:7016	9026:7016	9027:7016	9028:7016	9029:7016
9024:7017	9025:7017	9026:7017	9027:7017	9028:7017	9029:7017
9024:7018	9025:7018	9026:7018	9027:7018	9028:7018	9029:7018
9024:7019	9025:7019	9026:7019	9027:7019	9028:7019	9029:7019
9024:7020	9025:7020	9026:7020	9027:7020	9028:7020	9029:7020
9024:7021	9025:7021	9026:7021	9027:7021	9028:7021	9029:7021
9024:7022	9025:7022	9026:7022	9027:7022	9028:7022	9029:7022
9024:7023	9025:7023	9026:7023	9027:7023	9028:7023	9029:7023
9024:7024	9025:7024	9026:7024	9027:7024	9028:7024	9029:7024
9024:7025	9025:7025	9026:7025	9027:7025	9028:7025	9029:7025
9024:7026	9025:7026	9026:7026	9027:7026	9028:7026	9029:7026
9024:7027	9025:7027	9026:7027	9027:7027	9028:7027	9029:7027
9030:7000	9031:7000	9032:7000	9033:7000	9034:7000	9035:7000
9030:7001	9031:7001	9032:7001	9033:7001	9034:7001	9035:7001
9030:7002	9031:7002	9032:7002	9033:7002	9034:7002	9035:7002
9030:7003	9031:7003	9032:7003	9033:7003	9034:7003	9035:7003
9030:7004	9031:7004	9032:7004	9033:7004	9034:7004	9035:7004
9030:7005	9031:7005	9032:7005	9033:7005	9034:7005	9035:7005
9030:7006	9031:7006	9032:7006	9033:7006	9034:7006	9035:7006
9030:7007	9031:7007	9032:7007	9033:7007	9034:7007	9035:7007
9030:7008	9031:7008	9032:7008	9033:7008	9034:7008	9035:7008
9030:7009	9031:7009	9032:7009	9033:7009	9034:7009	9035:7009
9030:7010	9031:7010	9032:7010	9033:7010	9034:7010	9035:7010
9030:7011	9031:7011	9032:7011	9033:7011	9034:7011	9035:7011
9030:7012	9031:7012	9032:7012	9033:7012	9034:7012	9035:7012
9030:7013	9031:7013	9032:7013	9033:7013	9034:7013	9035:7013
9030:7014	9031:7014	9032:7014	9033:7014	9034:7014	9035:7014
9030:7015	9031:7015	9032:7015	9033:7015	9034:7015	9035:7015
9030:7016	9031:7016	9032:7016	9033:7016	9034:7016	9035:7016
9030:7017	9031:7017	9032:7017	9033:7017	9034:7017	9035:7017
9030:7018	9031:7018	9032:7018	9033:7018	9034:7018	9035:7018
9030:7019	9031:7019	9032:7019	9033:7019	9034:7019	9035:7019
9030:7020	9031:7020	9032:7020	9033:7020	9034:7020	9035:7020
9030:7021	9031:7021	9032:7021	9033:7021	9034:7021	9035:7021
9030:7022	9031:7022	9032:7022	9033:7022	9034:7022	9035:7022
9030:7023	9031:7023	9032:7023	9033:7023	9034:7023	9035:7023
9030:7024	9031:7024	9032:7024	9033:7024	9034:7024	9035:7024
9030:7025	9031:7025	9032:7025	9033:7025	9034:7025	9035:7025
9030:7026	9031:7026	9032:7026	9033:7026	9034:7026	9035:7026
9030:7027	9031:7027	9032:7027	9033:7027	9034:7027	9035:7027
9036:7000	9037:7000	9038:7000	9039:7000	9040:7000	9041:7000
9036:7001	9037:7001	9038:7001	9039:7001	9040:7001	9041:7001
9036:7002	9037:7002	9038:7002	9039:7002	9040:7002	9041:7002
9036:7003	9037:7003	9038:7003	9039:7003	9040:7003	9041:7003
9036:7004	9037:7004	9038:7004	9039:7004	9040:7004	9041:7004
9036:7005	9037:7005	9038:7005	9039:7005	9040:7005	9041:7005
9036:7006	9037:7006	9038:7006	9039:7006	9040:7006	9041:7006
9036:7007	9037:7007	9038:7007	9039:7007	9040:7007	9041:7007
9036:7008	9037:7008	9038:7008	9039:7008	9040:7008	9041:7008
9036:7009	9037:7009	9038:7009	9039:7009	9040:7009	9041:7009
9036:7010	9037:7010	9038:7010	9039:7010	9040:7010	9041:7010
9036:7011	9037:7011	9038:7011	9039:7011	9040:7011	9041:7011
9036:7012	9037:7012	9038:7012	9039:7012	9040:7012	9041:7012
9036:7013	9037:7013	9038:7013	9039:7013	9040:7013	9041:7013
9036:7014	9037:7014	9038:7014	9039:7014	9040:7014	9041:7014
9036:7015	9037:7015	9038:7015	9039:7015	9040:7015	9041:7015
9036:7016	9037:7016	9038:7016	9039:7016	9040:7016	9041:7016
9036:7017	9037:7017	9038:7017	9039:7017	9040:7017	9041:7017
9036:7018	9037:7018	9038:7018	9039:7018	9040:7018	9041:7018
9036:7019	9037:7019	9038:7019	9039:7019	9040:7019	9041:7019
9036:7020	9037:7020	9038:7020	9039:7020	9040:7020	9041:7020
9036:7021	9037:7021	9038:7021	9039:7021	9040:7021	9041:7021
9036:7022	9037:7022	9038:7022	9039:7022	9040:7022	9041:7022
9036:7023	9037:7023	9038:7023	9039:7023	9040:7023	9041:7023
9036:7024	9037:7024	9038:7024	9039:7024	9040:7024	9041:7024
9036:7025	9037:7025	9038:7025	9039:7025	9040:7025	9041:7025
9036:7026	9037:7026	9038:7026	9039:7026	9040:7026	9041:7026
9036:7027	9037:7027	9038:7027	9039:7027	9040:7027	9041:7027
9042:7000	9043:7000	9044:7000	9045:7000	9046:7000	9047:7000
9042:7001	9043:7001	9044:7001	9045:7001	9046:7001	9047:7001
9042:7002	9043:7002	9044:7002	9045:7002	9046:7002	9047:7002
9042:7003	9043:7003	9044:7003	9045:7003	9046:7003	9047:7003
9042:7004	9043:7004	9044:7004	9045:7004	9046:7004	9047:7004
9042:7005	9043:7005	9044:7005	9045:7005	9046:7005	9047:7005
9042:7006	9043:7006	9044:7006	9045:7006	9046:7006	9047:7006
9042:7007	9043:7007	9044:7007	9045:7007	9046:7007	9047:7007
9042:7008	9043:7008	9044:7008	9045:7008	9046:7008	9047:7008
9042:7009	9043:7009	9044:7009	9045:7009	9046:7009	9047:7009
9042:7010	9043:7010	9044:7010	9045:7010	9046:7010	9047:7010
9042:7011	9043:7011	9044:7011	9045:7011	9046:7011	9047:7011
9042:7012	9043:7012	9044:7012	9045:7012	9046:7012	9047:7012
9042:7013	9043:7013	9044:7013	9045:7013	9046:7013	9047:7013
9042:7014	9043:7014	9044:7014	9045:7014	9046:7014	9047:7014
9042:7015	9043:7015	9044:7015	9045:7015	9046:7015	9047:7015
9042:7016	9043:7016	9044:7016	9045:7016	9046:7016	9047:7016
9042:7017	9043:7017	9044:7017	9045:7017	9046:7017	9047:7017
9042:7018	9043:7018	9044:7018	9045:7018	9046:7018	9047:7018
9042:7019	9043:7019	9044:7019	9045:7019	9046:7019	9047:7019
9042:7020	9043:7020	9044:7020	9045:7020	9046:7020	9047:7020
9042:7021	9043:7021	9044:7021	9045:7021	9046:7021	9047:7021
9042:7022	9043:7022	9044:7022	9045:7022	9046:7022	9047:7022
9042:7023	9043:7023	9044:7023	9045:7023	9046:7023	9047:7023
9042:7024	9043:7024	9044:7024	9045:7024	9046:7024	9047:7024
9042:7025	9043:7025	9044:7025	9045:7025	9046:7025	9047:7025
9042:7026	9043:7026	9044:7026	9045:7026	9046:7026	9047:7026
9042:7027	9043:7027	9044:7027	9045:7027	9046:7027	9047:7027
9048:7000	9049:7000	9050:7000	9051:7000	9052:7000	9053:7000
9048:7001	9049:7001	9050:7001	9051:7001	9052:7001	9053:7001
9048:7002	9049:7002	9050:7002	9051:7002	9052:7002	9053:7002
9048:7003	9049:7003	9050:7003	9051:7003	9052:7003	9053:7003
9048:7004	9049:7004	9050:7004	9051:7004	9052:7004	9053:7004
9048:7005	9049:7005	9050:7005	9051:7005	9052:7005	9053:7005
9048:7006	9049:7006	9050:7006	9051:7006	9052:7006	9053:7006
9048:7007	9049:7007	9050:7007	9051:7007	9052:7007	9053:7007
9048:7008	9049:7008	9050:7008	9051:7008	9052:7008	9053:7008
9048:7009	9049:7009	9050:7009	9051:7009	9052:7009	9053:7009
9048:7010	9049:7010	9050:7010	9051:7010	9052:7010	9053:7010
9048:7011	9049:7011	9050:7011	9051:7011	9052:7011	9053:7011
9048:7012	9049:7012	9050:7012	9051:7012	9052:7012	9053:7012
9048:7013	9049:7013	9050:7013	9051:7013	9052:7013	9053:7013
9048:7014	9049:7014	9050:7014	9051:7014	9052:7014	9053:7014
9048:7015	9049:7015	9050:7015	9051:7015	9052:7015	9053:7015
9048:7016	9049:7016	9050:7016	9051:7016	9052:7016	9053:7016
9048:7017	9049:7017	9050:7017	9051:7017	9052:7017	9053:7017
9048:7018	9049:7018	9050:7018	9051:7018	9052:7018	9053:7018
9048:7019	9049:7019	9050:7019	9051:7019	9052:7019	9053:7019
9048:7020	9049:7020	9050:7020	9051:7020	9052:7020	9053:7020
9048:7021	9049:7021	9050:7021	9051:7021	9052:7021	9053:7021
9048:7022	9049:7022	9050:7022	9051:7022	9052:7022	9053:7022
9048:7023	9049:7023	9050:7023	9051:7023	9052:7023	9053:7023
9048:7024	9049:7024	9050:7024	9051:7024	9052:7024	9053:7024
9048:7025	9049:7025	9050:7025	9051:7025	9052:7025	9053:7025
9048:7026	9049:7026	9050:7026	9051:7026	9052:7026	9053:7026
9048:7027	9049:7027	9050:7027	9051:7027	9052:7027	9053:7027
9054:7000	9055:7000	9056:7000	9057:7000	9058:7000	9059:7000
9054:7001	9055:7001	9056:7001	9057:7001	9058:7001	9059:7001
9054:7002	9055:7002	9056:7002	9057:7002	9058:7002	9059:7002
9054:7003	9055:7003	9056:7003	9057:7003	9058:7003	9059:7003
9054:7004	9055:7004	9056:7004	9057:7004	9058:7004	9059:7004
9054:7005	9055:7005	9056:7005	9057:7005	9058:7005	9059:7005
9054:7006	9055:7006	9056:7006	9057:7006	9058:7006	9059:7006
9054:7007	9055:7007	9056:7007	9057:7007	9058:7007	9059:7007
9054:7008	9055:7008	9056:7008	9057:7008	9058:7008	9059:7008
9054:7009	9055:7009	9056:7009	9057:7009	9058:7009	9059:7009
9054:7010	9055:7010	9056:7010	9057:7010	9058:7010	9059:7010
9054:7011	9055:7011	9056:7011	9057:7011	9058:7011	9059:7011
9054:7012	9055:7012	9056:7012	9057:7012	9058:7012	9059:7012
9054:7013	9055:7013	9056:7013	9057:7013	9058:7013	9059:7013
9054:7014	9055:7014	9056:7014	9057:7014	9058:7014	9059:7014
9054:7015	9055:7015	9056:7015	9057:7015	9058:7015	9059:7015
9054:7016	9055:7016	9056:7016	9057:7016	9058:7016	9059:7016
9054:7017	9055:7017	9056:7017	9057:7017	9058:7017	9059:7017
9054:7018	9055:7018	9056:7018	9057:7018	9058:7018	9059:7018
9054:7019	9055:7019	9056:7019	9057:7019	9058:7019	9059:7019
9054:7020	9055:7020	9056:7020	9057:7020	9058:7020	9059:7020
9054:7021	9055:7021	9056:7021	9057:7021	9058:7021	9059:7021
9054:7022	9055:7022	9056:7022	9057:7022	9058:7022	9059:7022
9054:7023	9055:7023	9056:7023	9057:7023	9058:7023	9059:7023
9054:7024	9055:7024	9056:7024	9057:7024	9058:7024	9059:7024
9054:7025	9055:7025	9056:7025	9057:7025	9058:7025	9059:7025
9054:7026	9055:7026	9056:7026	9057:7026	9058:7026	9059:7026
9054:7027	9055:7027	9056:7027	9057:7027	9058:7027	9059:7027
9060:7000	9061:7000	9062:7000	9063:7000	9064:7000	9065:7000
9060:7001	9061:7001	9062:7001	9063:7001	9064:7001	9065:7001
9060:7002	9061:7002	9062:7002	9063:7002	9064:7002	9065:7002
9060:7003	9061:7003	9062:7003	9063:7003	9064:7003	9065:7003
9060:7004	9061:7004	9062:7004	9063:7004	9064:7004	9065:7004
9060:7005	9061:7005	9062:7005	9063:7005	9064:7005	9065:7005
9060:7006	9061:7006	9062:7006	9063:7006	9064:7006	9065:7006
9060:7007	9061:7007	9062:7007	9063:7007	9064:7007	9065:7007
9060:7008	9061:7008	9062:7008	9063:7008	9064:7008	9065:7008
9060:7009	9061:7009	9062:7009	9063:7009	9064:7009	9065:7009
9060:7010	9061:7010	9062:7010	9063:7010	9064:7010	9065:7010
9060:7011	9061:7011	9062:7011	9063:7011	9064:7011	9065:7011
9060:7012	9061:7012	9062:7012	9063:7012	9064:7012	9065:7012
9060:7013	9061:7013	9062:7013	9063:7013	9064:7013	9065:7013
9060:7014	9061:7014	9062:7014	9063:7014	9064:7014	9065:7014
9060:7015	9061:7015	9062:7015	9063:7015	9064:7015	9065:7015
9060:7016	9061:7016	9062:7016	9063:7016	9064:7016	9065:7016
9060:7017	9061:7017	9062:7017	9063:7017	9064:7017	9065:7017
9060:7018	9061:7018	9062:7018	9063:7018	9064:7018	9065:7018
9060:7019	9061:7019	9062:7019	9063:7019	9064:7019	9065:7019
9060:7020	9061:7020	9062:7020	9063:7020	9064:7020	9065:7020
9060:7021	9061:7021	9062:7021	9063:7021	9064:7021	9065:7021
9060:7022	9061:7022	9062:7022	9063:7022	9064:7022	9065:7022
9060:7023	9061:7023	9062:7023	9063:7023	9064:7023	9065:7023
9060:7024	9061:7024	9062:7024	9063:7024	9064:7024	9065:7024
9060:7025	9061:7025	9062:7025	9063:7025	9064:7025	9065:7025
9060:7026	9061:7026	9062:7026	9063:7026	9064:7026	9065:7026
9060:7027	9061:7027	9062:7027	9063:7027	9064:7027	9065:7027
9066:7000	9067:7000	9068:7000	9069:7000	9070:7000	9071:7000
9066:7001	9067:7001	9068:7001	9069:7001	9070:7001	9071:7001
9066:7002	9067:7002	9068:7002	9069:7002	9070:7002	9071:7002
9066:7003	9067:7003	9068:7003	9069:7003	9070:7003	9071:7003
9066:7004	9067:7004	9068:7004	9069:7004	9070:7004	9071:7004
9066:7005	9067:7005	9068:7005	9069:7005	9070:7005	9071:7005
9066:7006	9067:7006	9068:7006	9069:7006	9070:7006	9071:7006
9066:7007	9067:7007	9068:7007	9069:7007	9070:7007	9071:7007
9066:7008	9067:7008	9068:7008	9069:7008	9070:7008	9071:7008
9066:7009	9067:7009	9068:7009	9069:7009	9070:7009	9071:7009
9066:7010	9067:7010	9068:7010	9069:7010	9070:7010	9071:7010
9066:7011	9067:7011	9068:7011	9069:7011	9070:7011	9071:7011
9066:7012	9067:7012	9068:7012	9069:7012	9070:7012	9071:7012
9066:7013	9067:7013	9068:7013	9069:7013	9070:7013	9071:7013
9066:7014	9067:7014	9068:7014	9069:7014	9070:7014	9071:7014
9066:7015	9067:7015	9068:7015	9069:7015	9070:7015	9071:7015
9066:7016	9067:7016	9068:7016	9069:7016	9070:7016	9071:7016
9066:7017	9067:7017	9068:7017	9069:7017	9070:7017	9071:7017
9066:7018	9067:7018	9068:7018	9069:7018	9070:7018	9071:7018
9066:7019	9067:7019	9068:7019	9069:7019	9070:7019	9071:7019
9066:7020	9067:7020	9068:7020	9069:7020	9070:7020	9071:7020
9066:7021	9067:7021	9068:7021	9069:7021	9070:7021	9071:7021
9066:7022	9067:7022	9068:7022	9069:7022	9070:7022	9071:7022
9066:7023	9067:7023	9068:7023	9069:7023	9070:7023	9071:7023
9066:7024	9067:7024	9068:7024	9069:7024	9070:7024	9071:7024
9066:7025	9067:7025	9068:7025	9069:7025	9070:7025	9071:7025
9066:7026	9067:7026	9068:7026	9069:7026	9070:7026	9071:7026
9066:7027	9067:7027	9068:7027	9069:7027	9070:7027	9071:7027
9072:7000	9073:7000	9074:7000	9075:7000	9076:7000	9077:7000
9072:7001	9073:7001	9074:7001	9075:7001	9076:7001	9077:7001
9072:7002	9073:7002	9074:7002	9075:7002	9076:7002	9077:7002
9072:7003	9073:7003	9074:7003	9075:7003	9076:7003	9077:7003
9072:7004	9073:7004	9074:7004	9075:7004	9076:7004	9077:7004
9072:7005	9073:7005	9074:7005	9075:7005	9076:7005	9077:7005
9072:7006	9073:7006	9074:7006	9075:7006	9076:7006	9077:7006
9072:7007	9073:7007	9074:7007	9075:7007	9076:7007	9077:7007
9072:7008	9073:7008	9074:7008	9075:7008	9076:7008	9077:7008
9072:7009	9073:7009	9074:7009	9075:7009	9076:7009	9077:7009
9072:7010	9073:7010	9074:7010	9075:7010	9076:7010	9077:7010
9072:7011	9073:7011	9074:7011	9075:7011	9076:7011	9077:7011
9072:7012	9073:7012	9074:7012	9075:7012	9076:7012	9077:7012
9072:7013	9073:7013	9074:7013	9075:7013	9076:7013	9077:7013
9072:7014	9073:7014	9074:7014	9075:7014	9076:7014	9077:7014
9072:7015	9073:7015	9074:7015	9075:7015	9076:7015	9077:7015
9072:7016	9073:7016	9074:7016	9075:7016	9076:7016	9077:7016
9072:7017	9073:7017	9074:7017	9075:7017	9076:7017	9077:7017
9072:7018	9073:7018	9074:7018	9075:7018	9076:7018	9077:7018
9072:7019	9073:7019	9074:7019	9075:7019	9076:7019	9077:7019
9072:7020	9073:7020	9074:7020	9075:7020	9076:7020	9077:7020
9072:7021	9073:7021	9074:7021	9075:7021	9076:7021	9077:7021
9072:7022	9073:7022	9074:7022	9075:7022	9076:7022	9077:7022
9072:7023	9073:7023	9074:7023	9075:7023	9076:7023	9077:7023
9072:7024	9073:7024	9074:7024	9075:7024	9076:7024	9077:7024
9072:7025	9073:7025	9074:7025	9075:7025	9076:7025	9077:7025
9072:7026	9073:7026	9074:7026	9075:7026	9076:7026	9077:7026
9072:7027	9073:7027	9074:7027	9075:7027	9076:7027	9077:7027
9078:7000	9079:7000	9080:7000	9081:7000	9082:7000	9083:7000
9078:7001	9079:7001	9080:7001	9081:7001	9082:7001	9083:7001
9078:7002	9079:7002	9080:7002	9081:7002	9082:7002	9083:7002
9078:7003	9079:7003	9080:7003	9081:7003	9082:7003	9083:7003
9078:7004	9079:7004	9080:7004	9081:7004	9082:7004	9083:7004
9078:7005	9079:7005	9080:7005	9081:7005	9082:7005	9083:7005
9078:7006	9079:7006	9080:7006	9081:7006	9082:7006	9083:7006
9078:7007	9079:7007	9080:7007	9081:7007	9082:7007	9083:7007
9078:7008	9079:7008	9080:7008	9081:7008	9082:7008	9083:7008
9078:7009	9079:7009	9080:7009	9081:7009	9082:7009	9083:7009
9078:7010	9079:7010	9080:7010	9081:7010	9082:7010	9083:7010
9078:7011	9079:7011	9080:7011	9081:7011	9082:7011	9083:7011
9078:7012	9079:7012	9080:7012	9081:7012	9082:7012	9083:7012
9078:7013	9079:7013	9080:7013	9081:7013	9082:7013	9083:7013
9078:7014	9079:7014	9080:7014	9081:7014	9082:7014	9083:7014
9078:7015	9079:7015	9080:7015	9081:7015	9082:7015	9083:7015
9078:7016	9079:7016	9080:7016	9081:7016	9082:7016	9083:7016
9078:7017	9079:7017	9080:7017	9081:7017	9082:7017	9083:7017
9078:7018	9079:7018	9080:7018	9081:7018	9082:7018	9083:7018
9078:7019	9079:7019	9080:7019	9081:7019	9082:7019	9083:7019
9078:7020	9079:7020	9080:7020	9081:7020	9082:7020	9083:7020
9078:7021	9079:7021	9080:7021	9081:7021	9082:7021	9083:7021
9078:7022	9079:7022	9080:7022	9081:7022	9082:7022	9083:7022
9078:7023	9079:7023	9080:7023	9081:7023	9082:7023	9083:7023
9078:7024	9079:7024	9080:7024	9081:7024	9082:7024	9083:7024
9078:7025	9079:7025	9080:7025	9081:7025	9082:7025	9083:7025
9078:7026	9079:7026	9080:7026	9081:7026	9082:7026	9083:7026
9078:7027	9079:7027	9080:7027	9081:7027	9082:7027	9083:7027
9084:7000	9085:7000	9086:7000	9087:7000	9088:7000	9089:7000
9084:7001	9085:7001	9086:7001	9087:7001	9088:7001	9089:7001
9084:7002	9085:7002	9086:7002	9087:7002	9088:7002	9089:7002
9084:7003	9085:7003	9086:7003	9087:7003	9088:7003	9089:7003
9084:7004	9085:7004	9086:7004	9087:7004	9088:7004	9089:7004
9084:7005	9085:7005	9086:7005	9087:7005	9088:7005	9089:7005
9084:7006	9085:7006	9086:7006	9087:7006	9088:7006	9089:7006
9084:7007	9085:7007	9086:7007	9087:7007	9088:7007	9089:7007
9084:7008	9085:7008	9086:7008	9087:7008	9088:7008	9089:7008
9084:7009	9085:7009	9086:7009	9087:7009	9088:7009	9089:7009
9084:7010	9085:7010	9086:7010	9087:7010	9088:7010	9089:7010
9084:7011	9085:7011	9086:7011	9087:7011	9088:7011	9089:7011
9084:7012	9085:7012	9086:7012	9087:7012	9088:7012	9089:7012
9084:7013	9085:7013	9086:7013	9087:7013	9088:7013	9089:7013
9084:7014	9085:7014	9086:7014	9087:7014	9088:7014	9089:7014
9084:7015	9085:7015	9086:7015	9087:7015	9088:7015	9089:7015
9084:7016	9085:7016	9086:7016	9087:7016	9088:7016	9089:7016
9084:7017	9085:7017	9086:7017	9087:7017	9088:7017	9089:7017
9084:7018	9085:7018	9086:7018	9087:7018	9088:7018	9089:7018
9084:7019	9085:7019	9086:7019	9087:7019	9088:7019	9089:7019
9084:7020	9085:7020	9086:7020	9087:7020	9088:7020	9089:7020
9084:7021	9085:7021	9086:7021	9087:7021	9088:7021	9089:7021
9084:7022	9085:7022	9086:7022	9087:7022	9088:7022	9089:7022
9084:7023	9085:7023	9086:7023	9087:7023	9088:7023	9089:7023
9084:7024	9085:7024	9086:7024	9087:7024	9088:7024	9089:7024
9084:7025	9085:7025	9086:7025	9087:7025	9088:7025	9089:7025
9084:7026	9085:7026	9086:7026	9087:7026	9088:7026	9089:7026
9084:7027	9085:7027	9086:7027	9087:7027	9088:7027	9089:7027
9090:7000	9091:7000	9092:7000	9093:7000	9094:7000	9095:7000
9090:7001	9091:7001	9092:7001	9093:7001	9094:7001	9095:7001
9090:7002	9091:7002	9092:7002	9093:7002	9094:7002	9095:7002
9090:7003	9091:7003	9092:7003	9093:7003	9094:7003	9095:7003
9090:7004	9091:7004	9092:7004	9093:7004	9094:7004	9095:7004
9090:7005	9091:7005	9092:7005	9093:7005	9094:7005	9095:7005
9090:7006	9091:7006	9092:7006	9093:7006	9094:7006	9095:7006
9090:7007	9091:7007	9092:7007	9093:7007	9094:7007	9095:7007
9090:7008	9091:7008	9092:7008	9093:7008	9094:7008	9095:7008
9090:7009	9091:7009	9092:7009	9093:7009	9094:7009	9095:7009
9090:7010	9091:7010	9092:7010	9093:7010	9094:7010	9095:7010
9090:7011	9091:7011	9092:7011	9093:7011	9094:7011	9095:7011
9090:7012	9091:7012	9092:7012	9093:7012	9094:7012	9095:7012
9090:7013	9091:7013	9092:7013	9093:7013	9094:7013	9095:7013
9090:7014	9091:7014	9092:7014	9093:7014	9094:7014	9095:7014
9090:7015	9091:7015	9092:7015	9093:7015	9094:7015	9095:7015
9090:7016	9091:7016	9092:7016	9093:7016	9094:7016	9095:7016
9090:7017	9091:7017	9092:7017	9093:7017	9094:7017	9095:7017
9090:7018	9091:7018	9092:7018	9093:7018	9094:7018	9095:7018
9090:7019	9091:7019	9092:7019	9093:7019	9094:7019	9095:7019
9090:7020	9091:7020	9092:7020	9093:7020	9094:7020	9095:7020
9090:7021	9091:7021	9092:7021	9093:7021	9094:7021	9095:7021
9090:7022	9091:7022	9092:7022	9093:7022	9094:7022	9095:7022
9090:7023	9091:7023	9092:7023	9093:7023	9094:7023	9095:7023
9090:7024	9091:7024	9092:7024	9093:7024	9094:7024	9095:7024
9090:7025	9091:7025	9092:7025	9093:7025	9094:7025	9095:7025
9090:7026	9091:7026	9092:7026	9093:7026	9094:7026	9095:7026
9090:7027	9091:7027	9092:7027	9093:7027	9094:7027	9095:7027
9096:7000	9097:7000	9098:7000	9099:7000	9100:7000	9101:7000
9096:7001	9097:7001	9098:7001	9099:7001	9100:7001	9101:7001
9096:7002	9097:7002	9098:7002	9099:7002	9100:7002	9101:7002
9096:7003	9097:7003	9098:7003	9099:7003	9100:7003	9101:7003
9096:7004	9097:7004	9098:7004	9099:7004	9100:7004	9101:7004
9096:7005	9097:7005	9098:7005	9099:7005	9100:7005	9101:7005
9096:7006	9097:7006	9098:7006	9099:7006	9100:7006	9101:7006
9096:7007	9097:7007	9098:7007	9099:7007	9100:7007	9101:7007
9096:7008	9097:7008	9098:7008	9099:7008	9100:7008	9101:7008
9096:7009	9097:7009	9098:7009	9099:7009	9100:7009	9101:7009
9096:7010	9097:7010	9098:7010	9099:7010	9100:7010	9101:7010
9096:7011	9097:7011	9098:7011	9099:7011	9100:7011	9101:7011
9096:7012	9097:7012	9098:7012	9099:7012	9100:7012	9101:7012
9096:7013	9097:7013	9098:7013	9099:7013	9100:7013	9101:7013
9096:7014	9097:7014	9098:7014	9099:7014	9100:7014	9101:7014
9096:7015	9097:7015	9098:7015	9099:7015	9100:7015	9101:7015
9096:7016	9097:7016	9098:7016	9099:7016	9100:7016	9101:7016
9096:7017	9097:7017	9098:7017	9099:7017	9100:7017	9101:7017
9096:7018	9097:7018	9098:7018	9099:7018	9100:7018	9101:7018
9096:7019	9097:7019	9098:7019	9099:7019	9100:7019	9101:7019
9096:7020	9097:7020	9098:7020	9099:7020	9100:7020	9101:7020
9096:7021	9097:7021	9098:7021	9099:7021	9100:7021	9101:7021
9096:7022	9097:7022	9098:7022	9099:7022	9100:7022	9101:7022
9096:7023	9097:7023	9098:7023	9099:7023	9100:7023	9101:7023
9096:7024	9097:7024	9098:7024	9099:7024	9100:7024	9101:7024
9096:7025	9097:7025	9098:7025	9099:7025	9100:7025	9101:7025
9096:7026	9097:7026	9098:7026	9099:7026	9100:7026	9101:7026
9096:7027	9097:7027	9098:7027	9099:7027	9100:7027	9101:7027
9102:7000	9103:7000	9104:7000	9105:7000	—	—
9102:7001	9103:7001	9104:7001	9105:7001
9102:7002	9103:7002	9104:7002	9105:7002
9102:7003	9103:7003	9104:7003	9105:7003
9102:7004	9103:7004	9104:7004	9105:7004
9102:7005	9103:7005	9104:7005	9105:7005
9102:7006	9103:7006	9104:7006	9105:7006
9102:7007	9103:7007	9104:7007	9105:7007
9102:7008	9103:7008	9104:7008	9105:7008
9102:7009	9103:7009	9104:7009	9105:7009
9102:7010	9103:7010	9104:7010	9105:7010
9102:7011	9103:7011	9104:7011	9105:7011
9102:7012	9103:7012	9104:7012	9105:7012
9102:7013	9103:7013	9104:7013	9105:7013
9102:7014	9103:7014	9104:7014	9105:7014
9102:7015	9103:7015	9104:7015	9105:7015
9102:7016	9103:7016	9104:7016	9105:7016
9102:7017	9103:7017	9104:7017	9105:7017
9102:7018	9103:7018	9104:7018	9105:7018
9102:7019	9103:7019	9104:7019	9105:7019
9102:7020	9103:7020	9104:7020	9105:7020
9102:7021	9103:7021	9104:7021	9105:7021
9102:7022	9103:7022	9104:7022	9105:7022
9102:7023	9103:7023	9104:7023	9105:7023
9102:7024	9103:7024	9104:7024	9105:7024
9102:7025	9103:7025	9104:7025	9105:7025
9102:7026	9103:7026	9104:7026	9105:7026
9102:7027	9103:7027	9104:7027	9105:7027

TABLE D
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
6000:9000	6040:9000	6000:9001	6040:9001	6000:9002	6040:9002
6001:9000	6041:9000	6001:9001	6041:9001	6001:9002	6041:9002
6002:9000	6042:9000	6002:9001	6042:9001	6002:9002	6042:9002
6003:9000	6043:9000	6003:9001	6043:9001	6003:9002	6043:9002
6004:9000	6044:9000	6004:9001	6044:9001	6004:9002	6044:9002
6005:9000	6045:9000	6005:9001	6045:9001	6005:9002	6045:9002
6006:9000	6046:9000	6006:9001	6046:9001	6006:9002	6046:9002
6007:9000	6047:9000	6007:9001	6047:9001	6007:9002	6047:9002
6008:9000	6048:9000	6008:9001	6048:9001	6008:9002	6048:9002
6009:9000	6049:9000	6009:9001	6049:9001	6009:9002	6049:9002
6010:9000	6050:9000	6010:9001	6050:9001	6010:9002	6050:9002
6011:9000	6051:9000	6011:9001	6051:9001	6011:9002	6051:9002
6012:9000	6052:9000	6012:9001	6052:9001	6012:9002	6052:9002
6013:9000	6053:9000	6013:9001	6053:9001	6013:9002	6053:9002
6014:9000	6054:9000	6014:9001	6054:9001	6014:9002	6054:9002
6015:9000	6055:9000	6015:9001	6055:9001	6015:9002	6055:9002
6016:9000	6056:9000	6016:9001	6056:9001	6016:9002	6056:9002
6017:9000	6057:9000	6017:9001	6057:9001	6017:9002	6057:9002
6018:9000	6058:9000	6018:9001	6058:9001	6018:9002	6058:9002
6019:9000	6059:9000	6019:9001	6059:9001	6019:9002	6059:9002
6020:9000	6060:9000	6020:9001	6060:9001	6020:9002	6060:9002
6021:9000	6061:9000	6021:9001	6061:9001	6021:9002	6061:9002
6022:9000	6062:9000	6022:9001	6062:9001	6022:9002	6062:9002
6023:9000	6063:9000	6023:9001	6063:9001	6023:9002	6063:9002
6024:9000	6064:9000	6024:9001	6064:9001	6024:9002	6064:9002
6025:9000	6065:9000	6025:9001	6065:9001	6025:9002	6065:9002
6026:9000	6066:9000	6026:9001	6066:9001	6026:9002	6066:9002
6027:9000	6067:9000	6027:9001	6067:9001	6027:9002	6067:9002
6028:9000	6068:9000	6028:9001	6068:9001	6028:9002	6068:9002
6029:9000	6069:9000	6029:9001	6069:9001	6029:9002	6069:9002
6030:9000	6070:9000	6030:9001	6070:9001	6030:9002	6070:9002
6031:9000	6071:9000	6031:9001	6071:9001	6031:9002	6071:9002
6032:9000	6072:9000	6032:9001	6072:9001	6032:9002	6072:9002
6033:9000	6073:9000	6033:9001	6073:9001	6033:9002	6073:9002
6034:9000	6074:9000	6034:9001	6074:9001	6034:9002	6074:9002
6035:9000	6075:9000	6035:9001	6075:9001	6035:9002	6075:9002
6036:9000	6076:9000	6036:9001	6076:9001	6036:9002	6076:9002
6037:9000	6077:9000	6037:9001	6077:9001	6037:9002	6077:9002
6038:9000	6078:9000	6038:9001	6078:9001	6038:9002	6078:9002
6039:9000		6039:9001		6039:9002
6000:9003	6040:9003	6000:9004	6040:9004	6000:9005	6040:9005
6001:9003	6041:9003	6001:9004	6041:9004	6001:9005	6041:9005
6002:9003	6042:9003	6002:9004	6042:9004	6002:9005	6042:9005
6003:9003	6043:9003	6003:9004	6043:9004	6003:9005	6043:9005
6004:9003	6044:9003	6004:9004	6044:9004	6004:9005	6044:9005
6005:9003	6045:9003	6005:9004	6045:9004	6005:9005	6045:9005
6006:9003	6046:9003	6006:9004	6046:9004	6006:9005	6046:9005
6007:9003	6047:9003	6007:9004	6047:9004	6007:9005	6047:9005
6008:9003	6048:9003	6008:9004	6048:9004	6008:9005	6048:9005
6009:9003	6049:9003	6009:9004	6049:9004	6009:9005	6049:9005
6010:9003	6050:9003	6010:9004	6050:9004	6010:9005	6050:9005
6011:9003	6051:9003	6011:9004	6051:9004	6011:9005	6051:9005
6012:9003	6052:9003	6012:9004	6052:9004	6012:9005	6052:9005
6013:9003	6053:9003	6013:9004	6053:9004	6013:9005	6053:9005
6014:9003	6054:9003	6014:9004	6054:9004	6014:9005	6054:9005
6015:9003	6055:9003	6015:9004	6055:9004	6015:9005	6055:9005
6016:9003	6056:9003	6016:9004	6056:9004	6016:9005	6056:9005
6017:9003	6057:9003	6017:9004	6057:9004	6017:9005	6057:9005
6018:9003	6058:9003	6018:9004	6058:9004	6018:9005	6058:9005
6019:9003	6059:9003	6019:9004	6059:9004	6019:9005	6059:9005
6020:9003	6060:9003	6020:9004	6060:9004	6020:9005	6060:9005
6021:9003	6061:9003	6021:9004	6061:9004	6021:9005	6061:9005
6022:9003	6062:9003	6022:9004	6062:9004	6022:9005	6062:9005
6023:9003	6063:9003	6023:9004	6063:9004	6023:9005	6063:9005
6024:9003	6064:9003	6024:9004	6064:9004	6024:9005	6064:9005
6025:9003	6065:9003	6025:9004	6065:9004	6025:9005	6065:9005
6026:9003	6066:9003	6026:9004	6066:9004	6026:9005	6066:9005
6027:9003	6067:9003	6027:9004	6067:9004	6027:9005	6067:9005
6028:9003	6068:9003	6028:9004	6068:9004	6028:9005	6068:9005
6029:9003	6069:9003	6029:9004	6069:9004	6029:9005	6069:9005
6030:9003	6070:9003	6030:9004	6070:9004	6030:9005	6070:9005
6031:9003	6071:9003	6031:9004	6071:9004	6031:9005	6071:9005
6032:9003	6072:9003	6032:9004	6072:9004	6032:9005	6072:9005
6033:9003	6073:9003	6033:9004	6073:9004	6033:9005	6073:9005
6034:9003	6074:9003	6034:9004	6074:9004	6034:9005	6074:9005
6035:9003	6075:9003	6035:9004	6075:9004	6035:9005	6075:9005
6036:9003	6076:9003	6036:9004	6076:9004	6036:9005	6076:9005
6037:9003	6077:9003	6037:9004	6077:9004	6037:9005	6077:9005
6038:9003	6078:9003	6038:9004	6078:9004	6038:9005	6078:9005
6039:9003		6039:9004		6039:9005
6000:9006	6040:9006	6000:9007	6040:9007	6000:9008	6040:9008
6001:9006	6041:9006	6001:9007	6041:9007	6001:9008	6041:9008
6002:9006	6042:9006	6002:9007	6042:9007	6002:9008	6042:9008
6003:9006	6043:9006	6003:9007	6043:9007	6003:9008	6043:9008
6004:9006	6044:9006	6004:9007	6044:9007	6004:9008	6044:9008
6005:9006	6045:9006	6005:9007	6045:9007	6005:9008	6045:9008
6006:9006	6046:9006	6006:9007	6046:9007	6006:9008	6046:9008
6007:9006	6047:9006	6007:9007	6047:9007	6007:9008	6047:9008
6008:9006	6048:9006	6008:9007	6048:9007	6008:9008	6048:9008
6009:9006	6049:9006	6009:9007	6049:9007	6009:9008	6049:9008
6010:9006	6050:9006	6010:9007	6050:9007	6010:9008	6050:9008
6011:9006	6051:9006	6011:9007	6051:9007	6011:9008	6051:9008
6012:9006	6052:9006	6012:9007	6052:9007	6012:9008	6052:9008
6013:9006	6053:9006	6013:9007	6053:9007	6013:9008	6053:9008
6014:9006	6054:9006	6014:9007	6054:9007	6014:9008	6054:9008
6015:9006	6055:9006	6015:9007	6055:9007	6015:9008	6055:9008
6016:9006	6056:9006	6016:9007	6056:9007	6016:9008	6056:9008
6017:9006	6057:9006	6017:9007	6057:9007	6017:9008	6057:9008
6018:9006	6058:9006	6018:9007	6058:9007	6018:9008	6058:9008
6019:9006	6059:9006	6019:9007	6059:9007	6019:9008	6059:9008
6020:9006	6060:9006	6020:9007	6060:9007	6020:9008	6060:9008
6021:9006	6061:9006	6021:9007	6061:9007	6021:9008	6061:9008
6022:9006	6062:9006	6022:9007	6062:9007	6022:9008	6062:9008
6023:9006	6063:9006	6023:9007	6063:9007	6023:9008	6063:9008
6024:9006	6064:9006	6024:9007	6064:9007	6024:9008	6064:9008
6025:9006	6065:9006	6025:9007	6065:9007	6025:9008	6065:9008
6026:9006	6066:9006	6026:9007	6066:9007	6026:9008	6066:9008
6027:9006	6067:9006	6027:9007	6067:9007	6027:9008	6067:9008
6028:9006	6068:9006	6028:9007	6068:9007	6028:9008	6068:9008
6029:9006	6069:9006	6029:9007	6069:9007	6029:9008	6069:9008
6030:9006	6070:9006	6030:9007	6070:9007	6030:9008	6070:9008
6031:9006	6071:9006	6031:9007	6071:9007	6031:9008	6071:9008
6032:9006	6072:9006	6032:9007	6072:9007	6032:9008	6072:9008
6033:9006	6073:9006	6033:9007	6073:9007	6033:9008	6073:9008
6034:9006	6074:9006	6034:9007	6074:9007	6034:9008	6074:9008
6035:9006	6075:9006	6035:9007	6075:9007	6035:9008	6075:9008
6036:9006	6076:9006	6036:9007	6076:9007	6036:9008	6076:9008
6037:9006	6077:9006	6037:9007	6077:9007	6037:9008	6077:9008
6038:9006	6078:9006	6038:9007	6078:9007	6038:9008	6078:9008
6039:9006		6039:9007		6039:9008
6000:9009	6040:9009	6000:9010	6040:9010	6000:9011	6040:9011
6001:9009	6041:9009	6001:9010	6041:9010	6001:9011	6041:9011
6002:9009	6042:9009	6002:9010	6042:9010	6002:9011	6042:9011
6003:9009	6043:9009	6003:9010	6043:9010	6003:9011	6043:9011
6004:9009	6044:9009	6004:9010	6044:9010	6004:9011	6044:9011
6005:9009	6045:9009	6005:9010	6045:9010	6005:9011	6045:9011
6006:9009	6046:9009	6006:9010	6046:9010	6006:9011	6046:9011
6007:9009	6047:9009	6007:9010	6047:9010	6007:9011	6047:9011
6008:9009	6048:9009	6008:9010	6048:9010	6008:9011	6048:9011
6009:9009	6049:9009	6009:9010	6049:9010	6009:9011	6049:9011
6010:9009	6050:9009	6010:9010	6050:9010	6010:9011	6050:9011
6011:9009	6051:9009	6011:9010	6051:9010	6011:9011	6051:9011
6012:9009	6052:9009	6012:9010	6052:9010	6012:9011	6052:9011
6013:9009	6053:9009	6013:9010	6053:9010	6013:9011	6053:9011
6014:9009	6054:9009	6014:9010	6054:9010	6014:9011	6054:9011
6015:9009	6055:9009	6015:9010	6055:9010	6015:9011	6055:9011
6016:9009	6056:9009	6016:9010	6056:9010	6016:9011	6056:9011
6017:9009	6057:9009	6017:9010	6057:9010	6017:9011	6057:9011
6018:9009	6058:9009	6018:9010	6058:9010	6018:9011	6058:9011
6019:9009	6059:9009	6019:9010	6059:9010	6019:9011	6059:9011
6020:9009	6060:9009	6020:9010	6060:9010	6020:9011	6060:9011
6021:9009	6061:9009	6021:9010	6061:9010	6021:9011	6061:9011
6022:9009	6062:9009	6022:9010	6062:9010	6022:9011	6062:9011
6023:9009	6063:9009	6023:9010	6063:9010	6023:9011	6063:9011
6024:9009	6064:9009	6024:9010	6064:9010	6024:9011	6064:9011
6025:9009	6065:9009	6025:9010	6065:9010	6025:9011	6065:9011
6026:9009	6066:9009	6026:9010	6066:9010	6026:9011	6066:9011
6027:9009	6067:9009	6027:9010	6067:9010	6027:9011	6067:9011
6028:9009	6068:9009	6028:9010	6068:9010	6028:9011	6068:9011
6029:9009	6069:9009	6029:9010	6069:9010	6029:9011	6069:9011
6030:9009	6070:9009	6030:9010	6070:9010	6030:9011	6070:9011
6031:9009	6071:9009	6031:9010	6071:9010	6031:9011	6071:9011
6032:9009	6072:9009	6032:9010	6072:9010	6032:9011	6072:9011
6033:9009	6073:9009	6033:9010	6073:9010	6033:9011	6073:9011
6034:9009	6074:9009	6034:9010	6074:9010	6034:9011	6074:9011
6035:9009	6075:9009	6035:9010	6075:9010	6035:9011	6075:9011
6036:9009	6076:9009	6036:9010	6076:9010	6036:9011	6076:9011
6037:9009	6077:9009	6037:9010	6077:9010	6037:9011	6077:9011
6038:9009	6078:9009	6038:9010	6078:9010	6038:9011	6078:9011
6039:9009		6039:9010		6039:9011
6000:9012	6040:9012	6000:9013	6040:9013	6000:9014	6040:9014
6001:9012	6041:9012	6001:9013	6041:9013	6001:9014	6041:9014
6002:9012	6042:9012	6002:9013	6042:9013	6002:9014	6042:9014
6003:9012	6043:9012	6003:9013	6043:9013	6003:9014	6043:9014
6004:9012	6044:9012	6004:9013	6044:9013	6004:9014	6044:9014
6005:9012	6045:9012	6005:9013	6045:9013	6005:9014	6045:9014
6006:9012	6046:9012	6006:9013	6046:9013	6006:9014	6046:9014
6007:9012	6047:9012	6007:9013	6047:9013	6007:9014	6047:9014
6008:9012	6048:9012	6008:9013	6048:9013	6008:9014	6048:9014
6009:9012	6049:9012	6009:9013	6049:9013	6009:9014	6049:9014
6010:9012	6050:9012	6010:9013	6050:9013	6010:9014	6050:9014
6011:9012	6051:9012	6011:9013	6051:9013	6011:9014	6051:9014
6012:9012	6052:9012	6012:9013	6052:9013	6012:9014	6052:9014
6013:9012	6053:9012	6013:9013	6053:9013	6013:9014	6053:9014
6014:9012	6054:9012	6014:9013	6054:9013	6014:9014	6054:9014
6015:9012	6055:9012	6015:9013	6055:9013	6015:9014	6055:9014
6016:9012	6056:9012	6016:9013	6056:9013	6016:9014	6056:9014
6017:9012	6057:9012	6017:9013	6057:9013	6017:9014	6057:9014
6018:9012	6058:9012	6018:9013	6058:9013	6018:9014	6058:9014
6019:9012	6059:9012	6019:9013	6059:9013	6019:9014	6059:9014
6020:9012	6060:9012	6020:9013	6060:9013	6020:9014	6060:9014
6021:9012	6061:9012	6021:9013	6061:9013	6021:9014	6061:9014
6022:9012	6062:9012	6022:9013	6062:9013	6022:9014	6062:9014
6023:9012	6063:9012	6023:9013	6063:9013	6023:9014	6063:9014
6024:9012	6064:9012	6024:9013	6064:9013	6024:9014	6064:9014
6025:9012	6065:9012	6025:9013	6065:9013	6025:9014	6065:9014
6026:9012	6066:9012	6026:9013	6066:9013	6026:9014	6066:9014
6027:9012	6067:9012	6027:9013	6067:9013	6027:9014	6067:9014
6028:9012	6068:9012	6028:9013	6068:9013	6028:9014	6068:9014
6029:9012	6069:9012	6029:9013	6069:9013	6029:9014	6069:9014
6030:9012	6070:9012	6030:9013	6070:9013	6030:9014	6070:9014
6031:9012	6071:9012	6031:9013	6071:9013	6031:9014	6071:9014
6032:9012	6072:9012	6032:9013	6072:9013	6032:9014	6072:9014
6033:9012	6073:9012	6033:9013	6073:9013	6033:9014	6073:9014
6034:9012	6074:9012	6034:9013	6074:9013	6034:9014	6074:9014
6035:9012	6075:9012	6035:9013	6075:9013	6035:9014	6075:9014
6036:9012	6076:9012	6036:9013	6076:9013	6036:9014	6076:9014
6037:9012	6077:9012	6037:9013	6077:9013	6037:9014	6077:9014
6038:9012	6078:9012	6038:9013	6078:9013	6038:9014	6078:9014
6039:9012		6039:9013		6039:9014
6000:9015	6040:9015	6000:9016	6040:9016	6000:9017	6040:9017
6001:9015	6041:9015	6001:9016	6041:9016	6001:9017	6041:9017
6002:9015	6042:9015	6002:9016	6042:9016	6002:9017	6042:9017
6003:9015	6043:9015	6003:9016	6043:9016	6003:9017	6043:9017
6004:9015	6044:9015	6004:9016	6044:9016	6004:9017	6044:9017
6005:9015	6045:9015	6005:9016	6045:9016	6005:9017	6045:9017
6006:9015	6046:9015	6006:9016	6046:9016	6006:9017	6046:9017
6007:9015	6047:9015	6007:9016	6047:9016	6007:9017	6047:9017
6008:9015	6048:9015	6008:9016	6048:9016	6008:9017	6048:9017
6009:9015	6049:9015	6009:9016	6049:9016	6009:9017	6049:9017
6010:9015	6050:9015	6010:9016	6050:9016	6010:9017	6050:9017
6011:9015	6051:9015	6011:9016	6051:9016	6011:9017	6051:9017
6012:9015	6052:9015	6012:9016	6052:9016	6012:9017	6052:9017
6013:9015	6053:9015	6013:9016	6053:9016	6013:9017	6053:9017
6014:9015	6054:9015	6014:9016	6054:9016	6014:9017	6054:9017
6015:9015	6055:9015	6015:9016	6055:9016	6015:9017	6055:9017
6016:9015	6056:9015	6016:9016	6056:9016	6016:9017	6056:9017
6017:9015	6057:9015	6017:9016	6057:9016	6017:9017	6057:9017
6018:9015	6058:9015	6018:9016	6058:9016	6018:9017	6058:9017
6019:9015	6059:9015	6019:9016	6059:9016	6019:9017	6059:9017
6020:9015	6060:9015	6020:9016	6060:9016	6020:9017	6060:9017
6021:9015	6061:9015	6021:9016	6061:9016	6021:9017	6061:9017
6022:9015	6062:9015	6022:9016	6062:9016	6022:9017	6062:9017
6023:9015	6063:9015	6023:9016	6063:9016	6023:9017	6063:9017
6024:9015	6064:9015	6024:9016	6064:9016	6024:9017	6064:9017
6025:9015	6065:9015	6025:9016	6065:9016	6025:9017	6065:9017
6026:9015	6066:9015	6026:9016	6066:9016	6026:9017	6066:9017
6027:9015	6067:9015	6027:9016	6067:9016	6027:9017	6067:9017
6028:9015	6068:9015	6028:9016	6068:9016	6028:9017	6068:9017
6029:9015	6069:9015	6029:9016	6069:9016	6029:9017	6069:9017
6030:9015	6070:9015	6030:9016	6070:9016	6030:9017	6070:9017
6031:9015	6071:9015	6031:9016	6071:9016	6031:9017	6071:9017
6032:9015	6072:9015	6032:9016	6072:9016	6032:9017	6072:9017
6033:9015	6073:9015	6033:9016	6073:9016	6033:9017	6073:9017
6034:9015	6074:9015	6034:9016	6074:9016	6034:9017	6074:9017
6035:9015	6075:9015	6035:9016	6075:9016	6035:9017	6075:9017
6036:9015	6076:9015	6036:9016	6076:9016	6036:9017	6076:9017
6037:9015	6077:9015	6037:9016	6077:9016	6037:9017	6077:9017
6038:9015	6078:9015	6038:9016	6078:9016	6038:9017	6078:9017
6039:9015		6039:9016		6039:9017
6000:9018	6040:9018	6000:9019	6040:9019	6000:9020	6040:9020
6001:9018	6041:9018	6001:9019	6041:9019	6001:9020	6041:9020
6002:9018	6042:9018	6002:9019	6042:9019	6002:9020	6042:9020
6003:9018	6043:9018	6003:9019	6043:9019	6003:9020	6043:9020
6004:9018	6044:9018	6004:9019	6044:9019	6004:9020	6044:9020
6005:9018	6045:9018	6005:9019	6045:9019	6005:9020	6045:9020
6006:9018	6046:9018	6006:9019	6046:9019	6006:9020	6046:9020
6007:9018	6047:9018	6007:9019	6047:9019	6007:9020	6047:9020
6008:9018	6048:9018	6008:9019	6048:9019	6008:9020	6048:9020
6009:9018	6049:9018	6009:9019	6049:9019	6009:9020	6049:9020
6010:9018	6050:9018	6010:9019	6050:9019	6010:9020	6050:9020
6011:9018	6051:9018	6011:9019	6051:9019	6011:9020	6051:9020
6012:9018	6052:9018	6012:9019	6052:9019	6012:9020	6052:9020
6013:9018	6053:9018	6013:9019	6053:9019	6013:9020	6053:9020
6014:9018	6054:9018	6014:9019	6054:9019	6014:9020	6054:9020
6015:9018	6055:9018	6015:9019	6055:9019	6015:9020	6055:9020
6016:9018	6056:9018	6016:9019	6056:9019	6016:9020	6056:9020
6017:9018	6057:9018	6017:9019	6057:9019	6017:9020	6057:9020
6018:9018	6058:9018	6018:9019	6058:9019	6018:9020	6058:9020
6019:9018	6059:9018	6019:9019	6059:9019	6019:9020	6059:9020
6020:9018	6060:9018	6020:9019	6060:9019	6020:9020	6060:9020
6021:9018	6061:9018	6021:9019	6061:9019	6021:9020	6061:9020
6022:9018	6062:9018	6022:9019	6062:9019	6022:9020	6062:9020
6023:9018	6063:9018	6023:9019	6063:9019	6023:9020	6063:9020
6024:9018	6064:9018	6024:9019	6064:9019	6024:9020	6064:9020
6025:9018	6065:9018	6025:9019	6065:9019	6025:9020	6065:9020
6026:9018	6066:9018	6026:9019	6066:9019	6026:9020	6066:9020
6027:9018	6067:9018	6027:9019	6067:9019	6027:9020	6067:9020
6028:9018	6068:9018	6028:9019	6068:9019	6028:9020	6068:9020
6029:9018	6069:9018	6029:9019	6069:9019	6029:9020	6069:9020
6030:9018	6070:9018	6030:9019	6070:9019	6030:9020	6070:9020
6031:9018	6071:9018	6031:9019	6071:9019	6031:9020	6071:9020
6032:9018	6072:9018	6032:9019	6072:9019	6032:9020	6072:9020
6033:9018	6073:9018	6033:9019	6073:9019	6033:9020	6073:9020
6034:9018	6074:9018	6034:9019	6074:9019	6034:9020	6074:9020
6035:9018	6075:9018	6035:9019	6075:9019	6035:9020	6075:9020
6036:9018	6076:9018	6036:9019	6076:9019	6036:9020	6076:9020
6037:9018	6077:9018	6037:9019	6077:9019	6037:9020	6077:9020
6038:9018	6078:9018	6038:9019	6078:9019	6038:9020	6078:9020
6039:9018		6039:9019		6039:9020
6000:9021	6040:9021	6000:9022	6040:9022	6000:9023	6040:9023
6001:9021	6041:9021	6001:9022	6041:9022	6001:9023	6041:9023
6002:9021	6042:9021	6002:9022	6042:9022	6002:9023	6042:9023
6003:9021	6043:9021	6003:9022	6043:9022	6003:9023	6043:9023
6004:9021	6044:9021	6004:9022	6044:9022	6004:9023	6044:9023
6005:9021	6045:9021	6005:9022	6045:9022	6005:9023	6045:9023
6006:9021	6046:9021	6006:9022	6046:9022	6006:9023	6046:9023
6007:9021	6047:9021	6007:9022	6047:9022	6007:9023	6047:9023
6008:9021	6048:9021	6008:9022	6048:9022	6008:9023	6048:9023
6009:9021	6049:9021	6009:9022	6049:9022	6009:9023	6049:9023
6010:9021	6050:9021	6010:9022	6050:9022	6010:9023	6050:9023
6011:9021	6051:9021	6011:9022	6051:9022	6011:9023	6051:9023
6012:9021	6052:9021	6012:9022	6052:9022	6012:9023	6052:9023
6013:9021	6053:9021	6013:9022	6053:9022	6013:9023	6053:9023
6014:9021	6054:9021	6014:9022	6054:9022	6014:9023	6054:9023
6015:9021	6055:9021	6015:9022	6055:9022	6015:9023	6055:9023
6016:9021	6056:9021	6016:9022	6056:9022	6016:9023	6056:9023
6017:9021	6057:9021	6017:9022	6057:9022	6017:9023	6057:9023
6018:9021	6058:9021	6018:9022	6058:9022	6018:9023	6058:9023
6019:9021	6059:9021	6019:9022	6059:9022	6019:9023	6059:9023
6020:9021	6060:9021	6020:9022	6060:9022	6020:9023	6060:9023
6021:9021	6061:9021	6021:9022	6061:9022	6021:9023	6061:9023
6022:9021	6062:9021	6022:9022	6062:9022	6022:9023	6062:9023
6023:9021	6063:9021	6023:9022	6063:9022	6023:9023	6063:9023
6024:9021	6064:9021	6024:9022	6064:9022	6024:9023	6064:9023
6025:9021	6065:9021	6025:9022	6065:9022	6025:9023	6065:9023
6026:9021	6066:9021	6026:9022	6066:9022	6026:9023	6066:9023
6027:9021	6067:9021	6027:9022	6067:9022	6027:9023	6067:9023
6028:9021	6068:9021	6028:9022	6068:9022	6028:9023	6068:9023
6029:9021	6069:9021	6029:9022	6069:9022	6029:9023	6069:9023
6030:9021	6070:9021	6030:9022	6070:9022	6030:9023	6070:9023
6031:9021	6071:9021	6031:9022	6071:9022	6031:9023	6071:9023
6032:9021	6072:9021	6032:9022	6072:9022	6032:9023	6072:9023
6033:9021	6073:9021	6033:9022	6073:9022	6033:9023	6073:9023
6034:9021	6074:9021	6034:9022	6074:9022	6034:9023	6074:9023
6035:9021	6075:9021	6035:9022	6075:9022	6035:9023	6075:9023
6036:9021	6076:9021	6036:9022	6076:9022	6036:9023	6076:9023
6037:9021	6077:9021	6037:9022	6077:9022	6037:9023	6077:9023
6038:9021	6078:9021	6038:9022	6078:9022	6038:9023	6078:9023
6039:9021		6039:9022		6039:9023
6000:9024	6040:9024	6000:9025	6040:9025	6000:9026	6040:9026
6001:9024	6041:9024	6001:9025	6041:9025	6001:9026	6041:9026
6002:9024	6042:9024	6002:9025	6042:9025	6002:9026	6042:9026
6003:9024	6043:9024	6003:9025	6043:9025	6003:9026	6043:9026
6004:9024	6044:9024	6004:9025	6044:9025	6004:9026	6044:9026
6005:9024	6045:9024	6005:9025	6045:9025	6005:9026	6045:9026
6006:9024	6046:9024	6006:9025	6046:9025	6006:9026	6046:9026
6007:9024	6047:9024	6007:9025	6047:9025	6007:9026	6047:9026
6008:9024	6048:9024	6008:9025	6048:9025	6008:9026	6048:9026
6009:9024	6049:9024	6009:9025	6049:9025	6009:9026	6049:9026
6010:9024	6050:9024	6010:9025	6050:9025	6010:9026	6050:9026
6011:9024	6051:9024	6011:9025	6051:9025	6011:9026	6051:9026
6012:9024	6052:9024	6012:9025	6052:9025	6012:9026	6052:9026
6013:9024	6053:9024	6013:9025	6053:9025	6013:9026	6053:9026
6014:9024	6054:9024	6014:9025	6054:9025	6014:9026	6054:9026
6015:9024	6055:9024	6015:9025	6055:9025	6015:9026	6055:9026
6016:9024	6056:9024	6016:9025	6056:9025	6016:9026	6056:9026
6017:9024	6057:9024	6017:9025	6057:9025	6017:9026	6057:9026
6018:9024	6058:9024	6018:9025	6058:9025	6018:9026	6058:9026
6019:9024	6059:9024	6019:9025	6059:9025	6019:9026	6059:9026
6020:9024	6060:9024	6020:9025	6060:9025	6020:9026	6060:9026
6021:9024	6061:9024	6021:9025	6061:9025	6021:9026	6061:9026
6022:9024	6062:9024	6022:9025	6062:9025	6022:9026	6062:9026
6023:9024	6063:9024	6023:9025	6063:9025	6023:9026	6063:9026
6024:9024	6064:9024	6024:9025	6064:9025	6024:9026	6064:9026
6025:9024	6065:9024	6025:9025	6065:9025	6025:9026	6065:9026
6026:9024	6066:9024	6026:9025	6066:9025	6026:9026	6066:9026
6027:9024	6067:9024	6027:9025	6067:9025	6027:9026	6067:9026
6028:9024	6068:9024	6028:9025	6068:9025	6028:9026	6068:9026
6029:9024	6069:9024	6029:9025	6069:9025	6029:9026	6069:9026
6030:9024	6070:9024	6030:9025	6070:9025	6030:9026	6070:9026
6031:9024	6071:9024	6031:9025	6071:9025	6031:9026	6071:9026
6032:9024	6072:9024	6032:9025	6072:9025	6032:9026	6072:9026
6033:9024	6073:9024	6033:9025	6073:9025	6033:9026	6073:9026
6034:9024	6074:9024	6034:9025	6074:9025	6034:9026	6074:9026
6035:9024	6075:9024	6035:9025	6075:9025	6035:9026	6075:9026
6036:9024	6076:9024	6036:9025	6076:9025	6036:9026	6076:9026
6037:9024	6077:9024	6037:9025	6077:9025	6037:9026	6077:9026
6038:9024	6078:9024	6038:9025	6078:9025	6038:9026	6078:9026
6039:9024		6039:9025		6039:9026
6000:9027	6040:9027	6000:9028	6040:9028	6000:9029	6040:9029
6001:9027	6041:9027	6001:9028	6041:9028	6001:9029	6041:9029
6002:9027	6042:9027	6002:9028	6042:9028	6002:9029	6042:9029
6003:9027	6043:9027	6003:9028	6043:9028	6003:9029	6043:9029
6004:9027	6044:9027	6004:9028	6044:9028	6004:9029	6044:9029
6005:9027	6045:9027	6005:9028	6045:9028	6005:9029	6045:9029
6006:9027	6046:9027	6006:9028	6046:9028	6006:9029	6046:9029
6007:9027	6047:9027	6007:9028	6047:9028	6007:9029	6047:9029
6008:9027	6048:9027	6008:9028	6048:9028	6008:9029	6048:9029
6009:9027	6049:9027	6009:9028	6049:9028	6009:9029	6049:9029
6010:9027	6050:9027	6010:9028	6050:9028	6010:9029	6050:9029
6011:9027	6051:9027	6011:9028	6051:9028	6011:9029	6051:9029
6012:9027	6052:9027	6012:9028	6052:9028	6012:9029	6052:9029
6013:9027	6053:9027	6013:9028	6053:9028	6013:9029	6053:9029
6014:9027	6054:9027	6014:9028	6054:9028	6014:9029	6054:9029
6015:9027	6055:9027	6015:9028	6055:9028	6015:9029	6055:9029
6016:9027	6056:9027	6016:9028	6056:9028	6016:9029	6056:9029
6017:9027	6057:9027	6017:9028	6057:9028	6017:9029	6057:9029
6018:9027	6058:9027	6018:9028	6058:9028	6018:9029	6058:9029
6019:9027	6059:9027	6019:9028	6059:9028	6019:9029	6059:9029
6020:9027	6060:9027	6020:9028	6060:9028	6020:9029	6060:9029
6021:9027	6061:9027	6021:9028	6061:9028	6021:9029	6061:9029
6022:9027	6062:9027	6022:9028	6062:9028	6022:9029	6062:9029
6023:9027	6063:9027	6023:9028	6063:9028	6023:9029	6063:9029
6024:9027	6064:9027	6024:9028	6064:9028	6024:9029	6064:9029
6025:9027	6065:9027	6025:9028	6065:9028	6025:9029	6065:9029
6026:9027	6066:9027	6026:9028	6066:9028	6026:9029	6066:9029
6027:9027	6067:9027	6027:9028	6067:9028	6027:9029	6067:9029
6028:9027	6068:9027	6028:9028	6068:9028	6028:9029	6068:9029
6029:9027	6069:9027	6029:9028	6069:9028	6029:9029	6069:9029
6030:9027	6070:9027	6030:9028	6070:9028	6030:9029	6070:9029
6031:9027	6071:9027	6031:9028	6071:9028	6031:9029	6071:9029
6032:9027	6072:9027	6032:9028	6072:9028	6032:9029	6072:9029
6033:9027	6073:9027	6033:9028	6073:9028	6033:9029	6073:9029
6034:9027	6074:9027	6034:9028	6074:9028	6034:9029	6074:9029
6035:9027	6075:9027	6035:9028	6075:9028	6035:9029	6075:9029
6036:9027	6076:9027	6036:9028	6076:9028	6036:9029	6076:9029
6037:9027	6077:9027	6037:9028	6077:9028	6037:9029	6077:9029
6038:9027	6078:9027	6038:9028	6078:9028	6038:9029	6078:9029
6039:9027		6039:9028		6039:9029
6000:9030	6040:9030	6000:9031	6040:9031	6000:9032	6040:9032
6001:9030	6041:9030	6001:9031	6041:9031	6001:9032	6041:9032
6002:9030	6042:9030	6002:9031	6042:9031	6002:9032	6042:9032
6003:9030	6043:9030	6003:9031	6043:9031	6003:9032	6043:9032
6004:9030	6044:9030	6004:9031	6044:9031	6004:9032	6044:9032
6005:9030	6045:9030	6005:9031	6045:9031	6005:9032	6045:9032
6006:9030	6046:9030	6006:9031	6046:9031	6006:9032	6046:9032
6007:9030	6047:9030	6007:9031	6047:9031	6007:9032	6047:9032
6008:9030	6048:9030	6008:9031	6048:9031	6008:9032	6048:9032
6009:9030	6049:9030	6009:9031	6049:9031	6009:9032	6049:9032
6010:9030	6050:9030	6010:9031	6050:9031	6010:9032	6050:9032
6011:9030	6051:9030	6011:9031	6051:9031	6011:9032	6051:9032
6012:9030	6052:9030	6012:9031	6052:9031	6012:9032	6052:9032
6013:9030	6053:9030	6013:9031	6053:9031	6013:9032	6053:9032
6014:9030	6054:9030	6014:9031	6054:9031	6014:9032	6054:9032
6015:9030	6055:9030	6015:9031	6055:9031	6015:9032	6055:9032
6016:9030	6056:9030	6016:9031	6056:9031	6016:9032	6056:9032
6017:9030	6057:9030	6017:9031	6057:9031	6017:9032	6057:9032
6018:9030	6058:9030	6018:9031	6058:9031	6018:9032	6058:9032
6019:9030	6059:9030	6019:9031	6059:9031	6019:9032	6059:9032
6020:9030	6060:9030	6020:9031	6060:9031	6020:9032	6060:9032
6021:9030	6061:9030	6021:9031	6061:9031	6021:9032	6061:9032
6022:9030	6062:9030	6022:9031	6062:9031	6022:9032	6062:9032
6023:9030	6063:9030	6023:9031	6063:9031	6023:9032	6063:9032
6024:9030	6064:9030	6024:9031	6064:9031	6024:9032	6064:9032
6025:9030	6065:9030	6025:9031	6065:9031	6025:9032	6065:9032
6026:9030	6066:9030	6026:9031	6066:9031	6026:9032	6066:9032
6027:9030	6067:9030	6027:9031	6067:9031	6027:9032	6067:9032
6028:9030	6068:9030	6028:9031	6068:9031	6028:9032	6068:9032
6029:9030	6069:9030	6029:9031	6069:9031	6029:9032	6069:9032
6030:9030	6070:9030	6030:9031	6070:9031	6030:9032	6070:9032
6031:9030	6071:9030	6031:9031	6071:9031	6031:9032	6071:9032
6032:9030	6072:9030	6032:9031	6072:9031	6032:9032	6072:9032
6033:9030	6073:9030	6033:9031	6073:9031	6033:9032	6073:9032
6034:9030	6074:9030	6034:9031	6074:9031	6034:9032	6074:9032
6035:9030	6075:9030	6035:9031	6075:9031	6035:9032	6075:9032
6036:9030	6076:9030	6036:9031	6076:9031	6036:9032	6076:9032
6037:9030	6077:9030	6037:9031	6077:9031	6037:9032	6077:9032
6038:9030	6078:9030	6038:9031	6078:9031	6038:9032	6078:9032
6039:9030		6039:9031		6039:9032
6000:9033	6040:9033	6000:9034	6040:9034	6000:9035	6040:9035
6001:9033	6041:9033	6001:9034	6041:9034	6001:9035	6041:9035
6002:9033	6042:9033	6002:9034	6042:9034	6002:9035	6042:9035
6003:9033	6043:9033	6003:9034	6043:9034	6003:9035	6043:9035
6004:9033	6044:9033	6004:9034	6044:9034	6004:9035	6044:9035
6005:9033	6045:9033	6005:9034	6045:9034	6005:9035	6045:9035
6006:9033	6046:9033	6006:9034	6046:9034	6006:9035	6046:9035
6007:9033	6047:9033	6007:9034	6047:9034	6007:9035	6047:9035
6008:9033	6048:9033	6008:9034	6048:9034	6008:9035	6048:9035
6009:9033	6049:9033	6009:9034	6049:9034	6009:9035	6049:9035
6010:9033	6050:9033	6010:9034	6050:9034	6010:9035	6050:9035
6011:9033	6051:9033	6011:9034	6051:9034	6011:9035	6051:9035
6012:9033	6052:9033	6012:9034	6052:9034	6012:9035	6052:9035
6013:9033	6053:9033	6013:9034	6053:9034	6013:9035	6053:9035
6014:9033	6054:9033	6014:9034	6054:9034	6014:9035	6054:9035
6015:9033	6055:9033	6015:9034	6055:9034	6015:9035	6055:9035
6016:9033	6056:9033	6016:9034	6056:9034	6016:9035	6056:9035
6017:9033	6057:9033	6017:9034	6057:9034	6017:9035	6057:9035
6018:9033	6058:9033	6018:9034	6058:9034	6018:9035	6058:9035
6019:9033	6059:9033	6019:9034	6059:9034	6019:9035	6059:9035
6020:9033	6060:9033	6020:9034	6060:9034	6020:9035	6060:9035
6021:9033	6061:9033	6021:9034	6061:9034	6021:9035	6061:9035
6022:9033	6062:9033	6022:9034	6062:9034	6022:9035	6062:9035
6023:9033	6063:9033	6023:9034	6063:9034	6023:9035	6063:9035
6024:9033	6064:9033	6024:9034	6064:9034	6024:9035	6064:9035
6025:9033	6065:9033	6025:9034	6065:9034	6025:9035	6065:9035
6026:9033	6066:9033	6026:9034	6066:9034	6026:9035	6066:9035
6027:9033	6067:9033	6027:9034	6067:9034	6027:9035	6067:9035
6028:9033	6068:9033	6028:9034	6068:9034	6028:9035	6068:9035
6029:9033	6069:9033	6029:9034	6069:9034	6029:9035	6069:9035
6030:9033	6070:9033	6030:9034	6070:9034	6030:9035	6070:9035
6031:9033	6071:9033	6031:9034	6071:9034	6031:9035	6071:9035
6032:9033	6072:9033	6032:9034	6072:9034	6032:9035	6072:9035
6033:9033	6073:9033	6033:9034	6073:9034	6033:9035	6073:9035
6034:9033	6074:9033	6034:9034	6074:9034	6034:9035	6074:9035
6035:9033	6075:9033	6035:9034	6075:9034	6035:9035	6075:9035
6036:9033	6076:9033	6036:9034	6076:9034	6036:9035	6076:9035
6037:9033	6077:9033	6037:9034	6077:9034	6037:9035	6077:9035
6038:9033	6078:9033	6038:9034	6078:9034	6038:9035	6078:9035
6039:9033		6039:9034		6039:9035
6000:9036	6040:9036	6000:9037	6040:9037	6000:9038	6040:9038
6001:9036	6041:9036	6001:9037	6041:9037	6001:9038	6041:9038
6002:9036	6042:9036	6002:9037	6042:9037	6002:9038	6042:9038
6003:9036	6043:9036	6003:9037	6043:9037	6003:9038	6043:9038
6004:9036	6044:9036	6004:9037	6044:9037	6004:9038	6044:9038
6005:9036	6045:9036	6005:9037	6045:9037	6005:9038	6045:9038
6006:9036	6046:9036	6006:9037	6046:9037	6006:9038	6046:9038
6007:9036	6047:9036	6007:9037	6047:9037	6007:9038	6047:9038
6008:9036	6048:9036	6008:9037	6048:9037	6008:9038	6048:9038
6009:9036	6049:9036	6009:9037	6049:9037	6009:9038	6049:9038
6010:9036	6050:9036	6010:9037	6050:9037	6010:9038	6050:9038
6011:9036	6051:9036	6011:9037	6051:9037	6011:9038	6051:9038
6012:9036	6052:9036	6012:9037	6052:9037	6012:9038	6052:9038
6013:9036	6053:9036	6013:9037	6053:9037	6013:9038	6053:9038
6014:9036	6054:9036	6014:9037	6054:9037	6014:9038	6054:9038
6015:9036	6055:9036	6015:9037	6055:9037	6015:9038	6055:9038
6016:9036	6056:9036	6016:9037	6056:9037	6016:9038	6056:9038
6017:9036	6057:9036	6017:9037	6057:9037	6017:9038	6057:9038
6018:9036	6058:9036	6018:9037	6058:9037	6018:9038	6058:9038
6019:9036	6059:9036	6019:9037	6059:9037	6019:9038	6059:9038
6020:9036	6060:9036	6020:9037	6060:9037	6020:9038	6060:9038
6021:9036	6061:9036	6021:9037	6061:9037	6021:9038	6061:9038
6022:9036	6062:9036	6022:9037	6062:9037	6022:9038	6062:9038
6023:9036	6063:9036	6023:9037	6063:9037	6023:9038	6063:9038
6024:9036	6064:9036	6024:9037	6064:9037	6024:9038	6064:9038
6025:9036	6065:9036	6025:9037	6065:9037	6025:9038	6065:9038
6026:9036	6066:9036	6026:9037	6066:9037	6026:9038	6066:9038
6027:9036	6067:9036	6027:9037	6067:9037	6027:9038	6067:9038
6028:9036	6068:9036	6028:9037	6068:9037	6028:9038	6068:9038
6029:9036	6069:9036	6029:9037	6069:9037	6029:9038	6069:9038
6030:9036	6070:9036	6030:9037	6070:9037	6030:9038	6070:9038
6031:9036	6071:9036	6031:9037	6071:9037	6031:9038	6071:9038
6032:9036	6072:9036	6032:9037	6072:9037	6032:9038	6072:9038
6033:9036	6073:9036	6033:9037	6073:9037	6033:9038	6073:9038
6034:9036	6074:9036	6034:9037	6074:9037	6034:9038	6074:9038
6035:9036	6075:9036	6035:9037	6075:9037	6035:9038	6075:9038
6036:9036	6076:9036	6036:9037	6076:9037	6036:9038	6076:9038
6037:9036	6077:9036	6037:9037	6077:9037	6037:9038	6077:9038
6038:9036	6078:9036	6038:9037	6078:9037	6038:9038	6078:9038
6039:9036		6039:9037		6039:9038
6000:9039	6040:9039	6000:9040	6040:9040	6000:9041	6040:9041
6001:9039	6041:9039	6001:9040	6041:9040	6001:9041	6041:9041
6002:9039	6042:9039	6002:9040	6042:9040	6002:9041	6042:9041
6003:9039	6043:9039	6003:9040	6043:9040	6003:9041	6043:9041
6004:9039	6044:9039	6004:9040	6044:9040	6004:9041	6044:9041
6005:9039	6045:9039	6005:9040	6045:9040	6005:9041	6045:9041
6006:9039	6046:9039	6006:9040	6046:9040	6006:9041	6046:9041
6007:9039	6047:9039	6007:9040	6047:9040	6007:9041	6047:9041
6008:9039	6048:9039	6008:9040	6048:9040	6008:9041	6048:9041
6009:9039	6049:9039	6009:9040	6049:9040	6009:9041	6049:9041
6010:9039	6050:9039	6010:9040	6050:9040	6010:9041	6050:9041
6011:9039	6051:9039	6011:9040	6051:9040	6011:9041	6051:9041
6012:9039	6052:9039	6012:9040	6052:9040	6012:9041	6052:9041
6013:9039	6053:9039	6013:9040	6053:9040	6013:9041	6053:9041
6014:9039	6054:9039	6014:9040	6054:9040	6014:9041	6054:9041
6015:9039	6055:9039	6015:9040	6055:9040	6015:9041	6055:9041
6016:9039	6056:9039	6016:9040	6056:9040	6016:9041	6056:9041
6017:9039	6057:9039	6017:9040	6057:9040	6017:9041	6057:9041
6018:9039	6058:9039	6018:9040	6058:9040	6018:9041	6058:9041
6019:9039	6059:9039	6019:9040	6059:9040	6019:9041	6059:9041
6020:9039	6060:9039	6020:9040	6060:9040	6020:9041	6060:9041
6021:9039	6061:9039	6021:9040	6061:9040	6021:9041	6061:9041
6022:9039	6062:9039	6022:9040	6062:9040	6022:9041	6062:9041
6023:9039	6063:9039	6023:9040	6063:9040	6023:9041	6063:9041
6024:9039	6064:9039	6024:9040	6064:9040	6024:9041	6064:9041
6025:9039	6065:9039	6025:9040	6065:9040	6025:9041	6065:9041
6026:9039	6066:9039	6026:9040	6066:9040	6026:9041	6066:9041
6027:9039	6067:9039	6027:9040	6067:9040	6027:9041	6067:9041
6028:9039	6068:9039	6028:9040	6068:9040	6028:9041	6068:9041
6029:9039	6069:9039	6029:9040	6069:9040	6029:9041	6069:9041
6030:9039	6070:9039	6030:9040	6070:9040	6030:9041	6070:9041
6031:9039	6071:9039	6031:9040	6071:9040	6031:9041	6071:9041
6032:9039	6072:9039	6032:9040	6072:9040	6032:9041	6072:9041
6033:9039	6073:9039	6033:9040	6073:9040	6033:9041	6073:9041
6034:9039	6074:9039	6034:9040	6074:9040	6034:9041	6074:9041
6035:9039	6075:9039	6035:9040	6075:9040	6035:9041	6075:9041
6036:9039	6076:9039	6036:9040	6076:9040	6036:9041	6076:9041
6037:9039	6077:9039	6037:9040	6077:9040	6037:9041	6077:9041
6038:9039	6078:9039	6038:9040	6078:9040	6038:9041	6078:9041
6039:9039		6039:9040		6039:9041
6000:9042	6040:9042	6000:9043	6040:9043	6000:9044	6040:9044
6001:9042	6041:9042	6001:9043	6041:9043	6001:9044	6041:9044
6002:9042	6042:9042	6002:9043	6042:9043	6002:9044	6042:9044
6003:9042	6043:9042	6003:9043	6043:9043	6003:9044	6043:9044
6004:9042	6044:9042	6004:9043	6044:9043	6004:9044	6044:9044
6005:9042	6045:9042	6005:9043	6045:9043	6005:9044	6045:9044
6006:9042	6046:9042	6006:9043	6046:9043	6006:9044	6046:9044
6007:9042	6047:9042	6007:9043	6047:9043	6007:9044	6047:9044
6008:9042	6048:9042	6008:9043	6048:9043	6008:9044	6048:9044
6009:9042	6049:9042	6009:9043	6049:9043	6009:9044	6049:9044
6010:9042	6050:9042	6010:9043	6050:9043	6010:9044	6050:9044
6011:9042	6051:9042	6011:9043	6051:9043	6011:9044	6051:9044
6012:9042	6052:9042	6012:9043	6052:9043	6012:9044	6052:9044
6013:9042	6053:9042	6013:9043	6053:9043	6013:9044	6053:9044
6014:9042	6054:9042	6014:9043	6054:9043	6014:9044	6054:9044
6015:9042	6055:9042	6015:9043	6055:9043	6015:9044	6055:9044
6016:9042	6056:9042	6016:9043	6056:9043	6016:9044	6056:9044
6017:9042	6057:9042	6017:9043	6057:9043	6017:9044	6057:9044
6018:9042	6058:9042	6018:9043	6058:9043	6018:9044	6058:9044
6019:9042	6059:9042	6019:9043	6059:9043	6019:9044	6059:9044
6020:9042	6060:9042	6020:9043	6060:9043	6020:9044	6060:9044
6021:9042	6061:9042	6021:9043	6061:9043	6021:9044	6061:9044
6022:9042	6062:9042	6022:9043	6062:9043	6022:9044	6062:9044
6023:9042	6063:9042	6023:9043	6063:9043	6023:9044	6063:9044
6024:9042	6064:9042	6024:9043	6064:9043	6024:9044	6064:9044
6025:9042	6065:9042	6025:9043	6065:9043	6025:9044	6065:9044
6026:9042	6066:9042	6026:9043	6066:9043	6026:9044	6066:9044
6027:9042	6067:9042	6027:9043	6067:9043	6027:9044	6067:9044
6028:9042	6068:9042	6028:9043	6068:9043	6028:9044	6068:9044
6029:9042	6069:9042	6029:9043	6069:9043	6029:9044	6069:9044
6030:9042	6070:9042	6030:9043	6070:9043	6030:9044	6070:9044
6031:9042	6071:9042	6031:9043	6071:9043	6031:9044	6071:9044
6032:9042	6072:9042	6032:9043	6072:9043	6032:9044	6072:9044
6033:9042	6073:9042	6033:9043	6073:9043	6033:9044	6073:9044
6034:9042	6074:9042	6034:9043	6074:9043	6034:9044	6074:9044
6035:9042	6075:9042	6035:9043	6075:9043	6035:9044	6075:9044
6036:9042	6076:9042	6036:9043	6076:9043	6036:9044	6076:9044
6037:9042	6077:9042	6037:9043	6077:9043	6037:9044	6077:9044
6038:9042	6078:9042	6038:9043	6078:9043	6038:9044	6078:9044
6039:9042		6039:9043		6039:9044
6000:9045	6040:9045	6000:9046	6040:9046	6000:9047	6040:9047
6001:9045	6041:9045	6001:9046	6041:9046	6001:9047	6041:9047
6002:9045	6042:9045	6002:9046	6042:9046	6002:9047	6042:9047
6003:9045	6043:9045	6003:9046	6043:9046	6003:9047	6043:9047
6004:9045	6044:9045	6004:9046	6044:9046	6004:9047	6044:9047
6005:9045	6045:9045	6005:9046	6045:9046	6005:9047	6045:9047
6006:9045	6046:9045	6006:9046	6046:9046	6006:9047	6046:9047
6007:9045	6047:9045	6007:9046	6047:9046	6007:9047	6047:9047
6008:9045	6048:9045	6008:9046	6048:9046	6008:9047	6048:9047
6009:9045	6049:9045	6009:9046	6049:9046	6009:9047	6049:9047
6010:9045	6050:9045	6010:9046	6050:9046	6010:9047	6050:9047
6011:9045	6051:9045	6011:9046	6051:9046	6011:9047	6051:9047
6012:9045	6052:9045	6012:9046	6052:9046	6012:9047	6052:9047
6013:9045	6053:9045	6013:9046	6053:9046	6013:9047	6053:9047
6014:9045	6054:9045	6014:9046	6054:9046	6014:9047	6054:9047
6015:9045	6055:9045	6015:9046	6055:9046	6015:9047	6055:9047
6016:9045	6056:9045	6016:9046	6056:9046	6016:9047	6056:9047
6017:9045	6057:9045	6017:9046	6057:9046	6017:9047	6057:9047
6018:9045	6058:9045	6018:9046	6058:9046	6018:9047	6058:9047
6019:9045	6059:9045	6019:9046	6059:9046	6019:9047	6059:9047
6020:9045	6060:9045	6020:9046	6060:9046	6020:9047	6060:9047
6021:9045	6061:9045	6021:9046	6061:9046	6021:9047	6061:9047
6022:9045	6062:9045	6022:9046	6062:9046	6022:9047	6062:9047
6023:9045	6063:9045	6023:9046	6063:9046	6023:9047	6063:9047
6024:9045	6064:9045	6024:9046	6064:9046	6024:9047	6064:9047
6025:9045	6065:9045	6025:9046	6065:9046	6025:9047	6065:9047
6026:9045	6066:9045	6026:9046	6066:9046	6026:9047	6066:9047
6027:9045	6067:9045	6027:9046	6067:9046	6027:9047	6067:9047
6028:9045	6068:9045	6028:9046	6068:9046	6028:9047	6068:9047
6029:9045	6069:9045	6029:9046	6069:9046	6029:9047	6069:9047
6030:9045	6070:9045	6030:9046	6070:9046	6030:9047	6070:9047
6031:9045	6071:9045	6031:9046	6071:9046	6031:9047	6071:9047
6032:9045	6072:9045	6032:9046	6072:9046	6032:9047	6072:9047
6033:9045	6073:9045	6033:9046	6073:9046	6033:9047	6073:9047
6034:9045	6074:9045	6034:9046	6074:9046	6034:9047	6074:9047
6035:9045	6075:9045	6035:9046	6075:9046	6035:9047	6075:9047
6036:9045	6076:9045	6036:9046	6076:9046	6036:9047	6076:9047
6037:9045	6077:9045	6037:9046	6077:9046	6037:9047	6077:9047
6038:9045	6078:9045	6038:9046	6078:9046	6038:9047	6078:9047
6039:9045		6039:9046		6039:9047
6000:9048	6040:9048	6000:9049	6040:9049	6000:9050	6040:9050
6001:9048	6041:9048	6001:9049	6041:9049	6001:9050	6041:9050
6002:9048	6042:9048	6002:9049	6042:9049	6002:9050	6042:9050
6003:9048	6043:9048	6003:9049	6043:9049	6003:9050	6043:9050
6004:9048	6044:9048	6004:9049	6044:9049	6004:9050	6044:9050
6005:9048	6045:9048	6005:9049	6045:9049	6005:9050	6045:9050
6006:9048	6046:9048	6006:9049	6046:9049	6006:9050	6046:9050
6007:9048	6047:9048	6007:9049	6047:9049	6007:9050	6047:9050
6008:9048	6048:9048	6008:9049	6048:9049	6008:9050	6048:9050
6009:9048	6049:9048	6009:9049	6049:9049	6009:9050	6049:9050
6010:9048	6050:9048	6010:9049	6050:9049	6010:9050	6050:9050
6011:9048	6051:9048	6011:9049	6051:9049	6011:9050	6051:9050
6012:9048	6052:9048	6012:9049	6052:9049	6012:9050	6052:9050
6013:9048	6053:9048	6013:9049	6053:9049	6013:9050	6053:9050
6014:9048	6054:9048	6014:9049	6054:9049	6014:9050	6054:9050
6015:9048	6055:9048	6015:9049	6055:9049	6015:9050	6055:9050
6016:9048	6056:9048	6016:9049	6056:9049	6016:9050	6056:9050
6017:9048	6057:9048	6017:9049	6057:9049	6017:9050	6057:9050
6018:9048	6058:9048	6018:9049	6058:9049	6018:9050	6058:9050
6019:9048	6059:9048	6019:9049	6059:9049	6019:9050	6059:9050
6020:9048	6060:9048	6020:9049	6060:9049	6020:9050	6060:9050
6021:9048	6061:9048	6021:9049	6061:9049	6021:9050	6061:9050
6022:9048	6062:9048	6022:9049	6062:9049	6022:9050	6062:9050
6023:9048	6063:9048	6023:9049	6063:9049	6023:9050	6063:9050
6024:9048	6064:9048	6024:9049	6064:9049	6024:9050	6064:9050
6025:9048	6065:9048	6025:9049	6065:9049	6025:9050	6065:9050
6026:9048	6066:9048	6026:9049	6066:9049	6026:9050	6066:9050
6027:9048	6067:9048	6027:9049	6067:9049	6027:9050	6067:9050
6028:9048	6068:9048	6028:9049	6068:9049	6028:9050	6068:9050
6029:9048	6069:9048	6029:9049	6069:9049	6029:9050	6069:9050
6030:9048	6070:9048	6030:9049	6070:9049	6030:9050	6070:9050
6031:9048	6071:9048	6031:9049	6071:9049	6031:9050	6071:9050
6032:9048	6072:9048	6032:9049	6072:9049	6032:9050	6072:9050
6033:9048	6073:9048	6033:9049	6073:9049	6033:9050	6073:9050
6034:9048	6074:9048	6034:9049	6074:9049	6034:9050	6074:9050
6035:9048	6075:9048	6035:9049	6075:9049	6035:9050	6075:9050
6036:9048	6076:9048	6036:9049	6076:9049	6036:9050	6076:9050
6037:9048	6077:9048	6037:9049	6077:9049	6037:9050	6077:9050
6038:9048	6078:9048	6038:9049	6078:9049	6038:9050	6078:9050
6039:9048		6039:9049		6039:9050
6000:9051	6040:9051	6000:9052	6040:9052	6000:9053	6040:9053
6001:9051	6041:9051	6001:9052	6041:9052	6001:9053	6041:9053
6002:9051	6042:9051	6002:9052	6042:9052	6002:9053	6042:9053
6003:9051	6043:9051	6003:9052	6043:9052	6003:9053	6043:9053
6004:9051	6044:9051	6004:9052	6044:9052	6004:9053	6044:9053
6005:9051	6045:9051	6005:9052	6045:9052	6005:9053	6045:9053
6006:9051	6046:9051	6006:9052	6046:9052	6006:9053	6046:9053
6007:9051	6047:9051	6007:9052	6047:9052	6007:9053	6047:9053
6008:9051	6048:9051	6008:9052	6048:9052	6008:9053	6048:9053
6009:9051	6049:9051	6009:9052	6049:9052	6009:9053	6049:9053
6010:9051	6050:9051	6010:9052	6050:9052	6010:9053	6050:9053
6011:9051	6051:9051	6011:9052	6051:9052	6011:9053	6051:9053
6012:9051	6052:9051	6012:9052	6052:9052	6012:9053	6052:9053
6013:9051	6053:9051	6013:9052	6053:9052	6013:9053	6053:9053
6014:9051	6054:9051	6014:9052	6054:9052	6014:9053	6054:9053
6015:9051	6055:9051	6015:9052	6055:9052	6015:9053	6055:9053
6016:9051	6056:9051	6016:9052	6056:9052	6016:9053	6056:9053
6017:9051	6057:9051	6017:9052	6057:9052	6017:9053	6057:9053
6018:9051	6058:9051	6018:9052	6058:9052	6018:9053	6058:9053
6019:9051	6059:9051	6019:9052	6059:9052	6019:9053	6059:9053
6020:9051	6060:9051	6020:9052	6060:9052	6020:9053	6060:9053
6021:9051	6061:9051	6021:9052	6061:9052	6021:9053	6061:9053
6022:9051	6062:9051	6022:9052	6062:9052	6022:9053	6062:9053
6023:9051	6063:9051	6023:9052	6063:9052	6023:9053	6063:9053
6024:9051	6064:9051	6024:9052	6064:9052	6024:9053	6064:9053
6025:9051	6065:9051	6025:9052	6065:9052	6025:9053	6065:9053
6026:9051	6066:9051	6026:9052	6066:9052	6026:9053	6066:9053
6027:9051	6067:9051	6027:9052	6067:9052	6027:9053	6067:9053
6028:9051	6068:9051	6028:9052	6068:9052	6028:9053	6068:9053
6029:9051	6069:9051	6029:9052	6069:9052	6029:9053	6069:9053
6030:9051	6070:9051	6030:9052	6070:9052	6030:9053	6070:9053
6031:9051	6071:9051	6031:9052	6071:9052	6031:9053	6071:9053
6032:9051	6072:9051	6032:9052	6072:9052	6032:9053	6072:9053
6033:9051	6073:9051	6033:9052	6073:9052	6033:9053	6073:9053
6034:9051	6074:9051	6034:9052	6074:9052	6034:9053	6074:9053
6035:9051	6075:9051	6035:9052	6075:9052	6035:9053	6075:9053
6036:9051	6076:9051	6036:9052	6076:9052	6036:9053	6076:9053
6037:9051	6077:9051	6037:9052	6077:9052	6037:9053	6077:9053
6038:9051	6078:9051	6038:9052	6078:9052	6038:9053	6078:9053
6039:9051		6039:9052		6039:9053
6000:9054	6040:9054	6000:9055	6040:9055	6000:9056	6040:9056
6001:9054	6041:9054	6001:9055	6041:9055	6001:9056	6041:9056
6002:9054	6042:9054	6002:9055	6042:9055	6002:9056	6042:9056
6003:9054	6043:9054	6003:9055	6043:9055	6003:9056	6043:9056
6004:9054	6044:9054	6004:9055	6044:9055	6004:9056	6044:9056
6005:9054	6045:9054	6005:9055	6045:9055	6005:9056	6045:9056
6006:9054	6046:9054	6006:9055	6046:9055	6006:9056	6046:9056
6007:9054	6047:9054	6007:9055	6047:9055	6007:9056	6047:9056
6008:9054	6048:9054	6008:9055	6048:9055	6008:9056	6048:9056
6009:9054	6049:9054	6009:9055	6049:9055	6009:9056	6049:9056
6010:9054	6050:9054	6010:9055	6050:9055	6010:9056	6050:9056
6011:9054	6051:9054	6011:9055	6051:9055	6011:9056	6051:9056
6012:9054	6052:9054	6012:9055	6052:9055	6012:9056	6052:9056
6013:9054	6053:9054	6013:9055	6053:9055	6013:9056	6053:9056
6014:9054	6054:9054	6014:9055	6054:9055	6014:9056	6054:9056
6015:9054	6055:9054	6015:9055	6055:9055	6015:9056	6055:9056
6016:9054	6056:9054	6016:9055	6056:9055	6016:9056	6056:9056
6017:9054	6057:9054	6017:9055	6057:9055	6017:9056	6057:9056
6018:9054	6058:9054	6018:9055	6058:9055	6018:9056	6058:9056
6019:9054	6059:9054	6019:9055	6059:9055	6019:9056	6059:9056
6020:9054	6060:9054	6020:9055	6060:9055	6020:9056	6060:9056
6021:9054	6061:9054	6021:9055	6061:9055	6021:9056	6061:9056
6022:9054	6062:9054	6022:9055	6062:9055	6022:9056	6062:9056
6023:9054	6063:9054	6023:9055	6063:9055	6023:9056	6063:9056
6024:9054	6064:9054	6024:9055	6064:9055	6024:9056	6064:9056
6025:9054	6065:9054	6025:9055	6065:9055	6025:9056	6065:9056
6026:9054	6066:9054	6026:9055	6066:9055	6026:9056	6066:9056
6027:9054	6067:9054	6027:9055	6067:9055	6027:9056	6067:9056
6028:9054	6068:9054	6028:9055	6068:9055	6028:9056	6068:9056
6029:9054	6069:9054	6029:9055	6069:9055	6029:9056	6069:9056
6030:9054	6070:9054	6030:9055	6070:9055	6030:9056	6070:9056
6031:9054	6071:9054	6031:9055	6071:9055	6031:9056	6071:9056
6032:9054	6072:9054	6032:9055	6072:9055	6032:9056	6072:9056
6033:9054	6073:9054	6033:9055	6073:9055	6033:9056	6073:9056
6034:9054	6074:9054	6034:9055	6074:9055	6034:9056	6074:9056
6035:9054	6075:9054	6035:9055	6075:9055	6035:9056	6075:9056
6036:9054	6076:9054	6036:9055	6076:9055	6036:9056	6076:9056
6037:9054	6077:9054	6037:9055	6077:9055	6037:9056	6077:9056
6038:9054	6078:9054	6038:9055	6078:9055	6038:9056	6078:9056
6039:9054		6039:9055		6039:9056
6000:9057	6040:9057	6000:9058	6040:9058	6000:9059	6040:9059
6001:9057	6041:9057	6001:9058	6041:9058	6001:9059	6041:9059
6002:9057	6042:9057	6002:9058	6042:9058	6002:9059	6042:9059
6003:9057	6043:9057	6003:9058	6043:9058	6003:9059	6043:9059
6004:9057	6044:9057	6004:9058	6044:9058	6004:9059	6044:9059
6005:9057	6045:9057	6005:9058	6045:9058	6005:9059	6045:9059
6006:9057	6046:9057	6006:9058	6046:9058	6006:9059	6046:9059
6007:9057	6047:9057	6007:9058	6047:9058	6007:9059	6047:9059
6008:9057	6048:9057	6008:9058	6048:9058	6008:9059	6048:9059
6009:9057	6049:9057	6009:9058	6049:9058	6009:9059	6049:9059
6010:9057	6050:9057	6010:9058	6050:9058	6010:9059	6050:9059
6011:9057	6051:9057	6011:9058	6051:9058	6011:9059	6051:9059
6012:9057	6052:9057	6012:9058	6052:9058	6012:9059	6052:9059
6013:9057	6053:9057	6013:9058	6053:9058	6013:9059	6053:9059
6014:9057	6054:9057	6014:9058	6054:9058	6014:9059	6054:9059
6015:9057	6055:9057	6015:9058	6055:9058	6015:9059	6055:9059
6016:9057	6056:9057	6016:9058	6056:9058	6016:9059	6056:9059
6017:9057	6057:9057	6017:9058	6057:9058	6017:9059	6057:9059
6018:9057	6058:9057	6018:9058	6058:9058	6018:9059	6058:9059
6019:9057	6059:9057	6019:9058	6059:9058	6019:9059	6059:9059
6020:9057	6060:9057	6020:9058	6060:9058	6020:9059	6060:9059
6021:9057	6061:9057	6021:9058	6061:9058	6021:9059	6061:9059
6022:9057	6062:9057	6022:9058	6062:9058	6022:9059	6062:9059
6023:9057	6063:9057	6023:9058	6063:9058	6023:9059	6063:9059
6024:9057	6064:9057	6024:9058	6064:9058	6024:9059	6064:9059
6025:9057	6065:9057	6025:9058	6065:9058	6025:9059	6065:9059
6026:9057	6066:9057	6026:9058	6066:9058	6026:9059	6066:9059
6027:9057	6067:9057	6027:9058	6067:9058	6027:9059	6067:9059
6028:9057	6068:9057	6028:9058	6068:9058	6028:9059	6068:9059
6029:9057	6069:9057	6029:9058	6069:9058	6029:9059	6069:9059
6030:9057	6070:9057	6030:9058	6070:9058	6030:9059	6070:9059
6031:9057	6071:9057	6031:9058	6071:9058	6031:9059	6071:9059
6032:9057	6072:9057	6032:9058	6072:9058	6032:9059	6072:9059
6033:9057	6073:9057	6033:9058	6073:9058	6033:9059	6073:9059
6034:9057	6074:9057	6034:9058	6074:9058	6034:9059	6074:9059
6035:9057	6075:9057	6035:9058	6075:9058	6035:9059	6075:9059
6036:9057	6076:9057	6036:9058	6076:9058	6036:9059	6076:9059
6037:9057	6077:9057	6037:9058	6077:9058	6037:9059	6077:9059
6038:9057	6078:9057	6038:9058	6078:9058	6038:9059	6078:9059
6039:9057		6039:9058		6039:9059
6000:9060	6040:9060	6000:9061	6040:9061	6000:9062	6040:9062
6001:9060	6041:9060	6001:9061	6041:9061	6001:9062	6041:9062
6002:9060	6042:9060	6002:9061	6042:9061	6002:9062	6042:9062
6003:9060	6043:9060	6003:9061	6043:9061	6003:9062	6043:9062
6004:9060	6044:9060	6004:9061	6044:9061	6004:9062	6044:9062
6005:9060	6045:9060	6005:9061	6045:9061	6005:9062	6045:9062
6006:9060	6046:9060	6006:9061	6046:9061	6006:9062	6046:9062
6007:9060	6047:9060	6007:9061	6047:9061	6007:9062	6047:9062
6008:9060	6048:9060	6008:9061	6048:9061	6008:9062	6048:9062
6009:9060	6049:9060	6009:9061	6049:9061	6009:9062	6049:9062
6010:9060	6050:9060	6010:9061	6050:9061	6010:9062	6050:9062
6011:9060	6051:9060	6011:9061	6051:9061	6011:9062	6051:9062
6012:9060	6052:9060	6012:9061	6052:9061	6012:9062	6052:9062
6013:9060	6053:9060	6013:9061	6053:9061	6013:9062	6053:9062
6014:9060	6054:9060	6014:9061	6054:9061	6014:9062	6054:9062
6015:9060	6055:9060	6015:9061	6055:9061	6015:9062	6055:9062
6016:9060	6056:9060	6016:9061	6056:9061	6016:9062	6056:9062
6017:9060	6057:9060	6017:9061	6057:9061	6017:9062	6057:9062
6018:9060	6058:9060	6018:9061	6058:9061	6018:9062	6058:9062
6019:9060	6059:9060	6019:9061	6059:9061	6019:9062	6059:9062
6020:9060	6060:9060	6020:9061	6060:9061	6020:9062	6060:9062
6021:9060	6061:9060	6021:9061	6061:9061	6021:9062	6061:9062
6022:9060	6062:9060	6022:9061	6062:9061	6022:9062	6062:9062
6023:9060	6063:9060	6023:9061	6063:9061	6023:9062	6063:9062
6024:9060	6064:9060	6024:9061	6064:9061	6024:9062	6064:9062
6025:9060	6065:9060	6025:9061	6065:9061	6025:9062	6065:9062
6026:9060	6066:9060	6026:9061	6066:9061	6026:9062	6066:9062
6027:9060	6067:9060	6027:9061	6067:9061	6027:9062	6067:9062
6028:9060	6068:9060	6028:9061	6068:9061	6028:9062	6068:9062
6029:9060	6069:9060	6029:9061	6069:9061	6029:9062	6069:9062
6030:9060	6070:9060	6030:9061	6070:9061	6030:9062	6070:9062
6031:9060	6071:9060	6031:9061	6071:9061	6031:9062	6071:9062
6032:9060	6072:9060	6032:9061	6072:9061	6032:9062	6072:9062
6033:9060	6073:9060	6033:9061	6073:9061	6033:9062	6073:9062
6034:9060	6074:9060	6034:9061	6074:9061	6034:9062	6074:9062
6035:9060	6075:9060	6035:9061	6075:9061	6035:9062	6075:9062
6036:9060	6076:9060	6036:9061	6076:9061	6036:9062	6076:9062
6037:9060	6077:9060	6037:9061	6077:9061	6037:9062	6077:9062
6038:9060	6078:9060	6038:9061	6078:9061	6038:9062	6078:9062
6039:9060		6039:9061		6039:9062
6000:9063	6040:9063	6000:9064	6040:9064	6000:9065	6040:9065
6001:9063	6041:9063	6001:9064	6041:9064	6001:9065	6041:9065
6002:9063	6042:9063	6002:9064	6042:9064	6002:9065	6042:9065
6003:9063	6043:9063	6003:9064	6043:9064	6003:9065	6043:9065
6004:9063	6044:9063	6004:9064	6044:9064	6004:9065	6044:9065
6005:9063	6045:9063	6005:9064	6045:9064	6005:9065	6045:9065
6006:9063	6046:9063	6006:9064	6046:9064	6006:9065	6046:9065
6007:9063	6047:9063	6007:9064	6047:9064	6007:9065	6047:9065
6008:9063	6048:9063	6008:9064	6048:9064	6008:9065	6048:9065
6009:9063	6049:9063	6009:9064	6049:9064	6009:9065	6049:9065
6010:9063	6050:9063	6010:9064	6050:9064	6010:9065	6050:9065
6011:9063	6051:9063	6011:9064	6051:9064	6011:9065	6051:9065
6012:9063	6052:9063	6012:9064	6052:9064	6012:9065	6052:9065
6013:9063	6053:9063	6013:9064	6053:9064	6013:9065	6053:9065
6014:9063	6054:9063	6014:9064	6054:9064	6014:9065	6054:9065
6015:9063	6055:9063	6015:9064	6055:9064	6015:9065	6055:9065
6016:9063	6056:9063	6016:9064	6056:9064	6016:9065	6056:9065
6017:9063	6057:9063	6017:9064	6057:9064	6017:9065	6057:9065
6018:9063	6058:9063	6018:9064	6058:9064	6018:9065	6058:9065
6019:9063	6059:9063	6019:9064	6059:9064	6019:9065	6059:9065
6020:9063	6060:9063	6020:9064	6060:9064	6020:9065	6060:9065
6021:9063	6061:9063	6021:9064	6061:9064	6021:9065	6061:9065
6022:9063	6062:9063	6022:9064	6062:9064	6022:9065	6062:9065
6023:9063	6063:9063	6023:9064	6063:9064	6023:9065	6063:9065
6024:9063	6064:9063	6024:9064	6064:9064	6024:9065	6064:9065
6025:9063	6065:9063	6025:9064	6065:9064	6025:9065	6065:9065
6026:9063	6066:9063	6026:9064	6066:9064	6026:9065	6066:9065
6027:9063	6067:9063	6027:9064	6067:9064	6027:9065	6067:9065
6028:9063	6068:9063	6028:9064	6068:9064	6028:9065	6068:9065
6029:9063	6069:9063	6029:9064	6069:9064	6029:9065	6069:9065
6030:9063	6070:9063	6030:9064	6070:9064	6030:9065	6070:9065
6031:9063	6071:9063	6031:9064	6071:9064	6031:9065	6071:9065
6032:9063	6072:9063	6032:9064	6072:9064	6032:9065	6072:9065
6033:9063	6073:9063	6033:9064	6073:9064	6033:9065	6073:9065
6034:9063	6074:9063	6034:9064	6074:9064	6034:9065	6074:9065
6035:9063	6075:9063	6035:9064	6075:9064	6035:9065	6075:9065
6036:9063	6076:9063	6036:9064	6076:9064	6036:9065	6076:9065
6037:9063	6077:9063	6037:9064	6077:9064	6037:9065	6077:9065
6038:9063	6078:9063	6038:9064	6078:9064	6038:9065	6078:9065
6039:9063		6039:9064		6039:9065
6000:9066	6040:9066	6000:9067	6040:9067	6000:9068	6040:9068
6001:9066	6041:9066	6001:9067	6041:9067	6001:9068	6041:9068
6002:9066	6042:9066	6002:9067	6042:9067	6002:9068	6042:9068
6003:9066	6043:9066	6003:9067	6043:9067	6003:9068	6043:9068
6004:9066	6044:9066	6004:9067	6044:9067	6004:9068	6044:9068
6005:9066	6045:9066	6005:9067	6045:9067	6005:9068	6045:9068
6006:9066	6046:9066	6006:9067	6046:9067	6006:9068	6046:9068
6007:9066	6047:9066	6007:9067	6047:9067	6007:9068	6047:9068
6008:9066	6048:9066	6008:9067	6048:9067	6008:9068	6048:9068
6009:9066	6049:9066	6009:9067	6049:9067	6009:9068	6049:9068
6010:9066	6050:9066	6010:9067	6050:9067	6010:9068	6050:9068
6011:9066	6051:9066	6011:9067	6051:9067	6011:9068	6051:9068
6012:9066	6052:9066	6012:9067	6052:9067	6012:9068	6052:9068
6013:9066	6053:9066	6013:9067	6053:9067	6013:9068	6053:9068
6014:9066	6054:9066	6014:9067	6054:9067	6014:9068	6054:9068
6015:9066	6055:9066	6015:9067	6055:9067	6015:9068	6055:9068
6016:9066	6056:9066	6016:9067	6056:9067	6016:9068	6056:9068
6017:9066	6057:9066	6017:9067	6057:9067	6017:9068	6057:9068
6018:9066	6058:9066	6018:9067	6058:9067	6018:9068	6058:9068
6019:9066	6059:9066	6019:9067	6059:9067	6019:9068	6059:9068
6020:9066	6060:9066	6020:9067	6060:9067	6020:9068	6060:9068
6021:9066	6061:9066	6021:9067	6061:9067	6021:9068	6061:9068
6022:9066	6062:9066	6022:9067	6062:9067	6022:9068	6062:9068
6023:9066	6063:9066	6023:9067	6063:9067	6023:9068	6063:9068
6024:9066	6064:9066	6024:9067	6064:9067	6024:9068	6064:9068
6025:9066	6065:9066	6025:9067	6065:9067	6025:9068	6065:9068
6026:9066	6066:9066	6026:9067	6066:9067	6026:9068	6066:9068
6027:9066	6067:9066	6027:9067	6067:9067	6027:9068	6067:9068
6028:9066	6068:9066	6028:9067	6068:9067	6028:9068	6068:9068
6029:9066	6069:9066	6029:9067	6069:9067	6029:9068	6069:9068
6030:9066	6070:9066	6030:9067	6070:9067	6030:9068	6070:9068
6031:9066	6071:9066	6031:9067	6071:9067	6031:9068	6071:9068
6032:9066	6072:9066	6032:9067	6072:9067	6032:9068	6072:9068
6033:9066	6073:9066	6033:9067	6073:9067	6033:9068	6073:9068
6034:9066	6074:9066	6034:9067	6074:9067	6034:9068	6074:9068
6035:9066	6075:9066	6035:9067	6075:9067	6035:9068	6075:9068
6036:9066	6076:9066	6036:9067	6076:9067	6036:9068	6076:9068
6037:9066	6077:9066	6037:9067	6077:9067	6037:9068	6077:9068
6038:9066	6078:9066	6038:9067	6078:9067	6038:9068	6078:9068
6039:9066		6039:9067		6039:9068
6000:9069	6040:9069	6000:9070	6040:9070	6000:9071	6040:9071
6001:9069	6041:9069	6001:9070	6041:9070	6001:9071	6041:9071
6002:9069	6042:9069	6002:9070	6042:9070	6002:9071	6042:9071
6003:9069	6043:9069	6003:9070	6043:9070	6003:9071	6043:9071
6004:9069	6044:9069	6004:9070	6044:9070	6004:9071	6044:9071
6005:9069	6045:9069	6005:9070	6045:9070	6005:9071	6045:9071
6006:9069	6046:9069	6006:9070	6046:9070	6006:9071	6046:9071
6007:9069	6047:9069	6007:9070	6047:9070	6007:9071	6047:9071
6008:9069	6048:9069	6008:9070	6048:9070	6008:9071	6048:9071
6009:9069	6049:9069	6009:9070	6049:9070	6009:9071	6049:9071
6010:9069	6050:9069	6010:9070	6050:9070	6010:9071	6050:9071
6011:9069	6051:9069	6011:9070	6051:9070	6011:9071	6051:9071
6012:9069	6052:9069	6012:9070	6052:9070	6012:9071	6052:9071
6013:9069	6053:9069	6013:9070	6053:9070	6013:9071	6053:9071
6014:9069	6054:9069	6014:9070	6054:9070	6014:9071	6054:9071
6015:9069	6055:9069	6015:9070	6055:9070	6015:9071	6055:9071
6016:9069	6056:9069	6016:9070	6056:9070	6016:9071	6056:9071
6017:9069	6057:9069	6017:9070	6057:9070	6017:9071	6057:9071
6018:9069	6058:9069	6018:9070	6058:9070	6018:9071	6058:9071
6019:9069	6059:9069	6019:9070	6059:9070	6019:9071	6059:9071
6020:9069	6060:9069	6020:9070	6060:9070	6020:9071	6060:9071
6021:9069	6061:9069	6021:9070	6061:9070	6021:9071	6061:9071
6022:9069	6062:9069	6022:9070	6062:9070	6022:9071	6062:9071
6023:9069	6063:9069	6023:9070	6063:9070	6023:9071	6063:9071
6024:9069	6064:9069	6024:9070	6064:9070	6024:9071	6064:9071
6025:9069	6065:9069	6025:9070	6065:9070	6025:9071	6065:9071
6026:9069	6066:9069	6026:9070	6066:9070	6026:9071	6066:9071
6027:9069	6067:9069	6027:9070	6067:9070	6027:9071	6067:9071
6028:9069	6068:9069	6028:9070	6068:9070	6028:9071	6068:9071
6029:9069	6069:9069	6029:9070	6069:9070	6029:9071	6069:9071
6030:9069	6070:9069	6030:9070	6070:9070	6030:9071	6070:9071
6031:9069	6071:9069	6031:9070	6071:9070	6031:9071	6071:9071
6032:9069	6072:9069	6032:9070	6072:9070	6032:9071	6072:9071
6033:9069	6073:9069	6033:9070	6073:9070	6033:9071	6073:9071
6034:9069	6074:9069	6034:9070	6074:9070	6034:9071	6074:9071
6035:9069	6075:9069	6035:9070	6075:9070	6035:9071	6075:9071
6036:9069	6076:9069	6036:9070	6076:9070	6036:9071	6076:9071
6037:9069	6077:9069	6037:9070	6077:9070	6037:9071	6077:9071
6038:9069	6078:9069	6038:9070	6078:9070	6038:9071	6078:9071
6039:9069		6039:9070		6039:9071
6000:9072	6040:9072	6000:9073	6040:9073	6000:9074	6040:9074
6001:9072	6041:9072	6001:9073	6041:9073	6001:9074	6041:9074
6002:9072	6042:9072	6002:9073	6042:9073	6002:9074	6042:9074
6003:9072	6043:9072	6003:9073	6043:9073	6003:9074	6043:9074
6004:9072	6044:9072	6004:9073	6044:9073	6004:9074	6044:9074
6005:9072	6045:9072	6005:9073	6045:9073	6005:9074	6045:9074
6006:9072	6046:9072	6006:9073	6046:9073	6006:9074	6046:9074
6007:9072	6047:9072	6007:9073	6047:9073	6007:9074	6047:9074
6008:9072	6048:9072	6008:9073	6048:9073	6008:9074	6048:9074
6009:9072	6049:9072	6009:9073	6049:9073	6009:9074	6049:9074
6010:9072	6050:9072	6010:9073	6050:9073	6010:9074	6050:9074
6011:9072	6051:9072	6011:9073	6051:9073	6011:9074	6051:9074
6012:9072	6052:9072	6012:9073	6052:9073	6012:9074	6052:9074
6013:9072	6053:9072	6013:9073	6053:9073	6013:9074	6053:9074
6014:9072	6054:9072	6014:9073	6054:9073	6014:9074	6054:9074
6015:9072	6055:9072	6015:9073	6055:9073	6015:9074	6055:9074
6016:9072	6056:9072	6016:9073	6056:9073	6016:9074	6056:9074
6017:9072	6057:9072	6017:9073	6057:9073	6017:9074	6057:9074
6018:9072	6058:9072	6018:9073	6058:9073	6018:9074	6058:9074
6019:9072	6059:9072	6019:9073	6059:9073	6019:9074	6059:9074
6020:9072	6060:9072	6020:9073	6060:9073	6020:9074	6060:9074
6021:9072	6061:9072	6021:9073	6061:9073	6021:9074	6061:9074
6022:9072	6062:9072	6022:9073	6062:9073	6022:9074	6062:9074
6023:9072	6063:9072	6023:9073	6063:9073	6023:9074	6063:9074
6024:9072	6064:9072	6024:9073	6064:9073	6024:9074	6064:9074
6025:9072	6065:9072	6025:9073	6065:9073	6025:9074	6065:9074
6026:9072	6066:9072	6026:9073	6066:9073	6026:9074	6066:9074
6027:9072	6067:9072	6027:9073	6067:9073	6027:9074	6067:9074
6028:9072	6068:9072	6028:9073	6068:9073	6028:9074	6068:9074
6029:9072	6069:9072	6029:9073	6069:9073	6029:9074	6069:9074
6030:9072	6070:9072	6030:9073	6070:9073	6030:9074	6070:9074
6031:9072	6071:9072	6031:9073	6071:9073	6031:9074	6071:9074
6032:9072	6072:9072	6032:9073	6072:9073	6032:9074	6072:9074
6033:9072	6073:9072	6033:9073	6073:9073	6033:9074	6073:9074
6034:9072	6074:9072	6034:9073	6074:9073	6034:9074	6074:9074
6035:9072	6075:9072	6035:9073	6075:9073	6035:9074	6075:9074
6036:9072	6076:9072	6036:9073	6076:9073	6036:9074	6076:9074
6037:9072	6077:9072	6037:9073	6077:9073	6037:9074	6077:9074
6038:9072	6078:9072	6038:9073	6078:9073	6038:9074	6078:9074
6039:9072		6039:9073		6039:9074
6000:9075	6040:9075	6000:9076	6040:9076	6000:9077	6040:9077
6001:9075	6041:9075	6001:9076	6041:9076	6001:9077	6041:9077
6002:9075	6042:9075	6002:9076	6042:9076	6002:9077	6042:9077
6003:9075	6043:9075	6003:9076	6043:9076	6003:9077	6043:9077
6004:9075	6044:9075	6004:9076	6044:9076	6004:9077	6044:9077
6005:9075	6045:9075	6005:9076	6045:9076	6005:9077	6045:9077
6006:9075	6046:9075	6006:9076	6046:9076	6006:9077	6046:9077
6007:9075	6047:9075	6007:9076	6047:9076	6007:9077	6047:9077
6008:9075	6048:9075	6008:9076	6048:9076	6008:9077	6048:9077
6009:9075	6049:9075	6009:9076	6049:9076	6009:9077	6049:9077
6010:9075	6050:9075	6010:9076	6050:9076	6010:9077	6050:9077
6011:9075	6051:9075	6011:9076	6051:9076	6011:9077	6051:9077
6012:9075	6052:9075	6012:9076	6052:9076	6012:9077	6052:9077
6013:9075	6053:9075	6013:9076	6053:9076	6013:9077	6053:9077
6014:9075	6054:9075	6014:9076	6054:9076	6014:9077	6054:9077
6015:9075	6055:9075	6015:9076	6055:9076	6015:9077	6055:9077
6016:9075	6056:9075	6016:9076	6056:9076	6016:9077	6056:9077
6017:9075	6057:9075	6017:9076	6057:9076	6017:9077	6057:9077
6018:9075	6058:9075	6018:9076	6058:9076	6018:9077	6058:9077
6019:9075	6059:9075	6019:9076	6059:9076	6019:9077	6059:9077
6020:9075	6060:9075	6020:9076	6060:9076	6020:9077	6060:9077
6021:9075	6061:9075	6021:9076	6061:9076	6021:9077	6061:9077
6022:9075	6062:9075	6022:9076	6062:9076	6022:9077	6062:9077
6023:9075	6063:9075	6023:9076	6063:9076	6023:9077	6063:9077
6024:9075	6064:9075	6024:9076	6064:9076	6024:9077	6064:9077
6025:9075	6065:9075	6025:9076	6065:9076	6025:9077	6065:9077
6026:9075	6066:9075	6026:9076	6066:9076	6026:9077	6066:9077
6027:9075	6067:9075	6027:9076	6067:9076	6027:9077	6067:9077
6028:9075	6068:9075	6028:9076	6068:9076	6028:9077	6068:9077
6029:9075	6069:9075	6029:9076	6069:9076	6029:9077	6069:9077
6030:9075	6070:9075	6030:9076	6070:9076	6030:9077	6070:9077
6031:9075	6071:9075	6031:9076	6071:9076	6031:9077	6071:9077
6032:9075	6072:9075	6032:9076	6072:9076	6032:9077	6072:9077
6033:9075	6073:9075	6033:9076	6073:9076	6033:9077	6073:9077
6034:9075	6074:9075	6034:9076	6074:9076	6034:9077	6074:9077
6035:9075	6075:9075	6035:9076	6075:9076	6035:9077	6075:9077
6036:9075	6076:9075	6036:9076	6076:9076	6036:9077	6076:9077
6037:9075	6077:9075	6037:9076	6077:9076	6037:9077	6077:9077
6038:9075	6078:9075	6038:9076	6078:9076	6038:9077	6078:9077
6039:9075		6039:9076		6039:9077
6000:9078	6040:9078	6000:9079	6040:9079	6000:9080	6040:9080
6001:9078	6041:9078	6001:9079	6041:9079	6001:9080	6041:9080
6002:9078	6042:9078	6002:9079	6042:9079	6002:9080	6042:9080
6003:9078	6043:9078	6003:9079	6043:9079	6003:9080	6043:9080
6004:9078	6044:9078	6004:9079	6044:9079	6004:9080	6044:9080
6005:9078	6045:9078	6005:9079	6045:9079	6005:9080	6045:9080
6006:9078	6046:9078	6006:9079	6046:9079	6006:9080	6046:9080
6007:9078	6047:9078	6007:9079	6047:9079	6007:9080	6047:9080
6008:9078	6048:9078	6008:9079	6048:9079	6008:9080	6048:9080
6009:9078	6049:9078	6009:9079	6049:9079	6009:9080	6049:9080
6010:9078	6050:9078	6010:9079	6050:9079	6010:9080	6050:9080
6011:9078	6051:9078	6011:9079	6051:9079	6011:9080	6051:9080
6012:9078	6052:9078	6012:9079	6052:9079	6012:9080	6052:9080
6013:9078	6053:9078	6013:9079	6053:9079	6013:9080	6053:9080
6014:9078	6054:9078	6014:9079	6054:9079	6014:9080	6054:9080
6015:9078	6055:9078	6015:9079	6055:9079	6015:9080	6055:9080
6016:9078	6056:9078	6016:9079	6056:9079	6016:9080	6056:9080
6017:9078	6057:9078	6017:9079	6057:9079	6017:9080	6057:9080
6018:9078	6058:9078	6018:9079	6058:9079	6018:9080	6058:9080
6019:9078	6059:9078	6019:9079	6059:9079	6019:9080	6059:9080
6020:9078	6060:9078	6020:9079	6060:9079	6020:9080	6060:9080
6021:9078	6061:9078	6021:9079	6061:9079	6021:9080	6061:9080
6022:9078	6062:9078	6022:9079	6062:9079	6022:9080	6062:9080
6023:9078	6063:9078	6023:9079	6063:9079	6023:9080	6063:9080
6024:9078	6064:9078	6024:9079	6064:9079	6024:9080	6064:9080
6025:9078	6065:9078	6025:9079	6065:9079	6025:9080	6065:9080
6026:9078	6066:9078	6026:9079	6066:9079	6026:9080	6066:9080
6027:9078	6067:9078	6027:9079	6067:9079	6027:9080	6067:9080
6028:9078	6068:9078	6028:9079	6068:9079	6028:9080	6068:9080
6029:9078	6069:9078	6029:9079	6069:9079	6029:9080	6069:9080
6030:9078	6070:9078	6030:9079	6070:9079	6030:9080	6070:9080
6031:9078	6071:9078	6031:9079	6071:9079	6031:9080	6071:9080
6032:9078	6072:9078	6032:9079	6072:9079	6032:9080	6072:9080
6033:9078	6073:9078	6033:9079	6073:9079	6033:9080	6073:9080
6034:9078	6074:9078	6034:9079	6074:9079	6034:9080	6074:9080
6035:9078	6075:9078	6035:9079	6075:9079	6035:9080	6075:9080
6036:9078	6076:9078	6036:9079	6076:9079	6036:9080	6076:9080
6037:9078	6077:9078	6037:9079	6077:9079	6037:9080	6077:9080
6038:9078	6078:9078	6038:9079	6078:9079	6038:9080	6078:9080
6039:9078		6039:9079		6039:9080
6000:9081	6040:9081	6000:9082	6040:9082	6000:9083	6040:9083
6001:9081	6041:9081	6001:9082	6041:9082	6001:9083	6041:9083
6002:9081	6042:9081	6002:9082	6042:9082	6002:9083	6042:9083
6003:9081	6043:9081	6003:9082	6043:9082	6003:9083	6043:9083
6004:9081	6044:9081	6004:9082	6044:9082	6004:9083	6044:9083
6005:9081	6045:9081	6005:9082	6045:9082	6005:9083	6045:9083
6006:9081	6046:9081	6006:9082	6046:9082	6006:9083	6046:9083
6007:9081	6047:9081	6007:9082	6047:9082	6007:9083	6047:9083
6008:9081	6048:9081	6008:9082	6048:9082	6008:9083	6048:9083
6009:9081	6049:9081	6009:9082	6049:9082	6009:9083	6049:9083
6010:9081	6050:9081	6010:9082	6050:9082	6010:9083	6050:9083
6011:9081	6051:9081	6011:9082	6051:9082	6011:9083	6051:9083
6012:9081	6052:9081	6012:9082	6052:9082	6012:9083	6052:9083
6013:9081	6053:9081	6013:9082	6053:9082	6013:9083	6053:9083
6014:9081	6054:9081	6014:9082	6054:9082	6014:9083	6054:9083
6015:9081	6055:9081	6015:9082	6055:9082	6015:9083	6055:9083
6016:9081	6056:9081	6016:9082	6056:9082	6016:9083	6056:9083
6017:9081	6057:9081	6017:9082	6057:9082	6017:9083	6057:9083
6018:9081	6058:9081	6018:9082	6058:9082	6018:9083	6058:9083
6019:9081	6059:9081	6019:9082	6059:9082	6019:9083	6059:9083
6020:9081	6060:9081	6020:9082	6060:9082	6020:9083	6060:9083
6021:9081	6061:9081	6021:9082	6061:9082	6021:9083	6061:9083
6022:9081	6062:9081	6022:9082	6062:9082	6022:9083	6062:9083
6023:9081	6063:9081	6023:9082	6063:9082	6023:9083	6063:9083
6024:9081	6064:9081	6024:9082	6064:9082	6024:9083	6064:9083
6025:9081	6065:9081	6025:9082	6065:9082	6025:9083	6065:9083
6026:9081	6066:9081	6026:9082	6066:9082	6026:9083	6066:9083
6027:9081	6067:9081	6027:9082	6067:9082	6027:9083	6067:9083
6028:9081	6068:9081	6028:9082	6068:9082	6028:9083	6068:9083
6029:9081	6069:9081	6029:9082	6069:9082	6029:9083	6069:9083
6030:9081	6070:9081	6030:9082	6070:9082	6030:9083	6070:9083
6031:9081	6071:9081	6031:9082	6071:9082	6031:9083	6071:9083
6032:9081	6072:9081	6032:9082	6072:9082	6032:9083	6072:9083
6033:9081	6073:9081	6033:9082	6073:9082	6033:9083	6073:9083
6034:9081	6074:9081	6034:9082	6074:9082	6034:9083	6074:9083
6035:9081	6075:9081	6035:9082	6075:9082	6035:9083	6075:9083
6036:9081	6076:9081	6036:9082	6076:9082	6036:9083	6076:9083
6037:9081	6077:9081	6037:9082	6077:9082	6037:9083	6077:9083
6038:9081	6078:9081	6038:9082	6078:9082	6038:9083	6078:9083
6039:9081		6039:9082		6039:9083
6000:9084	6040:9084	6000:9085	6040:9085	6000:9086	6040:9086
6001:9084	6041:9084	6001:9085	6041:9085	6001:9086	6041:9086
6002:9084	6042:9084	6002:9085	6042:9085	6002:9086	6042:9086
6003:9084	6043:9084	6003:9085	6043:9085	6003:9086	6043:9086
6004:9084	6044:9084	6004:9085	6044:9085	6004:9086	6044:9086
6005:9084	6045:9084	6005:9085	6045:9085	6005:9086	6045:9086
6006:9084	6046:9084	6006:9085	6046:9085	6006:9086	6046:9086
6007:9084	6047:9084	6007:9085	6047:9085	6007:9086	6047:9086
6008:9084	6048:9084	6008:9085	6048:9085	6008:9086	6048:9086
6009:9084	6049:9084	6009:9085	6049:9085	6009:9086	6049:9086
6010:9084	6050:9084	6010:9085	6050:9085	6010:9086	6050:9086
6011:9084	6051:9084	6011:9085	6051:9085	6011:9086	6051:9086
6012:9084	6052:9084	6012:9085	6052:9085	6012:9086	6052:9086
6013:9084	6053:9084	6013:9085	6053:9085	6013:9086	6053:9086
6014:9084	6054:9084	6014:9085	6054:9085	6014:9086	6054:9086
6015:9084	6055:9084	6015:9085	6055:9085	6015:9086	6055:9086
6016:9084	6056:9084	6016:9085	6056:9085	6016:9086	6056:9086
6017:9084	6057:9084	6017:9085	6057:9085	6017:9086	6057:9086
6018:9084	6058:9084	6018:9085	6058:9085	6018:9086	6058:9086
6019:9084	6059:9084	6019:9085	6059:9085	6019:9086	6059:9086
6020:9084	6060:9084	6020:9085	6060:9085	6020:9086	6060:9086
6021:9084	6061:9084	6021:9085	6061:9085	6021:9086	6061:9086
6022:9084	6062:9084	6022:9085	6062:9085	6022:9086	6062:9086
6023:9084	6063:9084	6023:9085	6063:9085	6023:9086	6063:9086
6024:9084	6064:9084	6024:9085	6064:9085	6024:9086	6064:9086
6025:9084	6065:9084	6025:9085	6065:9085	6025:9086	6065:9086
6026:9084	6066:9084	6026:9085	6066:9085	6026:9086	6066:9086
6027:9084	6067:9084	6027:9085	6067:9085	6027:9086	6067:9086
6028:9084	6068:9084	6028:9085	6068:9085	6028:9086	6068:9086
6029:9084	6069:9084	6029:9085	6069:9085	6029:9086	6069:9086
6030:9084	6070:9084	6030:9085	6070:9085	6030:9086	6070:9086
6031:9084	6071:9084	6031:9085	6071:9085	6031:9086	6071:9086
6032:9084	6072:9084	6032:9085	6072:9085	6032:9086	6072:9086
6033:9084	6073:9084	6033:9085	6073:9085	6033:9086	6073:9086
6034:9084	6074:9084	6034:9085	6074:9085	6034:9086	6074:9086
6035:9084	6075:9084	6035:9085	6075:9085	6035:9086	6075:9086
6036:9084	6076:9084	6036:9085	6076:9085	6036:9086	6076:9086
6037:9084	6077:9084	6037:9085	6077:9085	6037:9086	6077:9086
6038:9084	6078:9084	6038:9085	6078:9085	6038:9086	6078:9086
6039:9084		6039:9085		6039:9086
6000:9087	6040:9087	6000:9088	6040:9088	6000:9089	6040:9089
6001:9087	6041:9087	6001:9088	6041:9088	6001:9089	6041:9089
6002:9087	6042:9087	6002:9088	6042:9088	6002:9089	6042:9089
6003:9087	6043:9087	6003:9088	6043:9088	6003:9089	6043:9089
6004:9087	6044:9087	6004:9088	6044:9088	6004:9089	6044:9089
6005:9087	6045:9087	6005:9088	6045:9088	6005:9089	6045:9089
6006:9087	6046:9087	6006:9088	6046:9088	6006:9089	6046:9089
6007:9087	6047:9087	6007:9088	6047:9088	6007:9089	6047:9089
6008:9087	6048:9087	6008:9088	6048:9088	6008:9089	6048:9089
6009:9087	6049:9087	6009:9088	6049:9088	6009:9089	6049:9089
6010:9087	6050:9087	6010:9088	6050:9088	6010:9089	6050:9089
6011:9087	6051:9087	6011:9088	6051:9088	6011:9089	6051:9089
6012:9087	6052:9087	6012:9088	6052:9088	6012:9089	6052:9089
6013:9087	6053:9087	6013:9088	6053:9088	6013:9089	6053:9089
6014:9087	6054:9087	6014:9088	6054:9088	6014:9089	6054:9089
6015:9087	6055:9087	6015:9088	6055:9088	6015:9089	6055:9089
6016:9087	6056:9087	6016:9088	6056:9088	6016:9089	6056:9089
6017:9087	6057:9087	6017:9088	6057:9088	6017:9089	6057:9089
6018:9087	6058:9087	6018:9088	6058:9088	6018:9089	6058:9089
6019:9087	6059:9087	6019:9088	6059:9088	6019:9089	6059:9089
6020:9087	6060:9087	6020:9088	6060:9088	6020:9089	6060:9089
6021:9087	6061:9087	6021:9088	6061:9088	6021:9089	6061:9089
6022:9087	6062:9087	6022:9088	6062:9088	6022:9089	6062:9089
6023:9087	6063:9087	6023:9088	6063:9088	6023:9089	6063:9089
6024:9087	6064:9087	6024:9088	6064:9088	6024:9089	6064:9089
6025:9087	6065:9087	6025:9088	6065:9088	6025:9089	6065:9089
6026:9087	6066:9087	6026:9088	6066:9088	6026:9089	6066:9089
6027:9087	6067:9087	6027:9088	6067:9088	6027:9089	6067:9089
6028:9087	6068:9087	6028:9088	6068:9088	6028:9089	6068:9089
6029:9087	6069:9087	6029:9088	6069:9088	6029:9089	6069:9089
6030:9087	6070:9087	6030:9088	6070:9088	6030:9089	6070:9089
6031:9087	6071:9087	6031:9088	6071:9088	6031:9089	6071:9089
6032:9087	6072:9087	6032:9088	6072:9088	6032:9089	6072:9089
6033:9087	6073:9087	6033:9088	6073:9088	6033:9089	6073:9089
6034:9087	6074:9087	6034:9088	6074:9088	6034:9089	6074:9089
6035:9087	6075:9087	6035:9088	6075:9088	6035:9089	6075:9089
6036:9087	6076:9087	6036:9088	6076:9088	6036:9089	6076:9089
6037:9087	6077:9087	6037:9088	6077:9088	6037:9089	6077:9089
6038:9087	6078:9087	6038:9088	6078:9088	6038:9089	6078:9089
6039:9087		6039:9088		6039:9089
6000:9090	6040:9090	6000:9091	6040:9091	6000:9092	6040:9092
6001:9090	6041:9090	6001:9091	6041:9091	6001:9092	6041:9092
6002:9090	6042:9090	6002:9091	6042:9091	6002:9092	6042:9092
6003:9090	6043:9090	6003:9091	6043:9091	6003:9092	6043:9092
6004:9090	6044:9090	6004:9091	6044:9091	6004:9092	6044:9092
6005:9090	6045:9090	6005:9091	6045:9091	6005:9092	6045:9092
6006:9090	6046:9090	6006:9091	6046:9091	6006:9092	6046:9092
6007:9090	6047:9090	6007:9091	6047:9091	6007:9092	6047:9092
6008:9090	6048:9090	6008:9091	6048:9091	6008:9092	6048:9092
6009:9090	6049:9090	6009:9091	6049:9091	6009:9092	6049:9092
6010:9090	6050:9090	6010:9091	6050:9091	6010:9092	6050:9092
6011:9090	6051:9090	6011:9091	6051:9091	6011:9092	6051:9092
6012:9090	6052:9090	6012:9091	6052:9091	6012:9092	6052:9092
6013:9090	6053:9090	6013:9091	6053:9091	6013:9092	6053:9092
6014:9090	6054:9090	6014:9091	6054:9091	6014:9092	6054:9092
6015:9090	6055:9090	6015:9091	6055:9091	6015:9092	6055:9092
6016:9090	6056:9090	6016:9091	6056:9091	6016:9092	6056:9092
6017:9090	6057:9090	6017:9091	6057:9091	6017:9092	6057:9092
6018:9090	6058:9090	6018:9091	6058:9091	6018:9092	6058:9092
6019:9090	6059:9090	6019:9091	6059:9091	6019:9092	6059:9092
6020:9090	6060:9090	6020:9091	6060:9091	6020:9092	6060:9092
6021:9090	6061:9090	6021:9091	6061:9091	6021:9092	6061:9092
6022:9090	6062:9090	6022:9091	6062:9091	6022:9092	6062:9092
6023:9090	6063:9090	6023:9091	6063:9091	6023:9092	6063:9092
6024:9090	6064:9090	6024:9091	6064:9091	6024:9092	6064:9092
6025:9090	6065:9090	6025:9091	6065:9091	6025:9092	6065:9092
6026:9090	6066:9090	6026:9091	6066:9091	6026:9092	6066:9092
6027:9090	6067:9090	6027:9091	6067:9091	6027:9092	6067:9092
6028:9090	6068:9090	6028:9091	6068:9091	6028:9092	6068:9092
6029:9090	6069:9090	6029:9091	6069:9091	6029:9092	6069:9092
6030:9090	6070:9090	6030:9091	6070:9091	6030:9092	6070:9092
6031:9090	6071:9090	6031:9091	6071:9091	6031:9092	6071:9092
6032:9090	6072:9090	6032:9091	6072:9091	6032:9092	6072:9092
6033:9090	6073:9090	6033:9091	6073:9091	6033:9092	6073:9092
6034:9090	6074:9090	6034:9091	6074:9091	6034:9092	6074:9092
6035:9090	6075:9090	6035:9091	6075:9091	6035:9092	6075:9092
6036:9090	6076:9090	6036:9091	6076:9091	6036:9092	6076:9092
6037:9090	6077:9090	6037:9091	6077:9091	6037:9092	6077:9092
6038:9090	6078:9090	6038:9091	6078:9091	6038:9092	6078:9092
6039:9090		6039:9091		6039:9092
6000:9093	6040:9093	6000:9094	6040:9094	6000:9095	6040:9095
6001:9093	6041:9093	6001:9094	6041:9094	6001:9095	6041:9095
6002:9093	6042:9093	6002:9094	6042:9094	6002:9095	6042:9095
6003:9093	6043:9093	6003:9094	6043:9094	6003:9095	6043:9095
6004:9093	6044:9093	6004:9094	6044:9094	6004:9095	6044:9095
6005:9093	6045:9093	6005:9094	6045:9094	6005:9095	6045:9095
6006:9093	6046:9093	6006:9094	6046:9094	6006:9095	6046:9095
6007:9093	6047:9093	6007:9094	6047:9094	6007:9095	6047:9095
6008:9093	6048:9093	6008:9094	6048:9094	6008:9095	6048:9095
6009:9093	6049:9093	6009:9094	6049:9094	6009:9095	6049:9095
6010:9093	6050:9093	6010:9094	6050:9094	6010:9095	6050:9095
6011:9093	6051:9093	6011:9094	6051:9094	6011:9095	6051:9095
6012:9093	6052:9093	6012:9094	6052:9094	6012:9095	6052:9095
6013:9093	6053:9093	6013:9094	6053:9094	6013:9095	6053:9095
6014:9093	6054:9093	6014:9094	6054:9094	6014:9095	6054:9095
6015:9093	6055:9093	6015:9094	6055:9094	6015:9095	6055:9095
6016:9093	6056:9093	6016:9094	6056:9094	6016:9095	6056:9095
6017:9093	6057:9093	6017:9094	6057:9094	6017:9095	6057:9095
6018:9093	6058:9093	6018:9094	6058:9094	6018:9095	6058:9095
6019:9093	6059:9093	6019:9094	6059:9094	6019:9095	6059:9095
6020:9093	6060:9093	6020:9094	6060:9094	6020:9095	6060:9095
6021:9093	6061:9093	6021:9094	6061:9094	6021:9095	6061:9095
6022:9093	6062:9093	6022:9094	6062:9094	6022:9095	6062:9095
6023:9093	6063:9093	6023:9094	6063:9094	6023:9095	6063:9095
6024:9093	6064:9093	6024:9094	6064:9094	6024:9095	6064:9095
6025:9093	6065:9093	6025:9094	6065:9094	6025:9095	6065:9095
6026:9093	6066:9093	6026:9094	6066:9094	6026:9095	6066:9095
6027:9093	6067:9093	6027:9094	6067:9094	6027:9095	6067:9095
6028:9093	6068:9093	6028:9094	6068:9094	6028:9095	6068:9095
6029:9093	6069:9093	6029:9094	6069:9094	6029:9095	6069:9095
6030:9093	6070:9093	6030:9094	6070:9094	6030:9095	6070:9095
6031:9093	6071:9093	6031:9094	6071:9094	6031:9095	6071:9095
6032:9093	6072:9093	6032:9094	6072:9094	6032:9095	6072:9095
6033:9093	6073:9093	6033:9094	6073:9094	6033:9095	6073:9095
6034:9093	6074:9093	6034:9094	6074:9094	6034:9095	6074:9095
6035:9093	6075:9093	6035:9094	6075:9094	6035:9095	6075:9095
6036:9093	6076:9093	6036:9094	6076:9094	6036:9095	6076:9095
6037:9093	6077:9093	6037:9094	6077:9094	6037:9095	6077:9095
6038:9093	6078:9093	6038:9094	6078:9094	6038:9095	6078:9095
6039:9093		6039:9094		6039:9095
6000:9096	6040:9096	6000:9097	6040:9097	6000:9098	6040:9098
6001:9096	6041:9096	6001:9097	6041:9097	6001:9098	6041:9098
6002:9096	6042:9096	6002:9097	6042:9097	6002:9098	6042:9098
6003:9096	6043:9096	6003:9097	6043:9097	6003:9098	6043:9098
6004:9096	6044:9096	6004:9097	6044:9097	6004:9098	6044:9098
6005:9096	6045:9096	6005:9097	6045:9097	6005:9098	6045:9098
6006:9096	6046:9096	6006:9097	6046:9097	6006:9098	6046:9098
6007:9096	6047:9096	6007:9097	6047:9097	6007:9098	6047:9098
6008:9096	6048:9096	6008:9097	6048:9097	6008:9098	6048:9098
6009:9096	6049:9096	6009:9097	6049:9097	6009:9098	6049:9098
6010:9096	6050:9096	6010:9097	6050:9097	6010:9098	6050:9098
6011:9096	6051:9096	6011:9097	6051:9097	6011:9098	6051:9098
6012:9096	6052:9096	6012:9097	6052:9097	6012:9098	6052:9098
6013:9096	6053:9096	6013:9097	6053:9097	6013:9098	6053:9098
6014:9096	6054:9096	6014:9097	6054:9097	6014:9098	6054:9098
6015:9096	6055:9096	6015:9097	6055:9097	6015:9098	6055:9098
6016:9096	6056:9096	6016:9097	6056:9097	6016:9098	6056:9098
6017:9096	6057:9096	6017:9097	6057:9097	6017:9098	6057:9098
6018:9096	6058:9096	6018:9097	6058:9097	6018:9098	6058:9098
6019:9096	6059:9096	6019:9097	6059:9097	6019:9098	6059:9098
6020:9096	6060:9096	6020:9097	6060:9097	6020:9098	6060:9098
6021:9096	6061:9096	6021:9097	6061:9097	6021:9098	6061:9098
6022:9096	6062:9096	6022:9097	6062:9097	6022:9098	6062:9098
6023:9096	6063:9096	6023:9097	6063:9097	6023:9098	6063:9098
6024:9096	6064:9096	6024:9097	6064:9097	6024:9098	6064:9098
6025:9096	6065:9096	6025:9097	6065:9097	6025:9098	6065:9098
6026:9096	6066:9096	6026:9097	6066:9097	6026:9098	6066:9098
6027:9096	6067:9096	6027:9097	6067:9097	6027:9098	6067:9098
6028:9096	6068:9096	6028:9097	6068:9097	6028:9098	6068:9098
6029:9096	6069:9096	6029:9097	6069:9097	6029:9098	6069:9098
6030:9096	6070:9096	6030:9097	6070:9097	6030:9098	6070:9098
6031:9096	6071:9096	6031:9097	6071:9097	6031:9098	6071:9098
6032:9096	6072:9096	6032:9097	6072:9097	6032:9098	6072:9098
6033:9096	6073:9096	6033:9097	6073:9097	6033:9098	6073:9098
6034:9096	6074:9096	6034:9097	6074:9097	6034:9098	6074:9098
6035:9096	6075:9096	6035:9097	6075:9097	6035:9098	6075:9098
6036:9096	6076:9096	6036:9097	6076:9097	6036:9098	6076:9098
6037:9096	6077:9096	6037:9097	6077:9097	6037:9098	6077:9098
6038:9096	6078:9096	6038:9097	6078:9097	6038:9098	6078:9098
6039:9096		6039:9097		6039:9098
6000:9099	6040:9099	6000:9100	6040:9100	6000:9101	6040:9101
6001:9099	6041:9099	6001:9100	6041:9100	6001:9101	6041:9101
6002:9099	6042:9099	6002:9100	6042:9100	6002:9101	6042:9101
6003:9099	6043:9099	6003:9100	6043:9100	6003:9101	6043:9101
6004:9099	6044:9099	6004:9100	6044:9100	6004:9101	6044:9101
6005:9099	6045:9099	6005:9100	6045:9100	6005:9101	6045:9101
6006:9099	6046:9099	6006:9100	6046:9100	6006:9101	6046:9101
6007:9099	6047:9099	6007:9100	6047:9100	6007:9101	6047:9101
6008:9099	6048:9099	6008:9100	6048:9100	6008:9101	6048:9101
6009:9099	6049:9099	6009:9100	6049:9100	6009:9101	6049:9101
6010:9099	6050:9099	6010:9100	6050:9100	6010:9101	6050:9101
6011:9099	6051:9099	6011:9100	6051:9100	6011:9101	6051:9101
6012:9099	6052:9099	6012:9100	6052:9100	6012:9101	6052:9101
6013:9099	6053:9099	6013:9100	6053:9100	6013:9101	6053:9101
6014:9099	6054:9099	6014:9100	6054:9100	6014:9101	6054:9101
6015:9099	6055:9099	6015:9100	6055:9100	6015:9101	6055:9101
6016:9099	6056:9099	6016:9100	6056:9100	6016:9101	6056:9101
6017:9099	6057:9099	6017:9100	6057:9100	6017:9101	6057:9101
6018:9099	6058:9099	6018:9100	6058:9100	6018:9101	6058:9101
6019:9099	6059:9099	6019:9100	6059:9100	6019:9101	6059:9101
6020:9099	6060:9099	6020:9100	6060:9100	6020:9101	6060:9101
6021:9099	6061:9099	6021:9100	6061:9100	6021:9101	6061:9101
6022:9099	6062:9099	6022:9100	6062:9100	6022:9101	6062:9101
6023:9099	6063:9099	6023:9100	6063:9100	6023:9101	6063:9101
6024:9099	6064:9099	6024:9100	6064:9100	6024:9101	6064:9101
6025:9099	6065:9099	6025:9100	6065:9100	6025:9101	6065:9101
6026:9099	6066:9099	6026:9100	6066:9100	6026:9101	6066:9101
6027:9099	6067:9099	6027:9100	6067:9100	6027:9101	6067:9101
6028:9099	6068:9099	6028:9100	6068:9100	6028:9101	6068:9101
6029:9099	6069:9099	6029:9100	6069:9100	6029:9101	6069:9101
6030:9099	6070:9099	6030:9100	6070:9100	6030:9101	6070:9101
6031:9099	6071:9099	6031:9100	6071:9100	6031:9101	6071:9101
6032:9099	6072:9099	6032:9100	6072:9100	6032:9101	6072:9101
6033:9099	6073:9099	6033:9100	6073:9100	6033:9101	6073:9101
6034:9099	6074:9099	6034:9100	6074:9100	6034:9101	6074:9101
6035:9099	6075:9099	6035:9100	6075:9100	6035:9101	6075:9101
6036:9099	6076:9099	6036:9100	6076:9100	6036:9101	6076:9101
6037:9099	6077:9099	6037:9100	6077:9100	6037:9101	6077:9101
6038:9099	6078:9099	6038:9100	6078:9100	6038:9101	6078:9101
6039:9099		6039:9100		6039:9101
6000:9102	6040:9102	6000:9103	6040:9103	6000:9104	6040:9104
6001:9102	6041:9102	6001:9103	6041:9103	6001:9104	6041:9104
6002:9102	6042:9102	6002:9103	6042:9103	6002:9104	6042:9104
6003:9102	6043:9102	6003:9103	6043:9103	6003:9104	6043:9104
6004:9102	6044:9102	6004:9103	6044:9103	6004:9104	6044:9104
6005:9102	6045:9102	6005:9103	6045:9103	6005:9104	6045:9104
6006:9102	6046:9102	6006:9103	6046:9103	6006:9104	6046:9104
6007:9102	6047:9102	6007:9103	6047:9103	6007:9104	6047:9104
6008:9102	6048:9102	6008:9103	6048:9103	6008:9104	6048:9104
6009:9102	6049:9102	6009:9103	6049:9103	6009:9104	6049:9104
6010:9102	6050:9102	6010:9103	6050:9103	6010:9104	6050:9104
6011:9102	6051:9102	6011:9103	6051:9103	6011:9104	6051:9104
6012:9102	6052:9102	6012:9103	6052:9103	6012:9104	6052:9104
6013:9102	6053:9102	6013:9103	6053:9103	6013:9104	6053:9104
6014:9102	6054:9102	6014:9103	6054:9103	6014:9104	6054:9104
6015:9102	6055:9102	6015:9103	6055:9103	6015:9104	6055:9104
6016:9102	6056:9102	6016:9103	6056:9103	6016:9104	6056:9104
6017:9102	6057:9102	6017:9103	6057:9103	6017:9104	6057:9104
6018:9102	6058:9102	6018:9103	6058:9103	6018:9104	6058:9104
6019:9102	6059:9102	6019:9103	6059:9103	6019:9104	6059:9104
6020:9102	6060:9102	6020:9103	6060:9103	6020:9104	6060:9104
6021:9102	6061:9102	6021:9103	6061:9103	6021:9104	6061:9104
6022:9102	6062:9102	6022:9103	6062:9103	6022:9104	6062:9104
6023:9102	6063:9102	6023:9103	6063:9103	6023:9104	6063:9104
6024:9102	6064:9102	6024:9103	6064:9103	6024:9104	6064:9104
6025:9102	6065:9102	6025:9103	6065:9103	6025:9104	6065:9104
6026:9102	6066:9102	6026:9103	6066:9103	6026:9104	6066:9104
6027:9102	6067:9102	6027:9103	6067:9103	6027:9104	6067:9104
6028:9102	6068:9102	6028:9103	6068:9103	6028:9104	6068:9104
6029:9102	6069:9102	6029:9103	6069:9103	6029:9104	6069:9104
6030:9102	6070:9102	6030:9103	6070:9103	6030:9104	6070:9104
6031:9102	6071:9102	6031:9103	6071:9103	6031:9104	6071:9104
6032:9102	6072:9102	6032:9103	6072:9103	6032:9104	6072:9104
6033:9102	6073:9102	6033:9103	6073:9103	6033:9104	6073:9104
6034:9102	6074:9102	6034:9103	6074:9103	6034:9104	6074:9104
6035:9102	6075:9102	6035:9103	6075:9103	6035:9104	6075:9104
6036:9102	6076:9102	6036:9103	6076:9103	6036:9104	6076:9104
6037:9102	6077:9102	6037:9103	6077:9103	6037:9104	6077:9104
6038:9102	6078:9102	6038:9103	6078:9103	6038:9104	6078:9104
6039:9102		6039:9103		6039:9104
6000:9105	6040:9105	—	—	—	—
6001:9105	6041:9105
6002:9105	6042:9105
6003:9105	6043:9105
6004:9105	6044:9105
6005:9105	6045:9105
6006:9105	6046:9105
6007:9105	6047:9105
6008:9105	6048:9105
6009:9105	6049:9105
6010:9105	6050:9105
6011:9105	6051:9105
6012:9105	6052:9105
6013:9105	6053:9105
6014:9105	6054:9105
6015:9105	6055:9105
6016:9105	6056:9105
6017:9105	6057:9105
6018:9105	6058:9105
6019:9105	6059:9105
6020:9105	6060:9105
6021:9105	6061:9105
6022:9105	6062:9105
6023:9105	6063:9105
6024:9105	6064:9105
6025:9105	6065:9105
6026:9105	6066:9105
6027:9105	6067:9105
6028:9105	6068:9105
6029:9105	6069:9105
6030:9105	6070:9105
6031:9105	6071:9105
6032:9105	6072:9105
6033:9105	6073:9105
6034:9105	6074:9105
6035:9105	6075:9105
6036:9105	6076:9105
6037:9105	6077:9105
6038:9105	6078:9105
6039:9105

TABLE E
Example combinations of a compound X with a compound Y.
X:Y	X:Y	X:Y	X:Y	X:Y	X:Y
8000:9000	8000:9001	8000:9002	8000:9003	8000:9004	8000:9005
8001:9000	8001:9001	8001:9002	8001:9003	8001:9004	8001:9005
8002:9000	8002:9001	8002:9002	8002:9003	8002:9004	8002:9005
8003:9000	8003:9001	8003:9002	8003:9003	8003:9004	8003:9005
8004:9000	8004:9001	8004:9002	8004:9003	8004:9004	8004:9005
8005:9000	8005:9001	8005:9002	8005:9003	8005:9004	8005:9005
8006:9000	8006:9001	8006:9002	8006:9003	8006:9004	8006:9005
8007:9000	8007:9001	8007:9002	8007:9003	8007:9004	8007:9005
8008:9000	8008:9001	8008:9002	8008:9003	8008:9004	8008:9005
8009:9000	8009:9001	8009:9002	8009:9003	8009:9004	8009:9005
8010:9000	8010:9001	8010:9002	8010:9003	8010:9004	8010:9005
8011:9000	8011:9001	8011:9002	8011:9003	8011:9004	8011:9005
8012:9000	8012:9001	8012:9002	8012:9003	8012:9004	8012:9005
8013:9000	8013:9001	8013:9002	8013:9003	8013:9004	8013:9005
8014:9000	8014:9001	8014:9002	8014:9003	8014:9004	8014:9005
8015:9000	8015:9001	8015:9002	8015:9003	8015:9004	8015:9005
8016:9000	8016:9001	8016:9002	8016:9003	8016:9004	8016:9005
8000:9006	8000:9007	8000:9008	8000:9009	8000:9010	8000:9011
8001:9006	8001:9007	8001:9008	8001:9009	8001:9010	8001:9011
8002:9006	8002:9007	8002:9008	8002:9009	8002:9010	8002:9011
8003:9006	8003:9007	8003:9008	8003:9009	8003:9010	8003:9011
8004:9006	8004:9007	8004:9008	8004:9009	8004:9010	8004:9011
8005:9006	8005:9007	8005:9008	8005:9009	8005:9010	8005:9011
8006:9006	8006:9007	8006:9008	8006:9009	8006:9010	8006:9011
8007:9006	8007:9007	8007:9008	8007:9009	8007:9010	8007:9011
8008:9006	8008:9007	8008:9008	8008:9009	8008:9010	8008:9011
8009:9006	8009:9007	8009:9008	8009:9009	8009:9010	8009:9011
8010:9006	8010:9007	8010:9008	8010:9009	8010:9010	8010:9011
8011:9006	8011:9007	8011:9008	8011:9009	8011:9010	8011:9011
8012:9006	8012:9007	8012:9008	8012:9009	8012:9010	8012:9011
8013:9006	8013:9007	8013:9008	8013:9009	8013:9010	8013:9011
8014:9006	8014:9007	8014:9008	8014:9009	8014:9010	8014:9011
8015:9006	8015:9007	8015:9008	8015:9009	8015:9010	8015:9011
8016:9006	8016:9007	8016:9008	8016:9009	8016:9010	8016:9011
8000:9012	8000:9013	8000:9014	8000:9015	8000:9016	8000:9017
8001:9012	8001:9013	8001:9014	8001:9015	8001:9016	8001:9017
8002:9012	8002:9013	8002:9014	8002:9015	8002:9016	8002:9017
8003:9012	8003:9013	8003:9014	8003:9015	8003:9016	8003:9017
8004:9012	8004:9013	8004:9014	8004:9015	8004:9016	8004:9017
8005:9012	8005:9013	8005:9014	8005:9015	8005:9016	8005:9017
8006:9012	8006:9013	8006:9014	8006:9015	8006:9016	8006:9017
8007:9012	8007:9013	8007:9014	8007:9015	8007:9016	8007:9017
8008:9012	8008:9013	8008:9014	8008:9015	8008:9016	8008:9017
8009:9012	8009:9013	8009:9014	8009:9015	8009:9016	8009:9017
8010:9012	8010:9013	8010:9014	8010:9015	8010:9016	8010:9017
8011:9012	8011:9013	8011:9014	8011:9015	8011:9016	8011:9017
8012:9012	8012:9013	8012:9014	8012:9015	8012:9016	8012:9017
8013:9012	8013:9013	8013:9014	8013:9015	8013:9016	8013:9017
8014:9012	8014:9013	8014:9014	8014:9015	8014:9016	8014:9017
8015:9012	8015:9013	8015:9014	8015:9015	8015:9016	8015:9017
8016:9012	8016:9013	8016:9014	8016:9015	8016:9016	8016:9017
8000:9018	8000:9019	8000:9020	8000:9021	8000:9022	8000:9023
8001:9018	8001:9019	8001:9020	8001:9021	8001:9022	8001:9023
8002:9018	8002:9019	8002:9020	8002:9021	8002:9022	8002:9023
8003:9018	8003:9019	8003:9020	8003:9021	8003:9022	8003:9023
8004:9018	8004:9019	8004:9020	8004:9021	8004:9022	8004:9023
8005:9018	8005:9019	8005:9020	8005:9021	8005:9022	8005:9023
8006:9018	8006:9019	8006:9020	8006:9021	8006:9022	8006:9023
8007:9018	8007:9019	8007:9020	8007:9021	8007:9022	8007:9023
8008:9018	8008:9019	8008:9020	8008:9021	8008:9022	8008:9023
8009:9018	8009:9019	8009:9020	8009:9021	8009:9022	8009:9023
8010:9018	8010:9019	8010:9020	8010:9021	8010:9022	8010:9023
8011:9018	8011:9019	8011:9020	8011:9021	8011:9022	8011:9023
8012:9018	8012:9019	8012:9020	8012:9021	8012:9022	8012:9023
8013:9018	8013:9019	8013:9020	8013:9021	8013:9022	8013:9023
8014:9018	8014:9019	8014:9020	8014:9021	8014:9022	8014:9023
8015:9018	8015:9019	8015:9020	8015:9021	8015:9022	8015:9023
8016:9018	8016:9019	8016:9020	8016:9021	8016:9022	8016:9023
8000:9024	8000:9025	8000:9026	8000:9027	8000:9028	8000:9029
8001:9024	8001:9025	8001:9026	8001:9027	8001:9028	8001:9029
8002:9024	8002:9025	8002:9026	8002:9027	8002:9028	8002:9029
8003:9024	8003:9025	8003:9026	8003:9027	8003:9028	8003:9029
8004:9024	8004:9025	8004:9026	8004:9027	8004:9028	8004:9029
8005:9024	8005:9025	8005:9026	8005:9027	8005:9028	8005:9029
8006:9024	8006:9025	8006:9026	8006:9027	8006:9028	8006:9029
8007:9024	8007:9025	8007:9026	8007:9027	8007:9028	8007:9029
8008:9024	8008:9025	8008:9026	8008:9027	8008:9028	8008:9029
8009:9024	8009:9025	8009:9026	8009:9027	8009:9028	8009:9029
8010:9024	8010:9025	8010:9026	8010:9027	8010:9028	8010:9029
8011:9024	8011:9025	8011:9026	8011:9027	8011:9028	8011:9029
8012:9024	8012:9025	8012:9026	8012:9027	8012:9028	8012:9029
8013:9024	8013:9025	8013:9026	8013:9027	8013:9028	8013:9029
8014:9024	8014:9025	8014:9026	8014:9027	8014:9028	8014:9029
8015:9024	8015:9025	8015:9026	8015:9027	8015:9028	8015:9029
8016:9024	8016:9025	8016:9026	8016:9027	8016:9028	8016:9029
8000:9030	8000:9031	8000:9032	8000:9033	8000:9034	8000:9035
8001:9030	8001:9031	8001:9032	8001:9033	8001:9034	8001:9035
8002:9030	8002:9031	8002:9032	8002:9033	8002:9034	8002:9035
8003:9030	8003:9031	8003:9032	8003:9033	8003:9034	8003:9035
8004:9030	8004:9031	8004:9032	8004:9033	8004:9034	8004:9035
8005:9030	8005:9031	8005:9032	8005:9033	8005:9034	8005:9035
8006:9030	8006:9031	8006:9032	8006:9033	8006:9034	8006:9035
8007:9030	8007:9031	8007:9032	8007:9033	8007:9034	8007:9035
8008:9030	8008:9031	8008:9032	8008:9033	8008:9034	8008:9035
8009:9030	8009:9031	8009:9032	8009:9033	8009:9034	8009:9035
8010:9030	8010:9031	8010:9032	8010:9033	8010:9034	8010:9035
8011:9030	8011:9031	8011:9032	8011:9033	8011:9034	8011:9035
8012:9030	8012:9031	8012:9032	8012:9033	8012:9034	8012:9035
8013:9030	8013:9031	8013:9032	8013:9033	8013:9034	8013:9035
8014:9030	8014:9031	8014:9032	8014:9033	8014:9034	8014:9035
8015:9030	8015:9031	8015:9032	8015:9033	8015:9034	8015:9035
8016:9030	8016:9031	8016:9032	8016:9033	8016:9034	8016:9035
8000:9036	8000:9037	8000:9038	8000:9039	8000:9040	8000:9041
8001:9036	8001:9037	8001:9038	8001:9039	8001:9040	8001:9041
8002:9036	8002:9037	8002:9038	8002:9039	8002:9040	8002:9041
8003:9036	8003:9037	8003:9038	8003:9039	8003:9040	8003:9041
8004:9036	8004:9037	8004:9038	8004:9039	8004:9040	8004:9041
8005:9036	8005:9037	8005:9038	8005:9039	8005:9040	8005:9041
8006:9036	8006:9037	8006:9038	8006:9039	8006:9040	8006:9041
8007:9036	8007:9037	8007:9038	8007:9039	8007:9040	8007:9041
8008:9036	8008:9037	8008:9038	8008:9039	8008:9040	8008:9041
8009:9036	8009:9037	8009:9038	8009:9039	8009:9040	8009:9041
8010:9036	8010:9037	8010:9038	8010:9039	8010:9040	8010:9041
8011:9036	8011:9037	8011:9038	8011:9039	8011:9040	8011:9041
8012:9036	8012:9037	8012:9038	8012:9039	8012:9040	8012:9041
8013:9036	8013:9037	8013:9038	8013:9039	8013:9040	8013:9041
8014:9036	8014:9037	8014:9038	8014:9039	8014:9040	8014:9041
8015:9036	8015:9037	8015:9038	8015:9039	8015:9040	8015:9041
8016:9036	8016:9037	8016:9038	8016:9039	8016:9040	8016:9041
8000:9042	8000:9043	8000:9044	8000:9045	8000:9046	8000:9047
8001:9042	8001:9043	8001:9044	8001:9045	8001:9046	8001:9047
8002:9042	8002:9043	8002:9044	8002:9045	8002:9046	8002:9047
8003:9042	8003:9043	8003:9044	8003:9045	8003:9046	8003:9047
8004:9042	8004:9043	8004:9044	8004:9045	8004:9046	8004:9047
8005:9042	8005:9043	8005:9044	8005:9045	8005:9046	8005:9047
8006:9042	8006:9043	8006:9044	8006:9045	8006:9046	8006:9047
8007:9042	8007:9043	8007:9044	8007:9045	8007:9046	8007:9047
8008:9042	8008:9043	8008:9044	8008:9045	8008:9046	8008:9047
8009:9042	8009:9043	8009:9044	8009:9045	8009:9046	8009:9047
8010:9042	8010:9043	8010:9044	8010:9045	8010:9046	8010:9047
8011:9042	8011:9043	8011:9044	8011:9045	8011:9046	8011:9047
8012:9042	8012:9043	8012:9044	8012:9045	8012:9046	8012:9047
8013:9042	8013:9043	8013:9044	8013:9045	8013:9046	8013:9047
8014:9042	8014:9043	8014:9044	8014:9045	8014:9046	8014:9047
8015:9042	8015:9043	8015:9044	8015:9045	8015:9046	8015:9047
8016:9042	8016:9043	8016:9044	8016:9045	8016:9046	8016:9047
8000:9048	8000:9049	8000:9050	8000:9051	8000:9052	8000:9053
8001:9048	8001:9049	8001:9050	8001:9051	8001:9052	8001:9053
8002:9048	8002:9049	8002:9050	8002:9051	8002:9052	8002:9053
8003:9048	8003:9049	8003:9050	8003:9051	8003:9052	8003:9053
8004:9048	8004:9049	8004:9050	8004:9051	8004:9052	8004:9053
8005:9048	8005:9049	8005:9050	8005:9051	8005:9052	8005:9053
8006:9048	8006:9049	8006:9050	8006:9051	8006:9052	8006:9053
8007:9048	8007:9049	8007:9050	8007:9051	8007:9052	8007:9053
8008:9048	8008:9049	8008:9050	8008:9051	8008:9052	8008:9053
8009:9048	8009:9049	8009:9050	8009:9051	8009:9052	8009:9053
8010:9048	8010:9049	8010:9050	8010:9051	8010:9052	8010:9053
8011:9048	8011:9049	8011:9050	8011:9051	8011:9052	8011:9053
8012:9048	8012:9049	8012:9050	8012:9051	8012:9052	8012:9053
8013:9048	8013:9049	8013:9050	8013:9051	8013:9052	8013:9053
8014:9048	8014:9049	8014:9050	8014:9051	8014:9052	8014:9053
8015:9048	8015:9049	8015:9050	8015:9051	8015:9052	8015:9053
8016:9048	8016:9049	8016:9050	8016:9051	8016:9052	8016:9053
8000:9054	8000:9055	8000:9056	8000:9057	8000:9058	8000:9059
8001:9054	8001:9055	8001:9056	8001:9057	8001:9058	8001:9059
8002:9054	8002:9055	8002:9056	8002:9057	8002:9058	8002:9059
8003:9054	8003:9055	8003:9056	8003:9057	8003:9058	8003:9059
8004:9054	8004:9055	8004:9056	8004:9057	8004:9058	8004:9059
8005:9054	8005:9055	8005:9056	8005:9057	8005:9058	8005:9059
8006:9054	8006:9055	8006:9056	8006:9057	8006:9058	8006:9059
8007:9054	8007:9055	8007:9056	8007:9057	8007:9058	8007:9059
8008:9054	8008:9055	8008:9056	8008:9057	8008:9058	8008:9059
8009:9054	8009:9055	8009:9056	8009:9057	8009:9058	8009:9059
8010:9054	8010:9055	8010:9056	8010:9057	8010:9058	8010:9059
8011:9054	8011:9055	8011:9056	8011:9057	8011:9058	8011:9059
8012:9054	8012:9055	8012:9056	8012:9057	8012:9058	8012:9059
8013:9054	8013:9055	8013:9056	8013:9057	8013:9058	8013:9059
8014:9054	8014:9055	8014:9056	8014:9057	8014:9058	8014:9059
8015:9054	8015:9055	8015:9056	8015:9057	8015:9058	8015:9059
8016:9054	8016:9055	8016:9056	8016:9057	8016:9058	8016:9059
8000:9060	8000:9061	8000:9062	8000:9063	8000:9064	8000:9065
8001:9060	8001:9061	8001:9062	8001:9063	8001:9064	8001:9065
8002:9060	8002:9061	8002:9062	8002:9063	8002:9064	8002:9065
8003:9060	8003:9061	8003:9062	8003:9063	8003:9064	8003:9065
8004:9060	8004:9061	8004:9062	8004:9063	8004:9064	8004:9065
8005:9060	8005:9061	8005:9062	8005:9063	8005:9064	8005:9065
8006:9060	8006:9061	8006:9062	8006:9063	8006:9064	8006:9065
8007:9060	8007:9061	8007:9062	8007:9063	8007:9064	8007:9065
8008:9060	8008:9061	8008:9062	8008:9063	8008:9064	8008:9065
8009:9060	8009:9061	8009:9062	8009:9063	8009:9064	8009:9065
8010:9060	8010:9061	8010:9062	8010:9063	8010:9064	8010:9065
8011:9060	8011:9061	8011:9062	8011:9063	8011:9064	8011:9065
8012:9060	8012:9061	8012:9062	8012:9063	8012:9064	8012:9065
8013:9060	8013:9061	8013:9062	8013:9063	8013:9064	8013:9065
8014:9060	8014:9061	8014:9062	8014:9063	8014:9064	8014:9065
8015:9060	8015:9061	8015:9062	8015:9063	8015:9064	8015:9065
8016:9060	8016:9061	8016:9062	8016:9063	8016:9064	8016:9065
8000:9066	8000:9067	8000:9068	8000:9069	8000:9070	8000:9071
8001:9066	8001:9067	8001:9068	8001:9069	8001:9070	8001:9071
8002:9066	8002:9067	8002:9068	8002:9069	8002:9070	8002:9071
8003:9066	8003:9067	8003:9068	8003:9069	8003:9070	8003:9071
8004:9066	8004:9067	8004:9068	8004:9069	8004:9070	8004:9071
8005:9066	8005:9067	8005:9068	8005:9069	8005:9070	8005:9071
8006:9066	8006:9067	8006:9068	8006:9069	8006:9070	8006:9071
8007:9066	8007:9067	8007:9068	8007:9069	8007:9070	8007:9071
8008:9066	8008:9067	8008:9068	8008:9069	8008:9070	8008:9071
8009:9066	8009:9067	8009:9068	8009:9069	8009:9070	8009:9071
8010:9066	8010:9067	8010:9068	8010:9069	8010:9070	8010:9071
8011:9066	8011:9067	8011:9068	8011:9069	8011:9070	8011:9071
8012:9066	8012:9067	8012:9068	8012:9069	8012:9070	8012:9071
8013:9066	8013:9067	8013:9068	8013:9069	8013:9070	8013:9071
8014:9066	8014:9067	8014:9068	8014:9069	8014:9070	8014:9071
8015:9066	8015:9067	8015:9068	8015:9069	8015:9070	8015:9071
8016:9066	8016:9067	8016:9068	8016:9069	8016:9070	8016:9071
8000:9072	8000:9073	8000:9074	8000:9075	8000:9076	8000:9077
8001:9072	8001:9073	8001:9074	8001:9075	8001:9076	8001:9077
8002:9072	8002:9073	8002:9074	8002:9075	8002:9076	8002:9077
8003:9072	8003:9073	8003:9074	8003:9075	8003:9076	8003:9077
8004:9072	8004:9073	8004:9074	8004:9075	8004:9076	8004:9077
8005:9072	8005:9073	8005:9074	8005:9075	8005:9076	8005:9077
8006:9072	8006:9073	8006:9074	8006:9075	8006:9076	8006:9077
8007:9072	8007:9073	8007:9074	8007:9075	8007:9076	8007:9077
8008:9072	8008:9073	8008:9074	8008:9075	8008:9076	8008:9077
8009:9072	8009:9073	8009:9074	8009:9075	8009:9076	8009:9077
8010:9072	8010:9073	8010:9074	8010:9075	8010:9076	8010:9077
8011:9072	8011:9073	8011:9074	8011:9075	8011:9076	8011:9077
8012:9072	8012:9073	8012:9074	8012:9075	8012:9076	8012:9077
8013:9072	8013:9073	8013:9074	8013:9075	8013:9076	8013:9077
8014:9072	8014:9073	8014:9074	8014:9075	8014:9076	8014:9077
8015:9072	8015:9073	8015:9074	8015:9075	8015:9076	8015:9077
8016:9072	8016:9073	8016:9074	8016:9075	8016:9076	8016:9077
8000:9078	8000:9079	8000:9080	8000:9081	8000:9082	8000:9083
8001:9078	8001:9079	8001:9080	8001:9081	8001:9082	8001:9083
8002:9078	8002:9079	8002:9080	8002:9081	8002:9082	8002:9083
8003:9078	8003:9079	8003:9080	8003:9081	8003:9082	8003:9083
8004:9078	8004:9079	8004:9080	8004:9081	8004:9082	8004:9083
8005:9078	8005:9079	8005:9080	8005:9081	8005:9082	8005:9083
8006:9078	8006:9079	8006:9080	8006:9081	8006:9082	8006:9083
8007:9078	8007:9079	8007:9080	8007:9081	8007:9082	8007:9083
8008:9078	8008:9079	8008:9080	8008:9081	8008:9082	8008:9083
8009:9078	8009:9079	8009:9080	8009:9081	8009:9082	8009:9083
8010:9078	8010:9079	8010:9080	8010:9081	8010:9082	8010:9083
8011:9078	8011:9079	8011:9080	8011:9081	8011:9082	8011:9083
8012:9078	8012:9079	8012:9080	8012:9081	8012:9082	8012:9083
8013:9078	8013:9079	8013:9080	8013:9081	8013:9082	8013:9083
8014:9078	8014:9079	8014:9080	8014:9081	8014:9082	8014:9083
8015:9078	8015:9079	8015:9080	8015:9081	8015:9082	8015:9083
8016:9078	8016:9079	8016:9080	8016:9081	8016:9082	8016:9083
8000:9084	8000:9085	8000:9086	8000:9087	8000:9088	8000:9089
8001:9084	8001:9085	8001:9086	8001:9087	8001:9088	8001:9089
8002:9084	8002:9085	8002:9086	8002:9087	8002:9088	8002:9089
8003:9084	8003:9085	8003:9086	8003:9087	8003:9088	8003:9089
8004:9084	8004:9085	8004:9086	8004:9087	8004:9088	8004:9089
8005:9084	8005:9085	8005:9086	8005:9087	8005:9088	8005:9089
8006:9084	8006:9085	8006:9086	8006:9087	8006:9088	8006:9089
8007:9084	8007:9085	8007:9086	8007:9087	8007:9088	8007:9089
8008:9084	8008:9085	8008:9086	8008:9087	8008:9088	8008:9089
8009:9084	8009:9085	8009:9086	8009:9087	8009:9088	8009:9089
8010:9084	8010:9085	8010:9086	8010:9087	8010:9088	8010:9089
8011:9084	8011:9085	8011:9086	8011:9087	8011:9088	8011:9089
8012:9084	8012:9085	8012:9086	8012:9087	8012:9088	8012:9089
8013:9084	8013:9085	8013:9086	8013:9087	8013:9088	8013:9089
8014:9084	8014:9085	8014:9086	8014:9087	8014:9088	8014:9089
8015:9084	8015:9085	8015:9086	8015:9087	8015:9088	8015:9089
8016:9084	8016:9085	8016:9086	8016:9087	8016:9088	8016:9089
8000:9090	8000:9091	8000:9092	8000:9093	8000:9094	8000:9095
8001:9090	8001:9091	8001:9092	8001:9093	8001:9094	8001:9095
8002:9090	8002:9091	8002:9092	8002:9093	8002:9094	8002:9095
8003:9090	8003:9091	8003:9092	8003:9093	8003:9094	8003:9095
8004:9090	8004:9091	8004:9092	8004:9093	8004:9094	8004:9095
8005:9090	8005:9091	8005:9092	8005:9093	8005:9094	8005:9095
8006:9090	8006:9091	8006:9092	8006:9093	8006:9094	8006:9095
8007:9090	8007:9091	8007:9092	8007:9093	8007:9094	8007:9095
8008:9090	8008:9091	8008:9092	8008:9093	8008:9094	8008:9095
8009:9090	8009:9091	8009:9092	8009:9093	8009:9094	8009:9095
8010:9090	8010:9091	8010:9092	8010:9093	8010:9094	8010:9095
8011:9090	8011:9091	8011:9092	8011:9093	8011:9094	8011:9095
8012:9090	8012:9091	8012:9092	8012:9093	8012:9094	8012:9095
8013:9090	8013:9091	8013:9092	8013:9093	8013:9094	8013:9095
8014:9090	8014:9091	8014:9092	8014:9093	8014:9094	8014:9095
8015:9090	8015:9091	8015:9092	8015:9093	8015:9094	8015:9095
8016:9090	8016:9091	8016:9092	8016:9093	8016:9094	8016:9095
8000:9096	8000:9097	8000:9098	8000:9099	8000:9100	8000:9101
8001:9096	8001:9097	8001:9098	8001:9099	8001:9100	8001:9101
8002:9096	8002:9097	8002:9098	8002:9099	8002:9100	8002:9101
8003:9096	8003:9097	8003:9098	8003:9099	8003:9100	8003:9101
8004:9096	8004:9097	8004:9098	8004:9099	8004:9100	8004:9101
8005:9096	8005:9097	8005:9098	8005:9099	8005:9100	8005:9101
8006:9096	8006:9097	8006:9098	8006:9099	8006:9100	8006:9101
8007:9096	8007:9097	8007:9098	8007:9099	8007:9100	8007:9101
8008:9096	8008:9097	8008:9098	8008:9099	8008:9100	8008:9101
8009:9096	8009:9097	8009:9098	8009:9099	8009:9100	8009:9101
8010:9096	8010:9097	8010:9098	8010:9099	8010:9100	8010:9101
8011:9096	8011:9097	8011:9098	8011:9099	8011:9100	8011:9101
8012:9096	8012:9097	8012:9098	8012:9099	8012:9100	8012:9101
8013:9096	8013:9097	8013:9098	8013:9099	8013:9100	8013:9101
8014:9096	8014:9097	8014:9098	8014:9099	8014:9100	8014:9101
8015:9096	8015:9097	8015:9098	8015:9099	8015:9100	8015:9101
8016:9096	8016:9097	8016:9098	8016:9099	8016:9100	8016:9101
8000:9102	8000:9103	8000:9104	8000:9105	—	—
8001:9102	8001:9103	8001:9104	8001:9105
8002:9102	8002:9103	8002:9104	8002:9105
8003:9102	8003:9103	8003:9104	8003:9105
8004:9102	8004:9103	8004:9104	8004:9105
8005:9102	8005:9103	8005:9104	8005:9105
8006:9102	8006:9103	8006:9104	8006:9105
8007:9102	8007:9103	8007:9104	8007:9105
8008:9102	8008:9103	8008:9104	8008:9105
8009:9102	8009:9103	8009:9104	8009:9105
8010:9102	8010:9103	8010:9104	8010:9105
8011:9102	8011:9103	8011:9104	8011:9105
8012:9102	8012:9103	8012:9104	8012:9105
8013:9102	8013:9103	8013:9104	8013:9105
8014:9102	8014:9103	8014:9104	8014:9105
8015:9102	8015:9103	8015:9104	8015:9105
8016:9102	8016:9103	8016:9104	8016:9105

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

2′-C-METHYL-4′-FLUOROURIDINE 1

To a stirred suspension of 1-1 (20 g, 77.5 mmol), PPh₃ (30 g, 114.5 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF (300 mL) was added a solution of I₂ (25 g, 98.4 mmol) in THF (100 mL) dropwise at 0° C. The mixture was warmed to room temperature (R.T.) and stirred at R.T. for 10 h. The reaction was quenched by MeOH (100 mL). The solvent was removed, and the residue was re-dissolved in a mixture ethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washed with saturated Na₂S₂O₃ aq., and the aqueous phase was extracted with a mixture of EA and THF (2 L, 10:1). The organic layer was combined and concentrated to give a residue, which was purified on a silica gel column (0-10% MeOH in DCM) to give 1-2 (22.5 g, 78.9%) as a white solid. ¹H NMR: (DMSO-d₆, 400 MHz) δ 11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H).

To a stirred solution of 1-2 (24.3 g, 66.03 mmol) in anhydrous MeOH (240 mL) was added NaOMe (10.69 g, 198.09 mmol) at R.T. under N₂. The mixture was refluxed for 3 h. The solvent was removed, and the residue was re-dissolved in anhydrous pyridine (200 mL). To the mixture was added Ac₂O (84.9 g, 833.3 mmol) at 0° C. The mixture was warmed to 60° C. and stirred for 10 h. The solvent was removed, and the residue was diluted with DCM, washed with saturated NaHCO₃ and brine. The organic layer was concentrated and purified on a silica gel column (10-50% EA in PE) to give 1-3 (15 g, 70.1%) as a white solid. ¹H NMR: (CDCl₃, 400 MHz) δ 8.82 (s, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.54 (s, 1H), 5.85 (s, 1H), 5.77 (dd, J=8.0, 2.0 Hz, 1H), 4.69 (d, J=2.4 Hz, 1H), 4.58 (d, J=2.8 Hz, 1H), 2.07 (d, J=5.2 Hz, 6H), 1.45 (s, 3H).

To an ice-cooled solution of 1-3 (15 g, 46.29 mmol) in anhydrous DCM (300 mL) was added AgF (29.39 g, 231.4 mmol). I₂ (23.51 g, 92.58 mmol) in anhydrous DCM (1.0 L) was added dropwise to the solution. The reaction mixture was stirred at R.T. for 5 h. The reaction was quenched with saturated Na₂S₂O₃ and NaHCO₃, and extracted with DCM. The organic layer was separated, dried and evaporated to dryness. The residue was purified on a silica gel column (10-30% EA in PE) to give 1-4 (9.5 g, 43.6%) as a white solid. ¹H NMR: (Methanol-d₄, 400 MHz) δ 7.52 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.73 (d, J=8.0 Hz, 1H), 3.58 (s, 1H), 3.54 (d, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.58 (s, 3H).

To a solution of 1-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) were added NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol). The reaction mixture was stirred at 130° C. for 6 h. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel column (10-30% EA in PE) to give 1-5 (2.8 g, 40.5%). ¹H NMR: (CDCl₃, 400 MHz) δ 8.84 (s, 1H), 8.04-8.06 (m, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.21-7.26 (m, 1H), 6.21 (s, 1H), 5.85 (d, J=18 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H), 4.59-4.72 (m, 2H), 2.14 (s, 6H), 1.64 (d, J=6.0 Hz, 3H). ESI-MS: m/z 444.9 [M−F+H]⁺.

A mixture of 1-5 (4.0 g; 8.6 mmol) and liquid ammonia was kept overnight at R. T. in a high-pressure stainless-steel vessel. Ammonia was then evaporated, and the residue purified on silica (50 g column) with a CH₂Cl₂/MeOH solvent mixture (4-12% gradient) to yield compound 1 as a colorless foam (2.0 g; 84% yield). ESI-MS: m/z 275.1 [M−H]⁻.

Example 2

Compound 2

To a solution of 1 (1.2 g; 4.3 mmol) in dioxane (30 mL) were added p-toluenesulphonic acid monohydrate (820 mg; 1 eq.) and trimethyl orthoformate (14 mL; 30 eq.). The mixture was stirred overnight at R.T. The mixture was then neutralized with methanolic ammonia and the solvent evaporated. Purification on silica gel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) yielded 2-1 (1.18 g, 87%).

To an ice cold solution of 2-1 (0.91 g; 2.9 mmol) in anhydrous THF (20 mL) was added iso-propylmagnesium chloride (2.1 mL; 2 M in THF). The mixture was stirred at 0° C. for 20 mins. A solution of phosphorochloridate reagent (2.2 g; 2.5 eq.) in THF (2 mL) was added dropwise. The mixture was stirred overnight at R.T. The reaction was quenched with saturated aq. NH₄Cl solution and stirred at R.T. for 10 mins. The mixture was then diluted with water and CH₂Cl₂, and the two layers were separated. The organic layer was washed with water, half saturated aq. NaHCO₃ and brine, and dried with Na₂SO₄. The evaporated residue was purified on silica gel column with CH₂Cl₂-iPrOH solvent system (4-10% gradient) to yield Rp/Sp-mixture of 2-2 (1.59 g; 93%).

A mixture of 2-2 (1.45 g; 2.45 mmol) and 80% aq. HCOOH (7 mL) was stirred at R.T. for 1.5 h. The solvent was evaporated and coevaporated with toluene. The obtained residue was dissolved in MeOH, treated with Et₃N (3 drops) and the solvent was evaporated. Purification on silica gel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) yielded Rp/Sp-mixture of compound 2 (950 mg; 70%). ³¹P-NMR (DMSO-d₆): δ 3.52, 3.47. MS: m/z=544 [M−1]⁻.

Example 3

Compound 3

To an ice cold solution of 3-1 (80 mg; 015 mmol) in anhydrous THF (2 mL) was added isopropylmagnesium chloride (0.22 mL; 2 M in THF). The mixture was stirred at 0° C. for 20 mins. A solution of the phosphorochloridate reagent (0.16 g; 0.45 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred overnight at R.T. The reaction was quenched with saturated aq. NH₄Cl solution and stirred at R.T. for 10 mins. The mixture was diluted with water and CH₂Cl₂, and the two layers were separated. The organic layer was washed with water, half saturated aq. NaHCO₃ and brine, and dried with Na₂SO₄. The evaporated residue was purified on silica gel column with CH₂Cl₂-MeOH solvent system (2-10% gradient) to yield Rp/Sp-mixture of 3-2 (102 mg; 80%).

A mixture of 3-2 (100 mg; 0.12 mmol) in EtOH (3 mL) and 10% Pd/C (10 mg) was stirred under the H₂ atmosphere for 1.5 h. The mixture was filtered through a Celite pad, evaporated and purified on silica gel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) to yield Rp/Sp-mixture of compound 3 (52 mg, 74%). ³¹P-NMR (DMSO-d₆): δ 3.51, 3.48. MS: m/z=584 [M−1]⁻.

Example 4

Compounds 4 and 6

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750 mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15 mins at bath temperature 42° C., and then cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃ (0.009 mL, 0.1 mmol). The mixture was kept at R.T. for 45 mins. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt of pyrophosphate (100 mg) was added. About 1 mL of dry DMF was added to get a homogeneous solution. In 1 h, the reaction was quenched with 2M ammonium acetate buffer (1 mL, pH=7.5), diluted water (10 mL) and loaded on a column HiLoad 16/10 with Q Sepharose High Performance. The separation was done in linear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractions eluted at 60% buffer B contained Compound 4 and at 80% buffer B contained Compound 6. The corresponding fractions were concentrated, and the residue purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. Compound 4: ³¹P-NMR (D₂O): −3.76 (s); MS: m/z 355.3 [M−H]⁻. Compound 6: ³¹P-NMR (D₂O): −9.28 (d, 1H, Pα), −12.31 (d, 1H, Pγ), −22.95 (t, 1H, Pβ); MS: m/z 515.0 [M−1]⁻.

Example 5

Compound 5

Compound 5 was synthesized as described for 2 on 0.1 mmol scale and with neopentyl ester of phosphorochloridate reagent. Yield was 36 mg (63%). ³¹P-NMR (CDCl₃): δ 2.57 (s), 2.43 (s). MS: 572.6 [M−1]⁻.

Example 6

Compound 7

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750 mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15 mins at bath temperature 42° C., and then cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by PSCl₃ (0.01 mL, 0.1 mmol). The mixture was kept at R.T. for 1 h. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt of pyrophosphate (200 mg) was added. About 1 mL of dry DMF was added to get a homogeneous solution. In 2 h, the reaction was quenched with 2M ammonium acetate buffer (1 mL, pH=7.5), diluted with water (10 mL) and loaded on a column HiLoad 16/10 with Q Sepharose High Performance. Separation was done in linear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractions eluted at 80% buffer B contained 7 (compounds 7a and 7b). The corresponding fractions were concentrated, and the residue purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 20% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. Two peaks were collected. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. Peak 1 (more polar): ³¹P-NMR (D₂O): +42.68 (d, 1H, Pα), −9.05 (d, 1H, Pγ), −22.95 (t, 1H, Pβ); MS 530.90 [M−1]⁻. Peak 2 (less polar): ³¹P-NMR (D₂O): +42.78 (d, 1H, Pα), −10.12 (bs, 1H, Pγ), −23.94 (t, 1H, Pβ); and MS 530.90 [M−1]⁻.

Example 7

Compound 23

To a stirred suspension of 23-1 (20.0 g, 81.3 mmol), imidazole (15.9 g, 234.0 mmol), PPh₃ (53.5 g, 203.3 mmol) and pyridine (90 mL) in anhydrous THF (100 mL) was added a solution of I₂ (41.3 g, 162.6 mmol) in THF (150 mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirred for 14 h. The reaction was quenched with sat. aq. Na₂S₂O₃ (150 mL) and extracted with THF/EA (1/1) (100 mL×3). The organic layer was dried over Na₂SO₄, and concentrated at a low pressure. The residue was recrystallized from EtOH to afford pure 23-2 (23 g, 79%) as a white solid.

To a stirred solution of 23-2 (23 g, 65 mmol) in anhydrous MeOH (200 mL) was added NaOCH₃ (10.5 g, 195 mmol) in MeOH (50 mL) at R.T. The mixture was stirred at 60° C. for 3 h, and quenched with dry ice. A solid precipitated and removed by filtration. The filtrate was concentrated at a low pressure. The residue was purified on column silica gel column (MeOH in DCM from 1% to 10%) to provide 23-3 (13.1 g, 92.5%) as a white foam solid.

To a stirred solution of 23-3 (12.0 g, 53 mmol) in anhydrous CH₃CN was added TEA.3HF (8.5 g, 53 mmol) and NIS (10.2 g, 63.6 mmol) at 0° C. The mixture was stirred for 30 mins, and slowly warmed to R.T. The mixture was stirred for another 30 mins. The solid was removed by filtration, and washed with DCM to give 23-4 (14 g, 73%) as a yellow solid. ESI-MS: m/z 373.0 [M+H]⁺.

To a stirred solution of 23-4 (12.0 g, 32 mmol) and DMAP (1.2 g, 9.6 mmol) in pyridine (100 mL) was added Bz₂O (21.7 g, 96 mmol) at R.T. The mixture was stirred at 50° C. for 16 h. The resulting solution was quenched with water, and concentrated to dryness at low pressure. The crude was purified on silica gel column (50% EA in PE) to give 23-5 (15 g, 81%) as a white solid. ESI-TOF-MS: m/z 581.0 [M+H]⁺.

Tetra-butylammonium hydroxide (288 mL as 54-56% aqueous solution, 576 mmol) was adjusted to pH˜4 by adding TFA (48 mL). The resulting solution was treated with a solution of 23-5 (14 g, 24 mmol) in DCM (200 mL). m-Cloroperbenzoic acid (30 g, 60-70%, 120 mmol) was added portion wise with vigorous stirring, and the mixture was stirred overnight. The organic layer was separated and washed with brine. The resulting solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 23-6 (7.5 g, 68%)

Compound 23-6 (5.0 g, 10.6 mmol) was treated with 7N NH₃.MeOH (100 mL), and the mixture was stirred for 5 h. The mixture was then concentrated to dryness at low pressure. The residue was washed with DCM, and the solid was filtered to give 23-7 (2.1 g, 75%) as a white foam. ESI-MS: m/z 263.0 [M+H]⁺.

To a solution of 23-7 (2.1 g, 8.0 mmol) in pyridine was added TIDPSCl (2.5 g, 8.0 mmol) dropwise at 0° C., and stirred for 12 h. at R.T. The solution was quenched with water, and concentrated to dryness at low pressure. The crude was purified by column chromatography (EA in PE from 10% to 50%) to give pure 23-8 (1.6 g, 40%) as a white foam.

A solution of 23-8 (1.5 g, 3.0 mmol) and IBX (1.69 g, 6.0 mmol) in anhydrous CH₃CN (10 mL) was stirred at 80° C. for 3 h. The mixture was cooled down to R.T. and filtered. The filtrate was concentrated to dryness at low pressure. The residue was purified by column chromatography (EA in PE from 2% to 50%) to give pure 23-9 (1.2 g, 80%) as a white foam. ESI-MS: m/z 503.0 [M+H]⁺

Compound 23-9 (500 mg, 1 mmol) was dissolved in dry THF (8 mL). Ethynyl magnesium bromide (8 mL of 0.5M solution in cyclohexane) was added at R.T. After 30 mins, additional ethynyl magnesium bromide (8 mL) was added. The mixture was left for 30 mins, and then quenched with sat. solution of ammonium chloride. The product was extracted with EA. The organic extracts were washed with brine, dried, and concentrated. The residue was purified by flash chromatography on silica gel in EA to remove the dark color. The yellow compound was dissolved in THF (3 mL) and treated with TBAF (1 mL, 2M solution in THF) for 30 mins. The solvent was evaporated, and the residue was subjected to silica gel chromatography on a Biotage cartridge (25 g). EA saturated with water was used for isocratic elution. Each fractions were analyzed by TLC in DCM-MeOH (9:1 v/v). Fractions containing only the isomer with a high Rf were concentrated to give pure compound 23 (110 mg). MS: 285.1 [M−1]⁻.

Example 8

Compound 22

Compound 23 (57 mg, 0.2 mmol) was dissolved in CH₃CN (2 mL), containing N-methylimidazole (40 uL). The phosphorochloridate (207 mg, 0.6 mmol) was added, and the mixture was kept overnight at 40° C. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The product was isolated by silica gel chromatography in gradient of methanol in DCM from 0% to 15%. Compound 22 was obtained (46 mg, 39%). MS: m/z 593.9 [M−1]⁻.

Example 9

Compound 51

To a solution of triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.74 mmol) in THF was added 51-1 (0.16 gg; 0.49 mmol). The mixture evaporated and rendered anhydrous by coevaporating with pyridine follow by toluene. The residue was dissolved in anhydrous THF and cooled in an ice-bath. Diisopropylethyl amine (0.34 mL) was added, followed by BOP—Cl (250 mg) and 3-nitro-1,2,4-triazole (112 mg) in THF (5 mL). The mixture was stirred at 0° C. for 90 mins, diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). The residue was purified on silica column with 3-10% i-PrOH in DCM to give 51-2 (0.2 g, 64%).

A solution of 51-2 (0.20 g; 0.31 mmol) in 80% aq. HCOOH was stirred at R.T. for 2 h, and then concentrated. The residue was coevaporated with toluene and then with MeOH containing a small amount of Et₃N (2 drops). Purification on silica gel (10 g column) with CH₂Cl₂/MeOH (4-10% gradient) was followed by RP-HPLC purification in 5 runs on a Synergi Hydro RP column 250×30 mm (Phenomenex P/N 00G-4375-U0-AX) using H₂O and ACN both 50 mM TEAA. The Gradient was 25-75% ACN in 20 mins at 24 mL/mins, 254 nM detection. The compound eluted at 16.0 minutes; and the pure fractions were pooled and lyophilized. TEAA was removed by dissolving the compound in DMSO (2 mL) and using the same column and same gradient, using only H₂O and ACN. Pure fractions were pooled and lyophilized to give compound 51 (18 mg). MS: m/z=1197 [2M+1]⁺.

Example 10

Compound 8

Compound 8-1 (5.0 g, 8.5 mmol) and 2-amino-6-chloropurine (3.0 g, 17.7 mmol) were co-concentrated with anhydrous toluene for 3 times. To a stirred suspension of the above mixtures in anhydrous MeCN (50 mL) was added DBU (7.5 g, 49 mmol) at 0° C. The mixture was stirred at 0° C. for 15 mins, and then TMSOTf (15 g, 67.6 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 15 mins. The mixture was heated at 70° C. overnight. The mixture was cooled to R.T., and diluted with EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified by column on silica gel (PE/EA: from 15/1 to 3/1) to give 8-2 (2.5 g, 46.3%) as a white foam.

To a solution of 8-2 (10 g, 15.7 mmol), AgNO₃ (8.0 g, 47 mmol) and collidine (10 mL) in anhydrous DCM (20 mL) was added MMTrCl (14.5 g, 47 mmol) in small portions under N₂. The mixture was stirred at R.T. overnight. The mixture was filtered, and the filtrate was washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/ME=20/1 to 8/1) to give 8-3 (10 g, 70%) as a yellow solid.

To a solution of 3-hydroxy-propionitrile (3.51 g, 49.4 mmol) in anhydrous THF (100 mL) was added NaH (2.8 g, 70 mmol) at 0° C., and the mixture was stirred at R.T. for 30 mins. A solution of 8-3 (8.5 g, 9.35 mmol) in anhydrous THF (100 mL) at 0° C. was added, and the mixture was stirred at R.T. overnight. The reaction was quenched with water, and extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 20/1) to give 8-4 (4.5 g, 83%) as a white solid.

Compound 8-4 (1.5 g, 2.6 mmol) was co-concentrated with anhydrous pyridine 3 times. To an ice-cooled solution of 8-4 in anhydrous pyridine (30 mL) was added TsCl (1.086 g, 5.7 mmol), and the mixture was stirred at 0° C. for 1 h. The reaction was quenched with water, and extracted with EA (80 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 15/1) to give 8-5 (1.4 g, 73%) as a white solid.

To a solution of 8-5 (4.22 g, 5.7 mmol) in acetone (60 mL) was added NaI (3.45 g, 23 mmol), and the mixture was refluxed overnight. The reaction was quenched with sat. aq. Na₂S₂O₃ and extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 15/1) to give 8-6 (4 g, 73%) as a white solid.

To a solution of 8-6 (4.0 g, 5.8 mmol) in anhydrous THF (60 mL) was added DBU (3.67 g, 24 mmol), and the mixture was stirred at 60° C. overnight. The mixture was diluted with EA (80 mL), and the solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1 to 20/1) to give 8-7 (2 g, 61%) as a white solid.

To an ice-cooled solution of 8-7 (500 mg, 0.89 mmol) in anhydrous DCM (20 mL) was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg, 1.97 mmol) in anhydrous DCM (20 mL). The mixture was stirred at R.T. for 3 h. The reaction was quenched with sat Na₂S₂O₃ and NaHCO₃ aqueous, and the mixture was extracted with DCM (50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated to give the crude 8-8 (250 mg) as a yellow solid.

To a solution of crude 8-8 (900 mg, 1.28 mmol) in anhydrous DCM (50 mL) was added DMAP (1.0 g, 8.2 mmol) and BzCl (795 mg, 5.66 mmol). The mixture was stirred at R.T. overnight. The mixture was washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by prep-TLC (DCM/MeOH=15:1) to give 8-9 (300 mg, 26%) as a white solid.

To a solution of crude 8-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL) was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). The mixture was stirred at 60° C. for 2 d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA=1:1) to give crude 8-10 (550 mg, 73%) as a white solid.

The crude 8-10 (550 mg, 0.6 mmol) was dissolved in NH₃/MeOH (7N, 50 mL). The mixture was stirred at R.T. overnight. The mixture was concentrated, and the residue was purified by silica gel column (DCM/MeOH from 100/1 to 20/1) to give 8-11 (62 mg, 17%) as a white solid. ESI-MS: m/z 598.0 [M+H]⁺

A solution of 8-11 (12 mg) in 80% formic acid (0.5 mL) stood at R.T. for 3.5 h and then was concentrated. The residue was co-evaporated with MeOH/toluene 4 times in a vial, and triturated with EtOAc at 40° C. The EtOAc solution removed with pippet. The trituration step was repeated several times, and the remaining solid was dissolved in MeOH. The solution was concentrated and dried to give compound 8 as off white solid (4.7 mg). ESI-MS: m/z 326.6 [M+H]⁺.

Example 11

Compounds 34 and 35

To a stirred suspension of 8-1 (50 g, 84.8 mmol) and 2-amino-6-chloropurine (28.6 g, 169.2 mmol) in anhydrous MeCN (500 mL) was added DBU (77.8 g, 508 mmol) at 0° C. The mixture was stirred at 0° C. for 30 mins, and TMSOTf (150.5 g, 678 mmol) was added dropwise at 0° C. The mixture was stirred at R.T. for 20 mins until a clear solution was formed. The mixture was stirred at 90-110° C. overnight. The mixture was cooled to R.T., and diluted with EA. The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ and then concentrated at low pressure. The residue was purified by silica gel column (PE/EA=2/1) to give 34-1 (30 g, 55.5%) as a white solid.

To a solution of 34-1 (30 g, 47.1 mmol) in anhydrous DCM (300 mL) was added collidine (30 mL), AgNO₃ (24 g, 141.4 mmol) and MMTrCl (43.6 g, 141.4 mmol). The mixture was stirred at R.T. overnight. The mixture was filtered, and the filtrate was washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=4/1) to give 34-2 (35 g, 82%) as a white solid.

To a stirred solution of 34-2 (35 g, 38.5 mmol) in anhydrous EtOH (150 mL) was added a solution of EtONa in EtOH (2N, 150 mL). The mixture was stirred at R.T. overnight, and then concentrated at low pressure. The residue was dissolved in EA (200 mL) and the solution was washed with water and brine. The organic layer was dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/2) to give 34-3 (19 g, 81%) as a white solid.

Compound 34-3 (19 g, 31.3 mmol) was co-concentrated with anhydrous pyridine for 3 times. To an ice-cooled solution of 34-3 in anhydrous pyridine (120 mL) was added a solution of TsCl (6.6 g, 34.6 mmol) in pyridine (40 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 16 h. The mixture was quenched with water, and the reaction mixture was concentrated. The residue was re-dissolved in EA (200 mL). The solution was washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated. The residue was purified by silica gel column (DCM/MeOH=100/1) to give 34-4 (16 g, 67%) as a yellow solid.

To a solution of 34-4 (15 g, 19.7 mmol) in acetone (100 mL) was added NaI (30 g, 197 mmol). The mixture was refluxed overnight, and then concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=100/1) to give 34-5 (9 g, 63.7%) as a white solid.

To a solution of 34-5 (8 g, 11.2 mmol) in anhydrous THF (60 mL) was added DBU (5.12 g, 33.5 mmol), and the mixture was heated at 60° C. overnight. The mixture was diluted with EA, and washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE/acetone=4/1) to give 34-6 (5.7 g, 86%) as a white solid. ¹H-NMR (CD₃OH, 400 MHz) δ=8.18 (s, 1H), 7.17-7.33 (m, 12H), 6.80 (d, J=8.8 Hz, 2H), 5.98 (s, 1H), 5.40 (d, J=8.6 Hz, 1H), 3.87 (m, 5H), 3.75 (s, 3H), 2.69 (s, 1H), 1.05 (s, 3H).

To an ice-cooled solution of 34-6 (4.44 g, 7.5 mmol) in anhydrous MeCN (45 mL) was added TEA.3HF (1.23 g, 7.6 mmol) and NIS (2.16 g, 9.5 mmol). The mixture was stirred at R.T. for 2-3 h. The reaction was quenched with sat. Na₂SO₃ and NaHCO₃ solution. The mixture was extracted with EA (3×100 mL). The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column (DCM/acetone=100/2) to give 34-7 (4.4 g, 79.8%) as a white solid.

To a solution of 34-7 (5.36 g, 7.3 mmol) in anhydrous DCM (50 mL) was added DMAP (3.6 g, 29.8 mmol) and BzCl (3.1 g, 22.1 mmol) at 0° C. The mixture was stirred at R.T. overnight. The mixture was washed with sat. aq. NaHCO₃ and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 34-8 (5.6 g, 81.3%) as a white solid.

To a solution of 34-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) was added NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). The mixture was stirred at 90-100° C. for 48 h. The mixture was diluted with EA, and washed with water and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 34-9 (3.9 g, 78.5%) as a white solid.

Compound 34-9 in NH₃ in MeOH (7N, 60 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure. The residue was purified by silica gel column (DCM/acetone=50/1) to give 34-10 (500 mg, 74.7%) as a white solid. ESI-MS: m/z 626.3 [M+H]⁺.

To a solution of 34-10 (350 mg, 0.56 mmol) in anhydrous pyridine (4 mL) was added imidazole (50 mg, 0.72 mmol) and TBSCl (108 mg, 0.72 mmol) at 0 to 5° C., and stirred at R.T. for 15 h. The reaction was quenched with absolute EtOH (0.5 mL). The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA (150 mL), and washed with water, sat. NaHCO₃ and brine. The combined organic layers were dried over Na₂SO₄, filtered and evaporated at low pressure. The residue was purified by silica gel column (10-30% EA in hexanes) to give 34-11 (338 mg, 81.8%) as a white solid.

To a solution of compound 34-11 (328 mg, 0.44 mmol), AgNO₃ (226 mg, 1.33 mmol) and collidine (0.59 mL, 4.84 mmol) in anhydrous DCM (4 mL) was added MMTrCl (410 mg, 1.33 mmol) under N₂. The mixture was stirred at R.T. overnight under N₂, and monitored by TLC to completion. The mixture was filtered through pre-packed Celite filter, and the filtrate was washed with water, 50% aqueous citric acid, and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by silica gel column (EA in hexanes from 0% to 30%) to give 34-12 (337 mg).

To a solution of 34-12 (337 mg, 0.33 mmol) in anhydrous THF (4 mL) was added 1.0 M solution of TBAF (0.66 ML, 0.66 mmol) at 0 to 5° C. The reaction was slowly warmed to R.T., and stirred for 1 h. The mixture was quenched with silica gel, and filtered. The solvents were evaporated to give the crude product, which was purified by silica gel column (EA in hexanes from 0% to 50%) to give 34-13 (188 mg).

To a stirred solution of 34-13 (180 mg, 0.16 mmol) in anhydrous CH₃CN (2.5 mL) was added N-methylimidazole (132 μL, 1.6 mmol) at 0-5° C. (ice/water bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (207 mg, 0.6 mmol, dissolved in 2 mL of CH₃CN). The solution was stirred at R.T. for 2.5 h, and the mixture was diluted with EA followed by addition of water (15 mL). The solution was washed H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give 34-14 (75.8 mg) and 34-15 (108 mg) as a slower eluting isomer.

Compound 34-14 (76 mg, 0.063 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (47 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile and water, and lyophilized to give compound 34 (26.6 mg). ESI-LCMS: m/z=663.3 [M+H]⁺.

Compound 34-15 (108 mg, 0.089 mmol) was dissolved in_anhydrous CH₃CN (0.7 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 60 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile and water, and lyophilized to give compound 35 (40.3 mg). ESI-LCMS: m/z=663.2 [M+H]⁺.

Example 12

Compound 25

To a solution of 25-1 (260 mg, 1 mmol), PPh₃ (780 mg, 3 mmol) and pyridine (0.5 mL) in anhydrous THF (8 mL) were added I₂ (504 mg, 2 mmol) at R.T., and the mixture was stirred at R.T. for 12 h. The mixture was diluted with EtOAc and washed with 1M HCl solution. The organic layer was dried over Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 25-2 (190 mg, 85%) as a white solid.

To a solution of 25-2 (190 mg, 0.52 mmol) in THF (4 mL) was added DBU (760 mg, 5 mmol) at R.T., and the mixture was heated at 50° C. overnight. The mixture was diluted with EtOAc, and washed with water. The organic layer was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 25-3 (75 mg, 52%) as a white solid.

To a solution of 25-3 (200 mg, 0.82 mmol) in MeCN (anhydrous, 4 mL) was added NIS (337 mg, 1.5 mmol) and TEA.3HF (213 mg, 1.25 mmol) at R.T., and the mixture was stirred at R.T. for 7 h. The reaction was quenched with sat. Na₂SO₃ solution and sat. aq. NaHCO₃ solution. The mixture was extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 25-4 (300 mg, 62%) as a white solid.

To a solution of 25-4 (194 mg, 0.5 mmol) in pyridine (5 mL) was added BzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T. for 5 h, and the reaction was quenched with water. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (20% EA in PE) to give 25-5 (397 mg, 81%) as a white solid.

To a solution of 25-5 (1.05 g, 2.13 mmol) in DCM (12 mL) was added a mixture of TFA (0.5 mL) and Bu₄NOH (1 mL), followed by addition of m-CPBA (1.3 g, 6 mmol) at R.T. The mixture was stirred at R.T. for 5 h. The mixture was washed with sat. Na₂SO₃ solution and aq. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 25-6 (450 mg, 63%) as a white solid.

Compound 25-6 (250 mg, 0.65 mmol) was dissolved in NH₃/MeOH (5 mL). The mixture was stirred at R.T. for 5 h, and then concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give compound 25 (120 mg, 66%) as a white powder. ESI-MS: m/z 279.0 [M+H]⁺.

Example 13

Compound 31

To a stirred solution of compound 25 (100 mg, 0.36 mmol) in anhydrous THF (3.0 mL) was added N-methylimidazole (236 μL, 2.87 mmol) at 0° C. (dry ice/acetone bath) followed by a solution of the phosphorochloridate (329 mg, 1.08 mmol, dissolved in 2 mL of THF). The solution was stirred at 0° C. for 1 h, the reaction temperature was raised up-to 10° C. during the next 1 h, and the solution was left at 10° C. for the next 4 h. The mixture was cooled to 0 to 5° C., diluted with EA, and water was added (15 mL). The solution was washed H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which dissolved in 25% CH₃CN/H₂O. The residue was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give a mixture of two isomers of compound 31 (17.5 mg). MS: m/z 546.05 [M−H]⁻.

Example 14

Compound 27

To a solution of compound 25 (139 mg, 0.5 mmol) in pyridine (5 mL) was added BzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T. for 5 h, diluted with EtOAc and washed with 1N HCl solution. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 27-1 (274 mg, 79%) as a white solid.

To a solution of 27-1 (490 mg, 1 mmol), DMAP (244 mg, 2 mmol) and TEA (205 mg, 2.1 mmol) in MeCN (10 mL) were added TPSCl (604 mg, 2 mmol) at 0° C. The mixture was stirred at R.T. for 2 h., and then NH₄OH aq. was added at R.T. The mixture was stirred for 0.5 h, diluted with EtOAc and washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 27-2 (250 mg, 41%) as a white solid.

Compound 27-2 (250 mg, 0.51 mmol) was dissolved in NH₃/MeOH (15 mL). The mixture was stirred at R.T. for 5 h. and then concentrated at low pressure. The residue was purified by silica gel column (5% DCM in DCM) to give compound 27 (95 mg, 66%) as a white powder. ESI-MS: m/z 278.1 [M+H]⁺.

Example 15

Compound 29

To a solution of compound 29-1 (30 g, 0.08 mol) in anhydrous THF (300 mL) was added a solution of lithium tri-tert-butoxyaluminohydride (120 mL, 0.12 mol) dropwise at −78° C. under N₂. The mixture was stirred at −20° C. for 1 h. The reaction was quenched with sat. aq. NH₄Cl and then filtered. The filtrate was extracted with EA (3×300 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 29-2 (26 g, 86%) as a colorless oil.

To a stirred solution of PPh₃ (37.7 g, 0.144 mol) in DCM (100 mL) was added compound 29-2 (27 g, 0.072 mol) at −20° C. under N₂. After the mixture was stirred at R.T. for 15 mins, CBr₄ (42 g, 0.129 mol) was added while maintaining the reaction temperature between −25 and −20° C. under N₂. The mixture was then stirred below −17° C. for 20 mins. Silica gel was added into the solution, and then purified by flash silica gel column separation to give the crude oil product. The crude was purified by silica gel column (EA in PE from 2% to 20%) to give 29-3 (α-isomer, 17 g, 55%) as a colorless oil.

A mixture of 6-Cl-guanine (11.6 g, 68.8 mmol) and t-BuOK (8.2 g, 73 mmol) in t-BuOH (200 mL) and MeCN (150 mL) was stirred at 35° C. for 30 mins, and then 29-3 (10 g, 22.9 mmol) in MeCN 100 mL) was added at R.T. The mixture was heated at 50° C. overnight. The reaction was quenched with a solution of NH₄Cl (5 g) in water (40 mL), and the mixture was filtered. The filtrate was evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-4 (6 g, 42%) as a yellow solid.

To a solution of 29-4 (12.5 g, 23.8 mol) in DCM (50 mL) was added AgNO₃ (8.1 g, 47.6 mmol), collidine (5.77 g, 47.6 mmol) and MMTrCl (11 g, 35.7 mmol). The mixture was stirred at R.T. overnight. The reaction was quenched with MeOH (5 mL), filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give the intermediate (16 g, 86%) as a yellow solid. To a solution of HOCH₂CH₂CN (4.7 g, 66 mmol) in THF (200 mL) was added NaH (3.7 g, 92 mmol) at 0° C. The mixture was stirred at R.T. for 30 mins. A solution of the intermediate (10.5 g, 13 mmol) in THF (50 mL) was added, and the reaction mixture was stirred at R.T. for 12 h. The reaction was quenched with MeOH (2 mL), diluted with EA (100 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 29-5 (5.8 g, 77%) as a yellow solid.

To a solution of PPh₃ (7.0 g, 26.6 mmol) in anhydrous pyridine (100 mL) was added I₂ (6.3 g, 24.9 mmol), and stirred at R.T. for 30 mins. The mixture was treated with a solution of 29-5 (9.5 g, 16.6 mmol) in pyridine (40 mL). The mixture was stirred at R.T. overnight. The reaction was quenched with sat. Na₂S₂O₃ solution, and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 29-6 (7 g, 66%) as a yellow solid.

To a solution of 29-6 (7.5 g, 11 mmol) in dry THF (50 mL) was added DBU (5.4 g, 33 mmol), and the mixture was heated to reflux for 4 h. The mixture was diluted with EA (3×100 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 29-7 (4.0 g, 67%) as a white solid.

To an ice-cooled solution of 29-7 (3.0 g, 5.4 mmol) in anhydrous MeCN (20 mL) was added TEA.3HF (0.65 g, 4.1 mmol) and NIS (1.53 g, 6.78 mmol) at R.T., and the reaction mixture was stirred at R.T. for 2 h. The mixture was diluted with EA (50 mL), and washed with sat. Na₂S₂O₃ solution and NaHCO₃aq. The organic layer was dried over anhydrous Na₂SO₄, and concentrated to dryness at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to separate the two isomers (about 1:1). NOE showed the polar one was 29-8 (0.6 g, 16%) as a white solid.

To a solution of 29-8 (0.7 g, 1 mmol) in dry pyridine (10 mL) was added BzCl (147 mg, 1.05 mmol) at 0° C. The mixture was stirred at R.T. for 3 h. The mixture was then diluted with EA, and washed with sat. NaHCO₃aq. and brine. The organic layer was dried over Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-9 (0.65 g, 81%) as a white solid.

To a solution of 29-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was added NaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture was stirred at 100° C. for 48 h. The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 mL), and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-10 (500 mg, 78%) as a white solid.

Compound 29-10 (400 mg, 0.5 mmol) in NH₃/MeOH (7N, 100 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (5% MeOH in DCM) to give 29-11 (220 mg, 63%) as a white solid. ESI-MS: m/z 590.3 [M+H]⁺.

Compound 29-11 (59 mg, 0.1 mmol) was dissolved in 50% TFA in methanol (10 mL), and the mixture was kept at R.T. for 2 h. The solvent was evaporated and co-evaporated with a methanol/toluene mixture to remove traces of the acid. The residue was suspended in CH₃CN (1 mL) and centrifuged. The precipitate was washed with CH₃CN (1 mL) and dried. Compound 29 was obtained as a colorless solid (21 mg, 65%. MS: m/z 316.2 [M−1]⁻.

Example 16

Compounds 42 and 43

A freshly prepared EtONa in dry EtOH (2N, 150 mL) was added to a solution of 29-4 (13.67 g, 17.15 mmol) in EtOH (50 mL) at 0° C. The mixture was stirred at R.T. for 1 h, and then concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 42-1 (10 g, 98%) as a yellow solid.

To a solution of PPh₃ (2.73 g, 10.4 mol) in anhydrous pyridine (60 mL) was added I₂ (2.48 g, 9.76 mmol) at R.T., and the reaction mixture was stirred R.T. for 30 mins. A solution of 42-1 (3.9 g, 6.51 mmol) in pyridine (10 mL) was added. The mixture was stirred at R.T. overnight. The reaction was quenched with sat. Na₂S₂O₃ solution and NaHCO₃aq., and then extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (2% MeOH in DCM) to give 42-2 (3.0 g, 75%) as a yellowed solid.

To a solution of 42-2 in dry THF (300 mL) was added DBU (14.0 g, 91.8 mmol), and the mixture was heated to reflux for 3 h. The mixture was concentrated at low pressure. The residue was dissolved in EA (100 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 42-3 (0.6 g, 37.5%) as a white solid.

To an ice-cooled solution of 42-3 (2.0 g, 3.44 mmol) in anhydrous MeCN (20 mL) was added NIS (0.975 g, 4.3 mmol) and TEA.3HF (0.82 g, 5.16 mmol) at 0° C. The mixture was stirred at R.T. for 2 h. The reaction was quenched with sat. Na₂SO₃ and NaHCO₃ aqueous solution, and then concentrated at low pressure. The residue was dissolved in EA (50 mL), washed with brine, dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 42-4 (1.5 g, 60%) as a white solid.

To a solution of 42-4 (1 g, 1.37 mmol) in dry pyridine (100 mL) was added BzCl (0.23 g, 1.65 mmol) at 0° C. The reaction was stirred for 30 mins and checked by LCMS. The mixture was concentrated at low pressure, and the residue was dissolved in EA (50 mL). The solution was washed with brine. The organic layer was dried over MgSO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (10% EA in PE) to give 42-5 (0.9 g, 78%) as a white solid.

To a solution of 42-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz (3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at 95° C. for 72 h. The mixture was then diluted with EA (100 mL), and washed with water and brine. The organic phase was dried over MgSO₄, and concentrated at low pressure. The residue was purified by silica gel column (15% EA in PE) to give 42-6 (1.5 g, 75%) as a white solid.

Compound 42-6 (1.35 g, 1.64 mmol) in NH₃/MeOH (150 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (5% MeOH in DCM) to give 42-7 (0.9 g, 90%) as a white solid. ESI-MS: m/z 618.3 [M+H]⁺.

To a solution of 42-7 (99 mg, 0.16 mmol) in DCM (1.0 mL), triethylamine (92.7 μL, 0.64 mmol) was added at R.T. The mixture was cooled to 0 to 5° C. (ice/water bath), and freshly prepared and distilled isopropyl phosphorodichloridate (36.6 μL, 0.2 mmol, prepared according to a procedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) was added to the mixture. The mixture was stirred 0 to 5° C. (ice/water bath) for 15 mins, followed by addition of N-methylimidazole (26.3 μL, 0.32 mmol). The mixture was then stirred for 1 h at 0 to 5° C. TLC showed absence of 42-7. EA (100 mL) was added, followed by water. The organic layer was washed H₂O, saturated aqueous NH₄Cl solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 10% iPrOH/DCM to give a mixture of 42-a and 42-b (61.5 mg).

A mixture of 42-a and 42-b (61.5 mg, 0.085 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (64 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give compound 42 (1.8 mg) and compound 43 (14.5 mg).

Compound 42: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 8.0 (s, 1H), 6.69 (d, J=16.0 Hz, 1H), 5.9-5.6 (br s, 1H), 4.94-4.85 (m, 1H), 4.68-4.52 (m, 3H), 1.49-1.3 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.8 (s), −160.06 (s); ³¹P NMR (CD₃OD-d₄) δ −7.97 (s). ESI-LCMS: m/z=450.1 [M+H]⁺; Compound 43: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.96 (s, 1H), 6.68 (s, 1H), 6.69 (d, J=16.8 Hz, 1H), 6.28-6.1 (br s, 1H), 4.81-4.5 (m, 4H), 1.45-1.39 (m, 12H); ³¹P NMR (CD₃OD-d₄) δ −5.84 (s). ESI-LCMS: m/z=450.0 [M+H]⁺.

Example 17

Compounds 32 and 33

To a solution of 42-7 (0.47 g, 0.65 mol) in DCM (3 mL) was added AgNO₃ (0.22 g, 1.29 mmol), collidine (0.15 g, 1.29 mmol) and MMTrCl (0.3 g, 0.974 mmol) at 0° C. The mixture was stirred at R.T. overnight. The mixture was filtered, and the filter was washed with sat. aq. NaHCO₃ solution and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column to give 32-1 (0.55, 85%) as a white solid.

To a solution of 32-1 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was added NaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirred at 95° C. for 72 h. The mixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO₄ and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 32-2 (0.3 g, 60%) as a white solid.

Compound 32-2 (0.3 g, 0.3 mmol) in NH₃/MeOH (30 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (20% EA in PE) to give 32-3 (145 mg, 56%) as a white solid. ESI-LCMS: m/z 890.5 [M+H]⁺.

To a stirred solution of 32-3 (161 mg, 0.16 mmol) in anhydrous CH₃CN (2.0 mL) was added N-methylimidazole (118 μL, 2.87 mmol) at 0 to 5° C. (ice/water bath) followed by solution of 32-4 (186 mg, 0.54 mmol, dissolved in 2 mL of CH₃CN). The solution was stirred at 0 to 5° C. for 4 h. The mixture was diluted with EA, and water was added (15 mL). The solution was washed H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give as 32-5 (82.6 mg) as the faster eluting isomer and 32-6 (106 mg) as the slower eluting isomer.

Compound 32-5 (82.6 mg, 0.07 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (35 μL) was added at 0 to 5° C. The mixture was stirred at R.T. for 1 h, and anhydrous EtOH (100 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, and purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give compound 32 (19.4 mg). ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.9 (s, 1H), 7.32-7.28 (t, J=8.0 Hz, 2H), 7.2-7.12 (m, 3H), 6.43 (d, J=17.6 Hz, 1H), 4.70-4.63 (m, 2H), 4.55-4.4 (m, 3H), 3.94-3.9 (m, 1H), 1.79-1.67 (m, 4H), 1.53-1.49 (m, 1H), 1.45-1.22 (m, 15H); ³¹P NMR (CD₃OD-d₄) δ 4.06 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.15 [M−H]⁻.

Compound 32-6 (100 mg, 0.083 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (50 μL) was added at 0 to 5° C. Following the procedure for obtaining compound 32, compound 33 (31.8 mg) was obtained. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.93 (s, 1H), 7.33-7.29 (m, 2H), 7.24-7.14 (m, 3H), 6.41 (d, J=17.6 Hz, 1H), 4.70-4.60 (m, 2H), 4.54-4.49 (m, 2H), 4.44-4.39 (m, 1H), 3.92-3.89 (m, 1H), 1.77-1.66 (m, 4H), 1.54-1.24 (m, 16H); ³¹P NMR (CD₃OD-d₄) 33.91 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.1 [M−H]⁻.

Example 18

Compound 53

Compound 53-1 (70 mg, 58%) was prepared from 32-3 (90 mg; 0.1 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.2 mmol) with DIPEA (87 μL), BopCl (44 mg), and 3-nitro-1,2,4-triazole (29 mg) in THF (2 mL) according to a method described for compound 51-2. Purification was done with hexanes/EtOAc solvent system, 20-80% gradient.

Compound 53 (25 mg, 64%) was prepared from 53-1 (70 mg) in acetonitrile (0.6 mL) and 4 N HCl/dioxane (50 μL) according to a method described for compound 51. MS: m/z=658 [M+1]⁺.

Example 19

Compounds 40 and 41

To a mixture of pre-silylated 6-Cl-guanine (using HMDS and (NH₄)₂SO₄) (25.2 g, 150 mmol) in DCE (300 mL) was added 40-1 (50 g, 100 mmol) and TMSOTf (33.3 g, 150 mmol) at 0° C. The mixture was stirred at 70° C. for 16 h, and then concentrated at low pressure. The residue was re-dissolved in EA, and washed with sat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified on silica gel column (PE/EA=2/1) to give pure 40-2 (45 g, 73%) as a white solid.

To a solution of 40-2 (45 g, 73.4 mmol) in EtOH (73 mL) was added with EtONa (1N in EtOH, 360 mL). The mixture was stirred at R.T. for 16 h. The mixture was then concentrated to give a residue, which was purified by silica gel column (DCM/MeOH=10/1) to give pure 40-3 (19 g, 83%) as a white solid.

To a solution of 40-3 (19 g, 61.1 mmol) in pyridine (120 mL) was added with TIPDSCl₂ (19.2 g, 61 mmol) dropwise at 0° C. The mixture was stirred at R.T. for 16 h, and then concentrated at low pressure. The residue was re-dissolved in EA, and washed with sat. aq. NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=20/1) to give pure 40-4 (22 g, 65%) as a white solid.

To a solution of 40-4 (22 g, 39.8 mmol) in DMF/pyridine (5/1, 100 mL) was added TMSCl (12.9 g, 119 mmol) dropwise at 0° C. The mixture was stirred at R.T. for 1 h and then treated with isobutyryl chloride (5.4 g, 50 mmol). The mixture was stirred at R.T. for 3 h and then quenched by NH₄OH. The mixture was concentrated at low pressure. The residue was dissolved in EA (200 mL). The solution was washed with sat. aq. NaHCO₃, and then the organic layer was dried and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=50/1) to give pure 40-5 (15 g, 60%) as a white solid.

To a solution of 40-5 (15 g, 24.1 mmol) in DCM (100 mL) was added PDC (13.5 g, 26 mmol) and Ac₂O (9.8 g, 96 mmol) at 0° C. The mixture was stirred at R.T. for 16 h. The reaction was quenched by sat. aq. NaHCO₃, and then extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was dissolved in anhydrous THF (100 mL). To a solution of TMSCCH (12 g, 112 mmol) in THF (200 mL) was added n-BuLi (2.5 N, 44 mL) at −78° C. The mixture was stirred at −78° C. for 15 mins and 0° C. for 15 mins. The mixture was treated with a solution of crude ketone in THF at −78° C. and stirred at −30° C. for 2 h. The reaction was quenched by sat. aq. NH₄Cl, and then extracted by EA. The combined organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=10/1) to give pure 40-6 (3.1 g, 18%) as a white solid.

To a solution of 40-6 (7 g, 7.5 mmol) and pyridine (1.4 g, 17 mmol) in DCM (35 mL) was added with DAST (5.6 g, 35 mmol) at −78° C. The mixture was stirred at −78° C. for 3 h. The reaction was quenched by sat. aq. NaHCO₃, and then extracted with EA. The combined organic layer was dried over anhydrous, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=10/1) to give pure 40-7 (3.1 g, 18%) as a white solid.

Compound 40-7 (4.1 g, 5.7 mmol) in sat. NH₃/MeOH (100 mL) was stirred at R.T. for 16 h, and concentrated at low pressure. The residue was re-dissolved in anhydrous DCM (300 mL), and was treated with AgNO₃ (27.0 g, 160 mmol), collidine (22 mL) and MMTrCl (23.0 g, 75.9 mmol) in small portions under N₂. The mixture was stirred at R.T. for 16 h. The mixture was filtered, and the filtrate was washed with sat. NaHCO₃ solution and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=10/1) to give the pure intermediate. The intermediate was dissolved in a solution of TBAF/THF (1N, 20 mL). The mixture was stirred at R.T. for 2 h and then concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH=50/1) to give pure 40-8 (3.0 g, 86%) as a white solid.

To a solution of 40-8 (3.0 g, 4.9 mmol) in THF (50 mL) was added imidazole (840 mg, 12 mmol), PPh₃ (3.2 g, 12 mmol), and I₂ (2.4 g, 9.2 mmol) at 0° C. The mixture was stirred at R.T. for 16 h. The reaction was quenched by sat. aq. Na₂S₂O₃, and then extracted with EA. The combined organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=2/1) to give crude 40-9 (4.2 g, >100%, containing TPPO) as a white solid.

To a solution of crude 40-9 in anhydrous THF (30 mL) was added DBU (2.7 g, 18 mmol), and heated to 80° C. The mixture was stirred for 1 h and checked by LCMS. The mixture was quenched by water, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated at low pressure. The residue was purified by silica gel column (PE/EA=2/1) to give 40-10 (2.0 g, 69%) as a white solid.

To an ice-cooled solution of 40-10 (2.0 g, 3.38 mmol) in anhydrous MeCN (15 mL) was added NIS (777 mg, 3.5 mmol) and NEt₃.3HF (536 g, 3.3 mmol) at 0° C. The mixture was stirred at R.T. for 16 h and checked by LCMS. After completion, the mixture was quenched by sat. Na₂SO₃ and sat. NaHCO₃ solution, and extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by silica gel column chromatography (PE/EA=10/1 to 3/1) to give 40-11 (2.1 g, 84.0%) as a white solid.

To a solution of crude 40-11 (2.1 g, 2.85 mmol) in anhydrous DCM (100 mL) was added DMAP (490 mg, 4 mmol), and BzCl (580 mg, 4 mmol) at 0° C. The mixture was stirred overnight and checked by LCMS. The reaction was washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (PE/EA=8/1 to 3/1) to give 40-12 (2.0 g, 83.4%) as a white solid.

To a solution of 40-12 (2.0 g, 2.4 mmol) in anhydrous DMF (60 mL) was added NaOBz (3.3 g, 23.0 mmol) and 15-crown-5 (5.11 g, 23 mmol). The mixture was stirred at 110° C. for 36 h. The reaction was quenched by water, and the mixture was extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA=5/1 to 3/1) to give 40-13 (830 mg, 42.0%) as a white solid. ESI-MS: m/z 836.11 [M+H]⁺.

A solution of 40-13 (831 mg, 1.0 mmol) in anhydrous n-butylamine (4 mL) was stirred at R.T. for 3 h under N₂ atmosphere. The reaction was monitored by TLC. The solvent was evaporated in vacuo, and the residue was purified by silica gel column (MeOH in DCM from 0% to 10%) to give the crude product, which as re-purified using silica gel column to give 40-14 as a light pink solid (563 mg).

To a solution of 40-14 (560 mg, 0.89 mmol) in anhydrous pyridine (5 mL) was added imidazole (78.6 mg, 1.16 mmol) and TBSCl (202 mg, 1.34 mmol) at 0 to 5° C. The mixture was stirred at R.T. for 15 h. The reaction was quenched by adding absolute EtOH (0.3 mL). The solution was concentrated to dryness under reduced pressure, and co-evaporated with toluene 3 times. The residue was dissolved in EA (150 mL), and washed with water, sat. NaHCO₃, and brine. The combined organic layer was dried over Na₂SO₄, filtered and evaporated at low pressure. The residue was purified by silica gel column (0-20% EA in hexanes) to give 40-15 (303 mg) as a white solid.

To a solution of 40-15 (303 mg, 0.41 mmol), AgNO₃ (208 mg, 1.23 mmol) and collidine (0.55 mL, 4.51 mmol) in anhydrous DCM (4 mL) was added MMTrCl (378 mg, 1.3 mmol) under N₂. The mixture was stirred at R.T. overnight under N₂, and monitored by TLC. The mixture was filtered through pre-packed celite filter, and the filtrate was washed with water and, 50% aqueous citric acid, and brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by silica gel column (EA in hexanes from 0% to 30%) to give 40-16 (374 mg, 90%).

To a solution of 40-16 (374 mg, 0.37 mmol) in anhydrous THF (4 mL) was added 1.0 M solution of TBAF (0.74 mL, 0.74 mmol) at 0 to 5° C. The mixture was stirred at R.T. for 1 h. The mixture was quenched with silica gel, and filtered. The solvents were evaporated to give the crude product, which was purified by silica gel column (EA in hexanes from 0% to 50%) to give 40-17 (265 mg).

To a stirred solution of 40-17 (187.5 mg, 0.16 mmol) in anhydrous CH₃CN (2.5 mL) was added N-methylimidazole (136 μL, 1.66 mmol) at 0-5° C. (ice/water bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (214 mg, 0.62 mmol, dissolved in 0.5 mL of CH₃CN). The solution was stirred at R.T. for 3 h, and then diluted with EA followed by the addition of water (15 mL). The solution was washed with H₂O, 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give (single isomers) of 40-18 (108 mg) Elution of the latter fraction gave (single isomers) of 40-19 (120 mg) as glassy solid.

Compound 40-18 (108 mg, 0.089 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give compound 40 (26.6 mg) as a white foam. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.89 (s, 1H), 7.33-7.29 (m, 2H), 7.20-7.13 (m, 3H), 7.17 (m, 1H), 6.62 (d, J=15.6 Hz, 1H), 5.39 (t, J=25.2 Hz, 1H), 4.75-4.42 (m, 6H), 3.92 (t, J=8.8 Hz, 1H), 3.24 (d, J=5.6 Hz, 1H), 1.76-1.51 (m, 5H), 1.45-1.25 (m, 12H); ³¹P NMR (CD₃OD-d₄) 34.04 (s); ESI-LCMS: m/z=665.2 [M+H]⁺.

Compound 41 (44.4 mg, single isomer) was obtained according to the procedure described for compound 40 using 40-19. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.93 (s, 1H)), 7.32 (t, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 2H), 7.16 (t, J=7.6 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 4.68-4.60 (m, 2H), 4.54-4.39 (m, 3H), 3.93-3.89 (m, 1H), 3.24 (d, J=5.6 Hz, 1H), 1.75-1.5 (m, 5H), 1.48-1.23 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.95 (s), −155.84-155.99 (m); ³¹P NMR (CD₃OD-d₄) 33.94 (s); ESI-LCMS: m/z=665.15 [M+H]⁺.

Example 20

Compound 49

To a solution of triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.33 mmol, prepared from 110 mg of bis(POC)phosphate and 46 μL of Et₃N) in THF was added 49-1 (91 mg, 0.11 mmol). The mixture evaporated and rendered anhydrous by co-evaporating with pyridine follow by toluene. The residue was dissolved in anhydrous THF (1.5 mL) and cooled in an ice-bath. Diisopropylethyl amine (0.19 mL, 10 eq.) was added, followed by BOP—Cl (0.14 g, 5 eq.), and 3-nitro-1,2,4-triazole (63 mg, 5 eq.). The mixture was stirred 0° C. for 90 mins, diluted with EtOAc (30 mL), washed with sat. aq. NaHCO₃, brine, and dried (Na₂SO₄). The residue was purified on silica (10 g column) with CH₂Cl₂/i-PrOH solvent system (2-10% gradient) to obtain 49-2 (13 mg, 10%) and 49-3 (95 mg, 58%).

A solution of 49-2 and 49-3 (13 mg and 95 mg, respectively) in 80% aq. HCOOH (3 mL) was stirred at R.T. for 3 h, then evaporated and co-evaporated with toluene. The residue was purified on silica (10 g column) with CH₂Cl₂/MeOH (4-10% gradient) to obtain compound 49 in (42 mg, 94%) yield. MS: m/z=628 [M+1]⁺.

Example 21

Compound 52

Compound 52-2 (158 mg, 50%) was from 52-1 (0.21 g; 0.35 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.54 mmol) with DIPEA (0.18 mL), BopCl (178 mg), and 3-nitro-1,2,4-triazole (80 mg) in THF (4 mL).

A solution of 52-2 (158 mg) in acetonitrile (1 mL) and HCl (4 N/dioxane; 85 μL) was stirred at R.T. for 30 mins. The reaction was quenched with MeOH and concentrated. The residue was purified on silica gel (10 g column) with CH₂Cl₂/i-PrOH (3-10% gradient) to give compound 52 (85 mg, 76%). MS: m/z=656 [M+1]⁺.

Example 22

Compound 11

A mixture of 11-1 (170 mg, 0.19 mmol) and methanolic ammonia (7 N; 3 mL) was stirred at R.T. for 8 h, concentrated and purified on silica gel (10 g column) with CH₂Cl₂/MeOH (4-11% gradient) to give 11-2 (100 mg, 90%).

Compound 11-2 was rendered anhydrous by co-evaporating with pyridine, followed by toluene. To a solution of 11-2 (24 mg, 0.04 mmol), and N-methylimidazole (17 μL, 5 eq.) in acetonitrile (1 mL) was added the phosphorochloridate (50 mg, 3.5 eq.) in 2 portions in 6 h intervals. The mixture was stirred at R.T. for 1 d and evaporated. Purification on silica (10 g column) with CH₂Cl₂/MeOH (4-12% gradient) yielded 11-3 (10 mg, 28%).

A solution of 11-3 (9 mg, 0.01 mmol) in 80% formic acid was stirred 3 h at R.T. The mixture was evaporated and purified on silica (10 g column) with CH₂Cl₂/MeOH (5-15% gradient) to give compound 11 (3 mg, 50%). MS: m/z=624 [M−1]⁻.

Example 23

Compound 14

A mixture of 14-1 (1.2 g, 4.3 mmol), PTSA monohydrate (0.82 g, 1 eq.), and trimethyl orthoformate (14 mL, 30 eq.) in dioxane (30 mL) was stirred overnight at R.T. The reaction was neutralized with 7 N NH₃/MeOH and a white solid removed by filtration. The residue was dissolved in THF (10 mL) and treated with 80% aq. AcOH (5 mL). The mixture was kept at R.T. for 45 mins and then evaporated. The residue was purified on silica gel (25 g column) with CH₂Cl₂/MeOH (4-10% gradient) to give 14-2 (1.18 g, 87%).

Compound 14-3 (137 mg, 75%) was prepared from 14-2 (93 mg, 0.29 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.44 mmol) with DIPEA (0.2 mL), BopCl (147 mg), and 3-nitro-1,2,4-triazole (66 mg) in THF (3 mL). Purification was done with CH₂Cl₂/i-PrOH solvent system (3-10% gradient).

A solution of 14-3 (137 mg) in 80% aq. HCOOH was stirred at R.T. for 2 h, and then concentrated. The residue was co-evaporated with toluene and then MeOH containing a small amount of a small amount of Et₃N (2 drops). Purification on silica (25 g column) with CH₂Cl₂/MeOH (4-10% gradient) gave compound 14 (100 mg, 77%). MS: m/z=1175 [2M−1]⁻.

Example 24

Compound 16

Compound 16-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixture was stirred at 0° C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 mins. The mixture was heated to 70° C., and stirred overnight. The solution was cooled to R.T. and diluted with EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 16-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]⁺.

To a solution of 16-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) and collidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g, 149.2 mmol) in small portions under N₂. The mixture was stirred at R.T. for 3 h under N₂. The reaction was monitored by TLC. The mixture was filtered, and the filter was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (EA in PE from 5% to 50%) to the give crude 16-3 (68 g, 98%). ESI-MS: m/z 900.1 [M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C., and slowly warmed to R.T. Compound 16-3 (68.0 g, 75.6 mmol) was treated with freshly prepared NaOEt solution, and stirred overnight at R.T. The reaction was monitored by TLC, and the mixture was concentrated at low pressure. The mixture was diluted with H₂O (100 mL), and extracted with EA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 16-4 (34.0 g, 75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 16-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrous pyridine 3 times. To an ice-cooled solution of 16-4 in anhydrous pyridine (100 mL) was added TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL) dropwise at 0° C. The mixture was stirred for 18 h. at 0° C. The reaction was checked by LCMS (about 70% was the desired product). The reaction was quenched with H₂O, and the solution was concentrated at low pressure. The residue was dissolved in EA (100 mL), and washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give crude 16-5 (25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 16-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was added NaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and refluxed overnight. The reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated at low pressure. The residue was dissolved in EA (100 mL), washed with brine, and dried over anhydrous Na₂SO₄. The organic solution was evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give the crude product. To a solution of the crude product in dry THE (200 mL) was added DBU (14.0 g, 91.8 mmol), and heated to 60° C. The mixture was stirred overnight, and checked by LCMS. The reaction was quenched with sat. NaHCO₃, and the solution was extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 16-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580 [M+H]⁺.

To an ice-cooled solution of 16-6 (8.0 g, 13.8 mmol) in dry MeCN (100 mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol) at 0° C. The mixture was stirred at R.T. for 18 h and checked by LCMS. After the reaction was complete, the reaction was quenched with sat Na₂SO₃ and sat. NaHCO₃ solution. The solution was extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 50%) to give 16-7 (7.2 g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]⁺.

To a solution of crude 16-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was added DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. The mixture was stirred overnight, and checked by LCMS. The mixture was washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give 16-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 16-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 16-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 16-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene 3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS, and the mixture was concentrated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 16-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 16-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydrous toluene 3 times, and was dissolved in MeCN (2 mL). The mixture was treated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridate reagent (338.1 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS. The mixture was diluted with 10% NaHCO₃ solution, and extracted with EA. The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 16-11 (240 mg, 53.3%) as a solid. ESI-MS: m/z 925 [M+H]⁺.

Compound 16-11 (240.0 mg, 0.26 mmol) was treated with 80% AcOH (10 mL), and the mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS. The mixture was concentrated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 3%) to give compound 16 (87.6 mg, 51.7%) as a solid. ESI-MS: m/z 653 [M+H]⁺.

Example 25

Compound 30

To a stirred solution of compound 25 (60 mg, 0.22 mmol) in anhydrous THF (2.0 mL) was added N-methylimidazole (0.142 mL, 1.73 mmol) at 0° C. (dry ice/acetone bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (235 mg, 0.68 mmol, dissolved in THF (2 mL). The resulting solution was stirred at 0° C. for 1 h, and the temperature was raised up-to 10° C. over the next 1 h. The reaction left at 10° C. for 3 h. The mixture was cooled to 0 to 5° C., diluted with EA, and water (5 mL) was added. The solution was washed with H₂O and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which dissolved in 25% CH₃CN/H₂O. The compound was purified on a reverse-phase HPLC (C18) using acetonitrile and water, followed by lyophilization gave a white foam. The produce was re-dissolved in EtOAc, washed with 50% aqueous citric acid solution, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum, and lyophilized to give two isomers (Rp/Sp) of compound 30 (6.3 mg). MS: m/z 586.05 [M−H]⁻.

Example 26

Compound 17

Compound 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixture was stirred at 0° C. for 30 mins, and TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 mins until a clear solution was observed. The mixture was heated to 70° C., and stirred overnight. The solution was cooled to R.T., and diluted with EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 17-2 (48.0 g, 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]⁺.

To a solution of 17-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) and collidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g, 149.2 mmol) in small portions under N₂. The mixture was stirred at R.T. for 3 h under N₂. Completion of the reaction was determined by TLC. After filtration, the filtrate was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column (EA in PE from 5% to 50%) to the give crude 17-3 (68 g, 98%). ESI-MS: m/z 900.1 [M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C., and slowly warmed to R.T. Compound 17-3 (68.0 g, 75.6 mmol) was treated with freshly prepared NaOEt solution, and stirred overnight at R.T. Completion of the reaction was determined by TLC and LCMS. The mixture was concentrated at a low pressure, diluted with H₂O (100 mL), and extracted with EA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 17-4 (34.0 g, 75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 17-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrous pyridine 3 times. To an ice-cooled solution of 17-4 (32.0 g, 53.5 mmol) in anhydrous pyridine (100 mL) was added a solution of TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL) dropwise at 0° C. The mixture was stirred for 18 h. at 0° C. The reaction was monitored by LCMS, and quenched with H₂O. The solution was concentrated at low pressure, and the residue was dissolved in EA (100 mL), and washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at a low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give crude 17-5 (25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 17-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was added NaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and the mixture was refluxed overnight. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was dissolved in EA (100 mL). The solution was washed with brine, and dried over anhydrous Na₂SO₄. The organic solution was evaporated at low pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give a crude product. To a solution of the crude product in dry THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and the mixture was heated to 60° C. and stirred overnight. The reaction was monitored by LCMS. The reaction was quenched with sat. NaHCO₃ solution, and the solution was extracted with EA (100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 17-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580 [M+H]⁺.

To an ice-cooled solution of 17-6 (8.0 g, 13.8 mmol) in anhydrous MeCN (100 mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol) at 0° C. The mixture was stirred at R.T. for 18 h, and the reaction was checked by LCMS. After the reaction was completed, the reaction was quenched with sat. Na₂SO₃ solution and sat. NaHCO₃ solution. The solution was extracted with EA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 50%) to give 17-7 (7.2 g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]⁺.

To a solution of 17-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was added DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. The mixture was stirred overnight, and checked by LCMS. The mixture was washed with sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give 17-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 17-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 17-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 17-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene 3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture was stirred for 18 h. at R.T. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give product 17-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 17-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydrous toluene 3 times, and was dissolved in MeCN (2 mL). The mixture was treated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridate reagent (326.3 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture was stirred for 18 h at R.T. and monitored by LCMS. The mixture was diluted with 10% NaHCO₃ solution, and extracted with EA (3×30 mL). The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 17-11 (210 mg, 47.5%) as a solid. ESI-MS: m/z 913.0 [M+H]⁺.

Compound 17-11 (210 mg, 0.26 mmol) was treated with 80% of AcOH (15 mL), and the mixture was stirred for 18 h at R.T. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 3%) to give compound 17 (71.8 mg, 48.7%) as a solid. ESI-MS: m/z 641.3 [M+H]⁺.

Example 27

Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and 76

Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and 76 were prepared in a manner similar to method for preparing compound 6. After the addition of POCl₃, the mixture was kept at R.T. for 20-40 mins. The reaction was controlled by LCMS and monitored by the appearance of corresponding nucleoside 5′-monophosphate. After completion of the reaction, tetrabutylammonium salt of pyrophosphate (150 mg) was added, followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 h at ambient temperature, the reaction was diluted with water (10 mL). The triphosphate (eluted at 75-80% B) were obtained as described for compound 6.

	MS	31P NMR
Structure	[M − 1]−	P(α)	P(β)	13(γ)
	556.2	−10.92 −11.03(d)	−23.18(t)	−11.86 −11.98(d)
	516.1	−7.49 −7.61(d)	−22.42(t)	−12.17 −12.30(d)
	554.0	−10.94 −11.06(d)	−23.25(t)	−11.85 −11.97(d)
	525.2	−8.53(bs)	−22.61 (bs)	−12.17 −12.29(d)
	564.4	−11.05 (bs)	−23.25 (bs)	−11.96 −12.08(d)
	566.0	−10.92 −11.04(d)	−23.18(t)	−11.93 −1(d)
	533.3	−10.89 −11.01(d)	−23.31(t)	−12.49 −1(d)
	513.8	−8.66(bs)	−22.80(t)	−12.17 −12.29(d)
	517.7	−13.73 −13.60(d)	−25.98(t)	−15.18 −15.06(d)
	539.5	−7.42 (br.s)	−22.57(t)	−12.23 −12.34(d)
	513.1	−6.36 −6.49(d)	−22.49(t)	−12.20 −12.33(d)
	526.8	−10.96 −11.08(d)	−23.33(t)	−12.41 −12.53(d)
	533.4	−10.78 (br.s)	−23.22(t)	−12.24 −12.36(d)

The following compounds can also be prepared using a method similar to the method described in Example 27:

Example 28

Compound 10

Compound 10-1 (5 g, 8.79 mmol) was co-evaporated with anhydrous pyridine. To an ice-cooled solution of 10-1 in anhydrous pyridine (15 mL) was added TsCl (3.43 g, 17.58 mmol), and stirred for 1 h at 0° C. The reaction was checked by LCMS and TLC. The reaction was quenched with H₂O, and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄, and evaporated at low pressure. Compound 10-2 (6.35 g, 100%) was used for next step directly.

To a solution of 10-2 (31.77 g, 43.94 mmol) in acetone (300 mL) was added NaI (65.86 g, 439.4 mmol), and heated to reflux overnight. The reaction was checked by LCMS. The reaction was quenched with sat. Na₂S₂O₃ solution, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 6%) to give 10-3 (11.5 g, 38%) as a white solid.

To a solution of 10-3 (11.5 g, 16.94 mmol) in dry THF (120 mL) was added DBU (12.87 g, 84.68 mmol), and heated to 60° C. The reaction was stirred overnight and checked by LCMS. The reaction was quenched with sat. NaHCO₃ solution, and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 10-4 (5.5 g, 54%) as a white solid.

To an ice-cooled solution of 10-4 (500 mg, 0.90 mmol) in dry DCM (20 ml) was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg, 1.97 mmol) in dry DCM (20 mL). The reaction was stirred for 3 h., and checked by LCMS. The reaction was quenched with sat Na₂S₂O₃ solution and sat. NaHCO₃ solution, and the mixture was extracted with DCM. The organic layer was dried by anhydrous Na₂SO₄, and evaporated at low pressure to give crude 10-5 (420 mg, 66%).

To a solution of crude 10-5 (250 mg, 0.36 mmol) in dry DCM (8 mL) was added DMAP (0.28 g, 2.33 mmol), TEA (145 mg, 1.44 mmol) and BzCl (230 mg, 1.62 mmol) in a solution of DCM (2 mL). The reaction was stirred overnight, and checked by LCMS. The mixture was washed with sat. NaHCO₃ solution and brine. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give crude 10-6 (150 mg, 46%).

To a solution of crude 10-6 (650 mg, 0.72 mmol) in dry HMPA (20 mL) was added NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). The reaction was stirred for 2 d at 60° C. The mixture was diluted with H₂O, and extracted with EA. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give 10-7 (210 mg, 32.4%). ESI-MS: m/z: 900.4 [M+H]⁺.

A mixture of 10-7 (25 mg) and BuNH₂ (0.8 mL) was stirred overnight at R.T. The mixture was evaporated and purified on silica gel (10 g column) with CH₂Cl₂/MeOH (4-15% gradient) to yield 10-8 (15 mg, 91%).

A mixture of 10-8 (15 mg, 0.02 mmol) in ACN (0.25 mL) and 4 N HCL/dioxane (19 uL) was stirred at R.T. for 45 mins. The mixture was diluted with MeOH and evaporated. The crude residue was treated with MeCN, and the solid was filtered to yield compound 10 (7 mg). MS: m/z=314 [M−1]⁻.

Example 29

Compounds 36 and 37

To a solution of 36-1 (150 mg, 0.24 mmol) in DCM (2.0 mL), triethylamine (141 μL, 2.0 mmol) was added at R.T. The mixture was cooled to 0 to 5° C. (ice/water bath), and freshly prepared and distilled isopropyl phosphorodichloridate (45 μL, 0.26 mmol, prepared according to a procedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) was added. The mixture was stirred at 0 to 5° C. (ice/water bath) for 15 mins, followed by N-methylimidazole (40 μL, 0.49 mmol). The mixture was stirred for 1 h at 0 to 5° C. TLC showed the absence of starting material 36-1. EA (100 mL) was added, followed by water. The organic layer was washed with H₂O, sat. aq. NH₄Cl solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 10% iPrOH/DCM to give 36-2a (16.9 mg, faster eluting isomer) and 36-2b (72.7 mg, slower eluting isomer).

Compounds 36-2a and 36-2b were deprotected using a procedure described herein. Compound 36 (7.3 mg, single isomers from 36-2a (16.5 mg, 0.0235 mmol)) and compound 37 (29.0 mg. single isomers from 36-2b (72.7 mg, 0.1 mmol)) were obtained.

Compound 36: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.94 (s, 1H), 6.32 (s, 1H), 6.00-5.9 (br s, 1H), 4.9-4.487 (m, 1H), 4.83-4.77 (m, 1H), 4.65-4.50 (m, 3H), 1.45-1.39 (s, 9H), 1.2 (s, 3H); ¹⁹F NMR (CD₃OD-d₄) δ −120.3 (s); ³¹P NMR (CD₃OD-d₄) δ −5.19 (s); ESI-LCMS: m/z=448.05 [M+H]⁺. Compound 37: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.98 (s, 1H), 6.34 (s, 1H), 5.78-5.64 (br s, 1H), 4.95-4.48 (m, 2H), 4.62-4.52 (m, 3H), 1.48-1.42 (s, 9H), 1.1 (s, 3H); ¹⁹F NMR (CD₃OD-d₄) δ −121.3 (s); ³¹P NMR (CD₃OD-d₄) δ −7.38 (s); ESI-LCMS: m/z=448.05 [M+H]⁺.

Example 30

Compound 48

To a solution of 48-1 (600 mg, 1.29 mmol) in anhydrous CH₃CN (4 mL) was added DMAP (315 mg, 2.59 mmol), TEA (391 mg, 3.87 mmol) and TPSCl (782 mg, 2.58 mmol). The mixture was stirred for 3 h. under N₂. A solution of NH₃ in THF (2 mL) was added, and stirred for 1 h. The reaction was quenched with sat. NH₄Cl solution, and extracted with EA. The organic layer was dried over anhydrous Na₂SO₄, and concentrated to dryness at low pressure. The residue was purified by column chromatography to provide 48-2 (370 mg, 62%) as a white foam solid.

Compound 48-2 (370 mg, 1.48 mmol) in methanolic ammonium was stirred at R.T. for 4 h. The solution was concentrated to dryness to give compound 48 (200 mg, 91%) as a white solid. ESI-MS: m/z 275.9 [M+H]⁺.

Example 31

Compounds 18 and 19

The diastereomers of compound 2 were separated by RP-HPLC. A gradient of 10-43% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4 u particle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 19 (29.5 mins) and compound 18 (30.1 mins). Pure fractions were lyophilized to produce a white powder. Compound 19: ³¹P-NMR (DMSO-d6) 3.448 ppm; MS: m/z: 544 [M−1]⁻; Compound 18: ³¹P-NMR (DMSO-d6) 3.538 ppm; MS: m/z: 544 [M−1]⁻.

Example 32

Compounds 20 and 21

The diastereomers of compound 3 were separated by RP-HPLC. A gradient of 25-52% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4 u particle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 21 (24.8 mins) and compound 20 (25.3 mins). Pure fractions were lyophilized to produce a white powder. Compound 21: ³¹P-NMR (DMSO-d6) 3.492 ppm; MS: m/z: 584 [M−1]⁻. Compound 20: ³¹P-NMR (DMSO-d6) 3.528 ppm; MS: m/z: 584 [M−1]⁻.

Example 33

Compound 13

Compound 2-1 (32 mg, 0.1 mmol) was dissolved in dry THF (3 mL) and 2M solution of isopropylmagnesium bromide in THF (0.1 mL) was added at 0° C. The reaction was left for 1 h at R.T., and phenyl(isopropyl-L-alaninyl) thiophosphorochloridate was added (0.3 mmol). The mixture was left overnight at R.T. LSMS analysis showed about 20% of unreacted starting material. The same amount of Grignard reagent and thiophosphorochloridate were added, and the mixture was heated at 37° C. for 4 h. The reaction was quenched with NH₄Cl. The product was extracted with EA, washed with brine, dried over Na₂SO₄, and evaporated. The resulting oil was dissolved in 80% formic acid (4 mL) and in 1 h evaporated. Compound 13 was purified by RP HPLC in gradient of methanol in water from 30% to 95% on Synergy 4 u Hydro-RP column (Phenominex) yielding a colorless solid. Compound 13 (7 mg, yield 12.5%). MS: m/z: 560.0 [M−1]⁻.

Example 34

Compound 39, Bis-Lithium Salt

Compound 39-1 was synthesized using a procedure similar for preparing compound 2 using alanine benzyl ester hydrochloride. LCMS: m/z 592 [M−1]⁻.

To a solution of 39-1 (1.1 g, 1.85 mmol) in dioxane (15 mL) and water (3 mL) was added aqueous triethylammonium acetate (2M, 2 mL, 4 mmol) followed by Pd—C (10%, 100 mg). The mixture was hydrogenated (balloon) for 2 h, and monitored by HPLC. The catalyst was filtered off, and the filtrate was concentrated to dryness. The residue was suspended in 3% solution of lithium perchlorate in acetone (25 mL). The solid was isolated by filtration, rinsed with acetone and dried under vacuum to give compound 39 (bis-lithium salt) (731 mg, 90%). LCMS: m/z 426 [M−1]⁻.

Example 35

Compound 55

Compound 1 (40 mg, 0.14 mmol) and triethylammonium bis(pivaloyloxymethyl)phosphate (0.21 mmol, prepared from 80 mg of bis(pivaloyloxymethyl)phosphate and 30 μL of Et₃N) were rendered anhydrous by coevaporating with pyridine, followed by toluene. The evaporated residue was dissolved in anhydrous THF (2 mL) and cooled in an ice-bath. Diisopropylethyl amine (73 μL, 3 eq.), BopCl (71 mg, 2 eq.), and 3-nitro-1,2,4-triazole (32 mg, 2 eq.) were added. The mixture was stirred at 0° C. for 90 mins. The mixture was then diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). Purification on silica gel column with CH₂Cl₂/i-PrOH solvent system (4-10% gradient) followed by RP-HPLC purification (A: water, B: MeCN) yielded compound 55 (13 mg, 16%). MS: m/z=1167 [2M−1].

Example 36

Compound 45

Compound 45-1 (15.0 g, 25.55 mmol) was treated with 90% HOAc (150 mL) at R.T. The mixture was stirred at 110° C. for 12 h, and then concentrated at a low pressure. The residue was dissolved in DCM, and the solution was washed with brine. The organic phase was dried over anhydrous Na₂SO₄, and then concentrated at a low pressure. The residue was purified by column chromatography (5% MeOH in DCM) to give 45-2 (11.0 g, 88.9%) as a white solid.

Compound 45-2 (12.0 g, 24.79 mmol) was treated with NH₃ in MeOH (200 mL, 7 M) at R.T. The solution was stirred at R.T. for 12 h, and then concentrated at a low pressure. The residue was purified by column chromatography (10% MeOH in DCM) to give 45-3 (6.5 g, 95.0%) as a white solid.

To a stirred suspension of 45-3 (4.3 g, 15.58 mmol), PPh₃ (8.16 g, 31.15 mmol), imidazole (2.11 g, 31.15 mmol) and pyridine (15 mL) in anhydrous THF (45 mL) was added a solution of I₂ (7.91 g, 31.15 mmol) in THF (100 mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirred overnight. The mixture was quenched with MeOH (100 mL). The solvent was removed at a low pressure, and the residue was re-dissolved in a mixture of EA and THF (0.2 L, 10:1). The organic phase was washed with sat. Na₂S₂O₃ aq. (2×). The aqueous phase was extracted with a mixture of EA and THF (0.2 L, 10:1, 2×). The concentrated organic phase was dried over anhydrous Na₂SO₄. The residue was purified on a silica gel column (0-10% MeOH in DCM) to afford 45-4 (5.1 g, 85.0%) as a white solid.

Compound 45-4 (800 mg, 2.07 mmol) was dissolved in a mixture of DBU (4 mL) and THF (4 mL) at R.T. under N₂. The solution was stirred at R.T. for 1 h. The mixture was neutralized with HOAc, and extracted with a mixture of EA and THF (10:1, 40 mL). The organic phase was washed with brine, and dried over anhydrous Na₂SO₄. The concentrated organic phase was purified by column chromatography (0-10% MeOH in DCM) to give 45-5 (240 mg, 44.9%) as a white solid.

To an ice-cooled solution of 45-5 (1.20 g, 4.65 mmol) in anhydrous MeCN (12 mL) was added NIS (1.57 g, 6.97 mmol) and TEA.3HF (1.12 g, 6.97 mmol) under N₂. The mixture was stirred at R.T. for 5 h. The reaction was quenched with sat. NaHCO₃ solution, and extracted with EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (0-5% MeOH in DCM) to give 45-6 (0.91 g, 48.6%) as a white solid.

To a stirred solution of 45-6 (1.2 g, 2.97 mmol) in anhydrous DCM (12 mL) was added BzCl (0.83 g, 5.94 mmol), TEA (0.6 g, 5.94 mmol) and DMAP (0.72 g, 5.94 mmol) successively at R.T. The mixture was stirred at R.T. for 12 h. The reaction was quenched with water, and extracted with EA (3×60 mL). The organic phase was concentrated at low pressure. The residue was purified by column chromatography (0-5% MeOH in DCM) to give 45-7 (1.2 g, 66.2%) as a white solid.

Tetra-butyl ammonium hydroxide (25.78 mL, 51.78 mmol) was neutralized with TFA (4.3 mL) to pH=4, and the solution was added to a solution of 45-7 (1.09 g, 2.14 mmol) in DCM (30 mL). m-CPBA (1.85 g, 10.74 mmol) was added portionwise under vigorous stirring, and the mixture was stirred for 12 h. The mixture was diluted with EA (100 mL), and washed with sat. sodium bicarbonate. The organic phase was concentrated at low pressure. The residue was purified by column chromatography (50% EA in PE) to give 45-8 (350 mg, 41.1%) as a white solid.

Compound 45-8 (280 mg, 0.704 mmol) was treated with NH₃ in MeOH (10 mL, 7 M) at R.T. The mixture was stirred at R.T. for 2 h. The mixture was concentrated at a low pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give compound 45 (110 mg, 53.1%) as a white solid. ESI-LCMS: m/z 295.1 [M+H]⁺.

Example 37

Compound 54

To an ice-cooled solution of 54-1 (10 g, 42 mmol) in anhydrous MeCN (200 mL) was added TEA.3HF (10 g, 62.5 mmol) and NIS (28 g, 126 mmol). The mixture was stirred at R.T. for 1.5 h, and monitored by LCMS. After the reaction was completed, the mixture was concentrated at a low pressure. The residue was purified by silica gel column chromatography (15% MeCN in DCM) to give 54-2 (12 g, 74%) as a yellow solid.

To a solution of 54-2 (22 g, 57 mmol) in anhydrous DCM (200 mL) was added DMAP (21 g, 171 mmol) and BzCl (17.6 g, 125 mol). The mixture was stirred for 5 h at R.T., and monitored by LCMS. The solution was washed with sat. NaHCO₃ solution, brine and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-3 (30 g, 88%) as a white foam.

To a solution of 54-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) was added NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at 95° C. for 48 h. The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200 mL), and the solution was washed with sat. NaHCO₃ solution, and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-4 (3 g crude, 46.1%) as an oil.

Compound 54-4 (3 g, crude) was treated with NH₃ in MeOH (120 mL, 7 M). The mixture was stirred for 3 h and monitored by TLC. The solution was concentrated at low pressure. The residue was purified by silica gel column chromatography (10% isopropanol in DCM) to give 54-5 (1.0 g, 67%) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=1.19 (s, 3H), 3.76-3.82 (m, 2H), 4.02 (d, J=19.8 Hz, 1H), 5.70 (d, J=8.07 Hz, 1H), 6.27 (s, 1H), 7.89 (d, J=8.07 Hz, 1H).

Compound 54-5 (100 mg, 0.36 mmol) was co-evaporated with toluene 3 times. To a stirred solution of 54-5 (100 mg, 0.36 mmol) in a mixture of MeCN (1.0 mL) and NMI (295 mg, 3.6 mmol) was added a solution of 54-C (255.6 mg, 0.72 mmol, preparation described below) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and diluted with EA (20 mL). The organic layer was washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄. The organic phase was concentrated at low pressure. The residue was purified on a silica gel column (5% i-PrOH in DCM) to give the crude product. The product was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 54 (46.7 mg, 23.3%) as a white solid. ESI-LCMS: m/z 618 [M+Na]⁺.

To a stirred solution of 54-A (2.0 g, 13.16 mmol) and naphthalen-1-ol (1.89 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. After addition, the mixture was gradually warmed to R.T., and stirred for 2 h. The solution was cooled to −78° C., and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed by TEA (2.66 g, 26.29 mmol) in DCM (20 mL) dropwise. The mixture was gradually warmed to R.T., and stirred for 2 h. The organic solvent was removed at low pressure. The residue was dissolved in methyl-butyl ether. The precipitate was filtered, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (anhydrous DCM) to give 54-C (1.0 g, 24.8%) as a colorless oil.

Example 38

Compounds 56 and 57

To a solution of 54-5 (300 mg, 1.08 mmol) and NMI (892 mg, 10 mmol) in anhydrous MeCN (4 mL) was added a solution of 57-C (736 mg, 2.17 mmol, preparation described below) in anhydrous MeCN (1 mL) dropwise at 0° C. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and diluted with EA (30 mL). The organic layer was washed with water and brine. The organic phase was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by a silica gel column (iPrOH in DCM from 1% to 5%) to give crude compound 56 (276 mg, crude). Crude compound 56 (96 mg) was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 56 (46 mg, 47.9%) as a white solid. ESI-LCMS: m/z 560 [M−F]⁺.

To a solution of compound 56 (180 mg, 0.31 mmol) in anhydrous pyridine (6 mL) was added acetic anhydride (158 mg, 1.54 mmol) dropwise at 0° C. The mixture was stirred at R.T. overnight. The solution was quenched with water and concentrated at a low pressure. The residue was dissolved in EA (10 mL), and washed with brine. The organic layer was dried over anhydrous Na₂SO₄. The organic phase was concentrated at low pressure. The residue was purified by silica gel column (i-PrOH in DCM from 1% to 3%) to give crude compound 57 (172 mg). Crude compound 57 was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 57 (46 mg, 23.8%) as a white solid. ESI-LCMS: m/z 602.3 [M−F]⁺.

Compound 56-C (1.02 g, 23%, a colorless oil) was prepared using a procedure similar to the preparation of 54-C using 54-A (2.00 g, 13.16 mmol) and 4-chlorophenol (1.68 g, 13.16 mmol).

Example 39

Compound 61

Compound 25 (109 mg, 0.39 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.6 mmol, prepared from 195 mg of bis(isopropyloxycarbonyloxymethyl)phosphate and 85 μL of Et₃N) were rendered anhydrous by coevaporating with pyridine, followed by toluene. The residue was dissolved in anhydrous THF (3 mL) and cooled in an ice-bath. Diisopropylethyl amine (0.2 mL, 3 eq.), BopCl (190 mg, 2 eq.), and 3-nitro-1,2,4-triazole (81 mg, 2 eq.) were added, and the mixture was stirred at 0° C. for 90 mins. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). Purification on silica gel column with CH₂Cl₂/i-PrOH (4-10% gradient) followed by RP-HPLC purification (A: 0.1% HCOOH in water, B: 0.1% HCOOH in MeCN) yielded compound 61 (28 mg, 12%). ¹H-NMR (CDCl₃): δ 7.24 (d, 1H), 6.6 (br, 1H), 5.84 (d, 1H), 5.65-5.73 (m, 4H), 4.94 (m, 2H), 4.38 (m, 2H), 4.1 (b, 1H), 2.88 (d, 1H), 1.47 (d, 3H), 1.33 (m, 12H).

Example 40

Compound 74

Dry nucleoside (0.05 mmol) was dissolved in a mixture of PO(OMe)₃ (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15 mins. at 42° C., then cooled to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃ (0.009 mL, 0.11 mmol). The mixture was kept at R.T. for 20-40 mins and monitored for the formation of compound 74 by LCMS. The reaction was quenched with water and isolated by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. MS: m/z 396.5 [M−1]⁻.

Example 41

Compound 68

The nucleoside (140 mg, 0.42 mmol) was dissolved in n-butylamine (0.5 mL). The mixture was kept for 2 h at R.T., and the amine was then evaporated. The residue was dissolved in EtOAc, and the organic layer was washed twice with 10% citric acid, dried over Na₂SO₄, and evaporated. The residue purified by column chromatography on silica gel in linear gradient of methanol in DCM from 0% to 12% over 10 column volumes. The fractions containing the product were concentrated and treated with 80% HCOOH for 1 h at R.T. The mixture was evaporated to dryness, and suspended in CH₃CN. The precipitate was separated, washed with CH₃CN (1 mL) and dried to yield compound 68 (27 mg, 50%). MS: m/z 326.5 [M−1]⁻.

Example 42

Compound 62

Compound 45 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL) and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol) was added, and the mixture was kept for 5 d at R.T. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The phosphoroamidate was isolated by silica gel chromatography in a gradient of methanol in DCM from 3% to 10%. The corresponding fractions were concentrated and re-purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol in DCM from 3% to 95% containing 0.1% formic acid was used for elution. Compound 62 was obtained as a mixture Rp and Rs isomers (9 mg, 16%). MS: m/z 562.1 [M−1]⁻.

Example 43

Compound 72

Compound 47 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL) and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol) was added, and the mixture was kept overnight at 40° C. The temperature was increased to 65° C. and heated for 1 h. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The azido-phosphoramidate was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 30% to 100% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The azido-phosphoramidate (8 mg) was dissolved in pyridine/Et₃N (3 mL, 8:1 v/v) and cooled to 0° C. H₂S gas was bubbled through the solution for 10 min, and the reaction was kept for 1 h at R.T. The solvents were evaporated, and the residue isolated by RP HPLC. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer, to provide compound 72 (1.2 mg) as mixture Rp and Rs isomers. MS: m/z 544.1 [M+1]⁺.

Example 44

Compound 65

To a solution of 65-1 (23.0 g, 39.5 mmol) in anhydrous toluene (200 mL) was added DAST (31.9 g, 198 mmol) dropwise at −78° C., and the solution was stirred at −78° C. for 3 h. The mixture was quenched with sat. NaHCO₃, extracted with EA (2×200 mL) and dried over with anhydrous Na₂SO₄. The solution was concentrated to dryness under low pressure. The residue was purified on a silica gel column (50% EA in PE) to give 65-2 (16.5 g, 71%) as a yellow foam.

A mixture of 65-2 (16.0 g, 27.4 mmol) and NH₄F (3.0 g, 82.2 mmol) in methanol (100 mL) was stirred at 70° C. for 12 h. The reaction was cooled, and the salt was removed by filtration. The filtrate was concentrated to dryness at low pressure. The residue was purified on a silica gel column (3% MeOH in DCM) to give 65-3 (5.1 g, 69.0%) as a white foam.

To a stirred suspension of 65-3 (4.1 g, 15.2 mmol), PPh₃ (8.0 g, 30.4 mmol), imidazole (2.1 g, 30.4 mmol) and pyridine (18.2 mL) in anhydrous THF (40 mL) was added dropwise a solution of I₂ (5.8 g, 22.8 mmol) in THF (20 mL) at 0° C. The mixture was stirred at R.T. for 12 h. The reaction was quenched with MeOH (100 mL), and the solvent was removed under reduced pressure. The residue was purified on a silica gel column (4% MeOH in DCM) to give pure 65-4 (4.4 g, 77%) as a white solid. ESI-MS: m/z 381.1 [M+1]⁺.

To a stirred solution of 65-4 (2.5 g, 0.7 mmol) in anhydrous THF (3 mL) was added DBU (2.1 g, 14 mmol) at R.T., and the mixture was stirred at R.T. for 1 h. The reaction was quenched with HOAc, and diluted with 2-Me-tetrahydrofuran. The solution was washed with brine, dried over with anhydrous Na₂SO₄ and concentrated to dryness at low pressure. The residue was purified on a silica gel column (MeOH 5% in DCM) to give 65-5 (1.1 g, 68.9%) as a white foam.

To a stirred solution of 65-5 (800 mg, 3.17 mmol) in anhydrous CH₃CN (10 mL) was added TEA.3HF (510 mg, 3.17 mmol) and NIS (785 mg, 3.49 mmol) at 0° C. The mixture was stirred for 30 mins, gradually warmed to R.T., and stirred for 1 h. The mixture was quenched with sat. NaHCO₃ solution and Na₂S₂O₃ solution, and extracted with EA (2×20 mL). The organic layer was dried over with anhydrous Na₂SO₄, and concentrated to dryness at low pressure. The residue was purified on a silica gel column to give pure 65-6 (695 mg, 57.9%) as a yellow solid.

To a stirred solution of 65-6 (650 mg, 1.63 mmol) in pyridine (3 mL) was added BzCl (507 mg, 3.59 mmol) at 0° C., and stirred at R.T. for 12 h. The mixture was quenched with water, and concentrated to dryness under reducing pressure. The residue was purified on a silica gel column (EA 50% in PE) to yield 65-7 (550 mg, 67%) as a white foam.

Tetra-butylammonium hydroxide (9 mL as 54-56% aqueous solution, 72 mmol) was neutralized with TFA to pH˜4 (1.5 mL), and the mixture was added to a solution of 65-7 (375 mg, 0.75 mmol) in DCM (9 mL). m-Chloroperbenzoic acid (924 mg, 60-70%, 3.75 mmol) was added in portions with vigorous stirring, and the mixture was stirred overnight. The mixture was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EA 50% in PE) to give 65-8 (230 mg, 78.8%) as a white foam. ESI-MS: m/z 393.1 [M+1]⁺.

Compound 65-8 (120 mg, 0.24 mmol) was treated with 7N NH₃.MeOH (20 mL), and stirred for 5 h. The mixture was concentrated to dryness at low pressure. The residue was purified on a silica gel column (propan-2-ol 15% in DCM) to yield compound 65 (53 mg, 60.2%) as a white solid. ESI-MS: m/z 288.8 [M+1]⁺.

Example 45

Compound 70

To a solution of 70-1 (3.0 g, 18.0 mmol) and POCl₃ (1.35 g, 9.0 mmol) in DCM (80 mL) was added TEA (3.6 g, 36.0 mmol) in DCM (20 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. A solution of pentafluorophenol (1.65 g, 9.0 mmol) and TEA (0.9 g, 9.0 mmol) in DCM (20 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 15 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed by TBME and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (20% EA in PE) to give 70-2 (2.7 g, 62.7%) as a white solid. ESI-MS: m/z 491.1 [M+1]⁺.

To a stirred solution of 1-((3aR,4R,6S,6aS)-6-fluoro-6-(hydroxymethyl)-2-methoxy-3a-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.47 mmol) in anhydrous THF (2 mL) was added a solution of t-BuMgCl (0.46 mL, 1M in THF) dropwise at 0° C. The mixture was stirred at R.T. for 40 mins, and re-cooled to 0° C. A solution of 70-2 (462 mg, 0.94 mmol) was added, and the mixture was stirred at R.T. for 4 h. The mixture was quenched with H₂O, and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated under reducing pressure. The residue was purified on a silica gel column (50% EA in PE) to give 70-3 as a white foam (230 mg, 78%).

Compound 70-3 (230 mg, 0.37 mmol) was dissolved in 80% HCOOH aqueous solution (20 mL), and the mixture was stirred at R.T. for 24 h. The solvent was removed at low pressure. The residue was purified on a silica gel column to give the crude product, which was purified by RP HPLC (HCOOH system) to give compound 70 as a mixture of two P-isomers (75 mg, 33%). ESI-TOF-MS: m/z 583.0 [M+H]⁺.

Example 46

Compound 75

To a solution of 75-1 (120 g, 0.26 mol) in CH₃CN (2.0 L) was added IBX (109 g, 0.39 mol), and refluxed for 12 h. The reaction was monitored by TLC and LCMS. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated at low pressure. The crude product was used directly for the next step.

Compound 75-2 (130 g, 0.26 mol) was co-evaporated with anhydrous toluene three times to remove H₂O. To a solution of 75-2 in THF (300 mL) was added dropwise vinyl magnesium bromide (700 mL, 0.78 mol, 1N in THF) over 30 min at −78° C. The mixture was stirred for about 1 h at R.T. After the starting material was consumed, the mixture was poured into a sat. NH₄Cl solution. The organic layer was washed with brine, dried with anhydrous Na₂SO₄ and filtered. The solution was concentrated at low pressure to get the crude product. To a solution of this crude product (170 g, 0.346 mol) in anhydrous CH₂Cl₂ was added TEA (105 g, 1.04 mol) and DMAP (84 g, 0.69 mol). Benzoyl chloride (146 g, 1.04 mol) was added slowly at R.T. for 12 h. The mixture was diluted with CH₂Cl₂ and then washed with sat. aq. NaHCO₃. The combined aq. phase was extracted with DCM (100 mL), and the combined organic phase was dried with Na₂SO₄. After filtration, the solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give 75-3 (107 g, 52%).

Uracil (44.8 g, 0.4 mol) (co-evaporated with toluene twice) and NOBSA (81.4 g, 0.4 mol) were dissolved in CH₃CN (500 mL). The mixture was refluxed for 1.5 h and then slowly cooled to R.T. The mixture was treated with 75-3 (59 g, 0.1 mol) and TMSOTf (155 g, 0.7 mol), and then warmed to 60-70° C. for 12 h. The mixture was neutralized with a sat. NaHCO₃ solution, and extracted with EA (3×1000 mL). The solution was dried over anhydrous MgSO4, and evaporated at low pressure. The residue was purified using a silica gel column to give pure 75-4 (40 g, 69%) as a white solid.

To a solution of 75-4 (50 g, 0.086 mol) in DMF was added PMBCl (16 g, 0.1 mol) and K₂CO₃ (17.8 g, 0.13 mol) at 0° C., and the mixture was stirred at R.T. for 12 h. The mixture was quenched with water (100 mL), and extracted with EA (3×200 mL). The organic phase was concentrated at low pressure to give crude 75-5 (65 g) which was used in the next step without further purification.

To a solution of crude 75-5 (65 g, 0.086 mol) in MeOH/DCM (4/1) (200 mL) was added NaOMe (16.8 g, 0.3 mol), and the mixture was stirred at R.T. for 2.5 h. The reaction was quenched with dry ice, and then concentrated at low pressure. The residue was dissolved in EA (200 mL) and washed with brine. The organic layer was concentrated at low pressure, and the residue was purified using a silica gel column using 1% MeOH in CH₂Cl₂ to give 75-6 as a yellow foam (25 g, 75%).

To a solution of 75-6 (25.5 g, 0.065 mol) in DMF was added NaH (10.5 g, 0.26 mol) slowly at 0° C., and the mixture was stirred for 30 mins. BnBr (36.3 g, 0.21 mol) was added, and the mixture was stirred at R.T. for 12 h. The reaction was quenched with sat. NH₄Cl (aq.), and then extracted with EA (3×100 mL). The solution was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified by a silica gel column using 10% EA in PE to give 75-7 (20 g, 46%) as a white solid.

To a solution of 75-7 (20 g, 0.03 mol) and NMMO (7 g, 0.06 mol) in THF:H₂O (5:1) (100 mL) was added OsO₄ (2.6 g, 0.01 mol) at R.T., and the mixture was stirred at R.T. for 24 h. The mixture was quenched with a sat. Na₂S₂O₃ solution, and extracted with EA (3×100 mL). The organic layer was washed with brine, and dried over anhydrous MgSO₄. The solution was evaporated at low pressure to give the crude compound, which was used in the next step without further purification.

To a solution of the crude diol (0.03 mol) in MeOH:H₂O:THF (170 mL:30 mL:50 mL) was added NaIO₄ (9.6 g, 0.045 mol), and the mixture was stirred at R.T. for 2 h. After filtration, the filtrate was used directly in the next step. This solution was treated with NaBH₄ (1.8 g, 0.048 mol) at 0° C., and the mixture was stirred at R.T. for 30 mins. The mixture was quenched with MeOH, and evaporated at low pressure. The residue was dissolved in EA (100 mL), and washed with brine. The solution was evaporated at low pressure, and the residue was purified by a silica gel column using 20% EA in EA to give 75-8 (12 g, 61% over three steps).

To a solution of 75-8 (14 g, 21 mmol) and DMAP (5.1 g, 42 mmol) in DCM (100 mL) was added MsCl (3.1 g, 27 mmol) at 0° C., and the mixture was stirred at R.T. for 40 mins. The reaction was quenched with sat. NaHCO₃(aq.), and washed with HCl (0.2 N) solution. The organic phase was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified by a silica gel column using 5% EA in PE to give mysolate product (14 g, 90%). The MsO-product (41 g, 55 mmol) was treated with TBAF (1 N in THF, 500 mL), and the mixture was stirred at 70-80° C. for 3 d. The mixture was concentrated at low pressure, and the residue was dissolved in EA (200 mL). The solution was washed with brine, dried over anhydrous MgSO₄ and evaporated at low pressure. The residue was purified by chromatography using 10% EA in PE to give 75-9 (9.9 g, 27%).

To a solution of 75-9 (6.3 g, 9.45 mmol) in CH₃CN:H₂O (3:1, 36 mL:12 mL) was added CAN (15.5 g, 28.3 mmol), and the mixture was stirred at R.T. overnight. The mixture was extracted with EA (3×50 mL). The solution was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified by chromatography using 20% EA in PE to give 75-10 (3.6 g, 71%) as a white solid.

To a solution of 75-10 (2.4 g, 4.4 mmol) in anhydrous DCM (10 mL) was added slowly BCl₃ (1 N, 30 mL CH₂Cl₂) at −70° C., and the mixture was stirred for 2 h. at −70° C. The mixture was quenched with the slow addition of MeOH at −70° C., and the mixture was concentrated at low pressure. The residue was purified by chromatography using 50% EA in PE to give 75-11 (1.2 g, 86%) as a white solid. ESI-MS: m/z 277.1 [M+H]⁺.

To a solution of PPh₃ (3.37 g, 12.8 mmol) in pyridine (15 mL) was added I₂ (3.06 g, 12 mmol) at 0° C., and the mixture was stirred at R.T. for 30-40 mins. The mixture was cooled to 0° C., and then treated with 75-11 (2.2 g, 8 mmol) in Py. (5 mL). The mixture was stirred at R.T. under N₂ for 12 h. The mixture was quenched with sat. Na₂S₂O₃ (aq.) and extracted with CH₂Cl₂ (3×50 mL). The organic phase was dried over anhydrous MgSO₄, and then concentrated at low pressure. The residue was purified by chromatography using 1-2% MeOH in CH₂Cl₂ to yield 75-12 (1.8 g, 58%) as a white solid.

To a solution of 75-12 (1.35 g, 3.5 mmol) in THF:CH₃CN (10 mL:5 mL) was added DBU (1.06 g, 7 mmol), and the mixture was stirred at 60-70° C. for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (20 mL). The solution was washed with 10% HCl solution and brine. The organic phase was dried over anhydrous MgSO₄ and concentrated at low pressure. The residue was purified by chromatography using 30% EA in PE to give 75-13 (0.5 g, 55%).

To a solution of 75-13 (670 mg, 2.6 mmol) in CH₃CN (6 mL) was added NIS (730 mg, 3.25 mmol) and 3HF.TEA (335 mg, 2.1 mmol) at 0° C., and the mixture was stirred at R.T. for 2 h. The mixture was quenched with sat. NaHCO₃(aq.) and Na₂S₂O₃ (aq.) solution. The mixture was extracted with EA (3×20 mL), dried over anhydrous MgSO4 and concentrated at low pressure. The residue was purified by chromatography using 1-2% MeOH in CH₂Cl₂ to give 75-14 (1.2 g, 80%).

To a solution of 75-14 (1.0 g, 2.47 mmol), DMAP (0.75 g, 6.2 mmol) and TEA (0.75 g, 7.42 mmol) in DCM (10 mL) was added BzCl (1.15 g, 8.16 mmol) in DCM (1 mL) at 0° C., and the mixture was stirred at R.T. for 12 h. The mixture was diluted with CH₂Cl₂ (10 mL), and then washed with HCl (0.1 N, 20 mL) solution and brine. The organic phase was dried over anhydrous MgSO₄, and concentrated at low pressure. The residue was purified by chromatography using 20% EA in PE to afford 75-15 (850 mg, purity˜80%).

To a solution of 75-15 (600 mg, 1 mmol) in DMF (25 mL) was added BzONa (1.45 g, 10 mmol), 15-crown-5 (2.2 g, 10 mmol), and the mixture was stirred at 90-100° C. for 24 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (20 mL), and washed with brine. The organic phase was dried over anhydrous MgSO₄, and then concentrated at low pressure. The residue was purified by chromatography using 15% EA in PE to give 75-16 (275 mg, 37%) as a light yellow foam.

Compound 75-16 (250 mg, 0.41 mmol) was treated with NH₃.MeOH (7 N, 5 mL), and the mixture stirred at R.T. for 15 h. The mixture was concentrated at low pressure, and the residue was purified by prep-HPLC to give compound 75 (33 mg, 25%) as a white solid. ESI-MS: m/z 295.1 [M+H]⁺.

Example 47

Compound 73

To a solution of IBX (133.33 g, 476 mmol) in dry CH₃CN (2 L) was added 73-1 (100.0 g, 216 mol) at R.T. The mixture was refluxed and stirred for 12 h. The mixture was filtered, and the filtrate was concentrated at low pressure to give 73-2 as a yellow oil (90.0 g, 90.4%).

Compound 73-2 (50.0 g, 108.70 mmol) was coevaporated with anhydrous toluene twice to remove H₂O. Ethynyl magnesium bromide, (800 mL, 400.0 mmol) was added dropwise into a solution of 73-2 in THF (500 mL) over 20 mins at −78° C. The mixture was stirred for about 10 mins at −78° C. When the starting material was consumed, the ice-acetone cooling bath was removed. The mixture was quenched with a sat. NH₄Cl solution with stirring, and then warmed to R.T. The mixture was extracted with EA, filtered through Celite and washed with brine. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure to give crude 73-3 as a deep yellow oil (48.0 g, yield: 90.8%).

Compound 73-3 (200.0 g, 411.52 mmol) was dissolved in anhydrous CH₂Cl₂ (2000 mL) and then DMAP (100.41 g, 823.05 mmol) and Et₃N (124.94 g, 1.23 mol) were added at R.T. The mixture was treated with benzoyl chloride (173.46 g, 1.23 mol) at 0° C. After stirring for 12 h at R.T., the reaction was quenched with H₂O. The combined aq. phase was extracted with DCM. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and evaporated to dryness under reduced pressure to give a black oil. The oil was purified by column chromatography using 7%-20% EA in PE as the eluent to give a yellow oil. The residue triturated with CH₃OH and filtered. The filter cake was concentrated in vacuo to give 73-4 as a white solid (30.0 g, 36.4%).

Uracil (34.17 g, 305.08 mmol) were coevaporated with anhydrous toluene twice to remove H₂O. To a stirred suspension of uracil in anhydrous MeCN (150 mL) was added N,O-BSA (123.86 g, 610.17 mmol) at R.T. The mixture was refluxed for 1.5 h and then cooled to R.T. Compound 73-4 (90 g, 152.54 mmol, which were coevaporated with anhydrous toluene twice to remove H₂O) was added. TMSOTf (237.05 g, 1.07 mol) was then added at R.T. The mixture was heated to 70° C., and then stirred overnight and then monitored by LCMS. The mixture was cooled to R.T., and quenched with a sat. NaHCO₃ solution. The solution was extracted with EA. The organic layer was dried over Na₂SO₄, and then concentrated at low pressure. The residue was purified using a silica gel column eluted with 10%-50% EA in PE to give 73-5 as a white solid (45 g, 50.9%).

Compound 73-5 (50 g, 86.21 mmol) was treated with NH₃ in MeOH (1 L) at R.T., and then stirred for 48 h. The mixture was concentrated at low pressure, and the residue was purified by column chromatography (10% MeOH in DCM) to give 73-6 (12.6 g, 54.55%) as a white solid.

To a solution of cyclopentanone (100 g, 1.189 mmol) and trimethyl orthoformate (150 mL) in MeOH (600 mL) was added TsOH.H₂O (1.13 g, 5.9 mmol), and the mixture was stirred at R.T. for 30 mins. The reaction was quenched with NaOMe (0.32 g, 5.9 mmol) and H₂O, and the solution was extracted by n-hexane. The organic layer was dried over anhydrous Na₂SO₄, and then concentrated at low pressure. The cyclopentyl dimethoxy acetal and 73-6 (20 g, 74.63 mmol) was dissolved in DCE (200 mL), and then treated with TsOH.H₂O (0.71 g, 3.73 mmol). The mixture was stirred at 50° C. for 12 h, and then concentrated at low pressure. The residue was purified by silica gel column chromatography (1-10% MeOH in DCM) to give 73-7 (15.4 g, 61.8%) as a white solid.

Compound 73-7 (20.0 g, 0.06 mol) was coevaporated with anhydrous pyridine three times to remove H₂O. To an ice-cold solution of 73-7 in anhydrous pyridine (100 ml) was added TsCl (22.8 g, 0.12 mol) at 0° C., and the mixture was stirred overnight and monitored by LCMS and TLC. The reaction was quenched with H₂O and extracted with EA. The organic phase was dried over anhydrous NaSO₄ and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 78-8 (20.0 g, 69.0%) as a white solid.

To a solution of 73-8 (20.0 g, 0.04 mol) in acetone (200 ml) was added NaI (31.0 g, 0.2 mol) and heated to reflux overnight and monitored by LCMS. The mixture was quenched with a sat. Na₂S₂O₃ solution, and extracted with EA. The organic phase was dried over anhydrous Na₂SO₄ and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 73-9 (15.0 g, 83.3%) as a white solid.

To 73-9 (30.0 g, 0.068 mol) in dioxane (60 mL) in sealed tube was added CuBr (4.9 g, 0.034 mol), i-Pr₂NH (13.6 g, 0.135 mol) and (CH₂O)_n (5.1 g, 0.17 mol) under N₂. The mixture was heated at reflux for 16 h. The mixture was diluted with EtOAc, and washed with a sat. NH₄Cl solution and brine. The solution was dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=100:1 to 15:1) to give 73-10 (10.0 g, 32.3%) as a white solid.

Compound 73-10 (10 g, 21.83 mmol) was treated with HCOOH (80%) in H₂O at R.T. The solution was stirred at 60° C. for 2 h, and then concentrated at a low pressure. The residue was purified by column chromatography (1%-10% MeOH in DCM) to give 73-11 (5.1 g, 58.55%) as a white solid.

Compound 73-11 (5 g, 12.79 mmol) was dissolved in anhydrous MeOH (100 mL) and treated with NaOMe (4.83 g, 89.5 mmol) at R.T. The solution was stirred at 60° C. for 36 h. The mixture was quenched with CO₂ and then concentrated at low pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give 73-12 (2.3 g, 68.05%) as a yellow solid. ¹H-NMR (CDCl₃, 400 MHz)=7.29 (d, J=8 Hz 1H), 6.10 (s, 1H), 5.71 (d, J=8.0 Hz 1H), 5.18 (t, J=6.4 Hz, 1H), 4.79-4.84 (m, 1H), 4.61 (d, J=8.0 Hz, 2H), 4.39 (s, 1H), 3.45 (s, 1H).

To an ice-cold solution of 73-12 (1.5 g, 5.68 mmol) in anhydrous MeCN (15 mL) was added NIS (1.66 g, 7.39 mmol) and TEA.3HF (0.73 g, 4.55 mmol) under N₂. The mixture was stirred at R.T. for 1 h. The reaction was quenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extracted with EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (0-5% MeOH in DCM) to give 73-13 (1.08 g, 46.2%) as a yellow solid.

To a stirred solution of 73-13 (1 g, 2.44 mmol) in anhydrous DCM (10 mL) was added DMAP (0.60 g, 4.88 mmol) and Et₃N (0.74 g, 7.32 mmol) at R.T. The mixture was treated with benzoyl chloride (0.79 g, 5.61 mmol) at 0° C. and then stirred at R.T. for 3 h. The reaction was quenched with water, and extracted with EA (3×60 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography (0-10% MeOH in DCM) to give 73-14 (0.9 g, 59.6%) as a white solid.

Bu₄NOH (55% in H₂O, 13.74 mL) was treated with TFA (to adjust pH=3-4). The mixture was cooled to R.T. To a solution of 73-14 (0.9 g, 1.46 mmol) in DCM (9 mL) was added m-CPBA (80%, 1.57 g, 7.28 mmol) at R.T. The mixture was stirred at 25° C. for 48 h. The mixture was washed with sat. aq. NaHCO₃. The organic layer was passed through an anhydrous Al₂O₃ column, and the solution was concentrated at low pressure. The residue was purified by a silica gel column (30% EA in PE) to give 73-15 (0.26 g, 35.1%) as a yellow solid.

Compound 73-15 (0.25 g, 0.49 mmol) was dissolved in NH₃/MeOH (5 mL, 7 M), and the mixture was stirred at R.T. for 24 h under N₂. The mixture was concentrated at low pressure at R.T., and the residue was purified by a silica gel column (5% MeOH in DCM) to give 73-16 (100 g, 67.75%) as a white solid. ¹H-NMR (CD₃OD, 400 MHz)=7.83 (d, J=8 Hz 1H), 6.29 (s, 1H), 5.67 (d, J=6.0 Hz 1H), 5.12 (t, J=6.8 Hz, 1H), 4.99-5.01 (m, 1H), 4.38 (d, J=19.6 Hz 1H), 3.74-3.81 (m, 2H), 3.35 (s, 1H).

Compound 73-16 (100 mg, 0.33 mmol) was co-evaporated with toluene three times to remove H₂O. To a stirred solution of 73-16 (100 mg, 0.33 mmol) in a mixture of MeCN (1.0 mL) and NMI (271 mg, 3.3 mmol) was added a solution of 73-C (216.5 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight and then reaction was quenched with water. The mixture was diluted with EA (20 mL), and the organic layer was washed with water and brine, and dried over anhydrous Na₂SO₄. The organic phase was concentrated at low pressure, and the residue was purified on a silica gel column (5% i-PrOH in DCM) to give the crude product. The crude product was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 73 (35.6 mg, 19.0%) as a white solid. ESI-LCMS: m/z 592 [M+Na]⁺.

To a stirred solution of 73-A (2.0 g, 13.16 mmol) and phenol (1.22 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was warmed gradually to R.T., and then stirred for 2 h. The solution was re-cooled to −78° C., and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed by the dropwise addition of TEA (2.66 g, 26.29 mmol) in DCM (20 mL). The mixture was warmed gradually to R.T., and then stirred for 2 h. The organic solvent was removed at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was filtered, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (anhydrous DCM) to give 73-C (0.9 g, 22.3%) as a colorless oil.

Example 48

Compound 66

Compound 66-2 (2648 g, 7.3 mol) was dissolved in anhydrous dichloromethane (10 L), and the solution was cooled to −40° C. with stirring under N₂. Compound 66-1 (1 kg, 7.69 mol) was dissolved in anhydrous CH₂Cl₂ (3 L) and added to the solution of 66-2 over 30 mins at −40° C. The stirred mixture was allowed to warm to R.T. overnight. The mixture was concentrated under reduced pressure to dryness, and the residue was suspended in TMBE (6 L). The suspension was filtered to remove Ph₃PO, and the filtrate was concentrated under reduced pressure to afford crude 66-3 (1230 g, 78.6%). ¹H NMR (400 Hz) (CDCl₃): δ 6.65 (dt, J=7.6 Hz, 1H), 4.82 (dd, J=14.8, 7.6 Hz, 1H), 4.20-4.10 (m, 3H), 3.59 (t, J=8.0 Hz, 1H), 1.86 (d, J=1.2 Hz, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.26 (t, J=6.8 Hz, 3H).

Crude 66-3 (1230 g, 5.74 mol) was dissolved in acetone (30 L) at 0-5° C. KMnO₄ (1107 g, 5.17 mol) was added in one portion. After being stirred at 0-5° C. for 5 h, the reaction was quenched with sat. aq. sodium sulfite (20 L). After 30 mins, a colorless suspension was formed. The solid was removed by filtration and washed with EA (6 L). The filtrate was extracted with EA (3×2 L). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid residue. The residue was dissolved in EA, and PE was added to give a precipitate. The solid was collected by filtration and recrystallization was 3 times to give 66-4 (770 g, 53.6%) as a white solid.

To a stirred solution of 66-4 (770 g, 3.1 mol) in anhydrous DCM (5 L) and triethylamine (1.1 L, 8.05 mol) at 0° C. was added slowly sulfuryl chloride (300 mL, 3.6 mmol). The mixture was stirred at R.T. for 2 h, diluted with DCM (3 L), and washed with sat. NaHCO₃aq. and brine. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column using PE:EA=1:0 to 10:1 as the eluent to give 66-5 (490 g, 50.6%) as an oil.

Tetraethylammonium fluoride hydrate (650 g, 3.7 mol) was added into a solution of 66-5 (490 g, 1.6 mol) in anhydrous dioxane (3 L), and the mixture was heated to 120° C. for 16 h. The mixture was then cooled to ambient temperature. 2,2-Dimethoxypropane (3 L) was added followed by conc. aq hydrochloric acid (200 mL). The mixture was stirred for 3 h at ambient temperature. The solvent was concentrated to ⅓ of the original volume, and then diluted with EA (3 L). The mixture was washed with cold sat. aq. sodium bicarbonate and brine. The combined aqueous layer was back-extracted with EA (1 L). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated at low pressure to give crude 66-6 (220 g, 70.8%).

Crude 66-6 (220 g, 0.89 mol) was dissolved in ethanol (2 L) and conc. aq. HCl (60 mL). The solution was stirred at ambient temperature for 48 h. and then concentrated under reduced pressure followed by co-evaporations with toluene 3 times to give 66-7 as a pale yellow solid (110 g).

Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoyl chloride (200 mL, 1.67 mol) was added slowly at 0-5° C. The mixture was stirred at ambient temperature for 45 mins. The reaction was quenched with ice and MeOH to form a precipitate. After filtration, the filtrate was washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.

To a solution of 66-8 (100 g, 269 mmol) in anhydrous THF (1000 ml) was added dropwise a solution of lithium tri-tert-butoxyaluminohydride (400 ml, 1M, 0.4 mol) at −78° C. under N₂ for 30 mins. The solution was stirred at −20° C. for 1 h, and TLC (PE:EA=3:1) showed that the reaction was complete. The mixture was quenched with sat.NH₄Cl, and diluted with EA. After filtration, the filtrate was extracted with EA. The combined layers were dried over Na₂SO₄, and concentrated at low pressure. The residue was purified by a silica column gel (PE:EA=20:1) to give 66-9 (100 g, 100%) as a colorless oil.

To a stirred solution of PPh₃ (140 g, 382 mol) in CH₂Cl₂ (1000 ml) was added 66-9 (100 g, 269 mmol) at −20° C. under N₂. After stirring for 15 mins, CBr₄ (177 g, 382 mol) was added dropwise while maintaining the temperature between −25 and −20° C. under N₂. The mixture was stirred below −17° C. for 20 mins. Silica gel was added to the mixture. The mixture was filtered through cold silica column gel and washed with PE:EA (50:1 to 4:1). The combined filtrates were concentrated under reduced pressure at R.T. to give the crude oil product. The residue was purified by a silica column gel a second time (PE:EA=50:1 to 4:1) to give 66-10 (α-isomer, 64 g, yield: 55%) as a colorless oil.

A mixture of 6-chloro-guanine (55.8 g, 316.5 mol) and t-BuOK (39.5 g, 352.7 mmol) in t-BuOH (500 mL) and MeCN (280 mL) was stirred for 30 mins. Compound 66-10 (48 g, 105.5 mmol) was added at R.T., and the mixture was heated to 50° C. and stirred overnight. The reaction was monitored by TLC (PE:EA=2:1). The mixture was quenched with solid NH₄Cl. After stirring for 1 h, the mixture was filtered and washed with MeCN. The filtrate was evaporated at low pressure, and the residue was purified by a silica gel column to give 66-11 (33 g, 57%).

To a solution of 66-11 (49 g, 93.1 mol) in CH₂Cl₂ (200 mL) was added AgNO₃ (31.7 g, 186 mmol), collidine (22.5 g, 186 mmol) and MMTrCl (43 g, 140 mmol) in small portions under N₂ at 0° C. The mixture was stirred at R.T., and monitored by TLC (PE:EA=4:1). After filtration, the organic phase was washed with NaHCO₃ aqueous and brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by a silica gel column (PE:ME=20:1 to 1:1) to give 66-12 (70 g, 94.2%).

Sodium (10.1 g, 439 mmol) was dissolved in dry EtOH (600 mL) at 70° C. and then cooled to 0° C. To a solution of 66-12 (70 g, 87.7 mmol) was added a freshly prepared NaOEt solution in portions at 0° C., and the mixture was stirred for 1 h. at R.T. After TLC and LCMS showed the reaction was completed, the reaction was quenched with carbon dioxide. The mixture was evaporated at low pressure, and the residue was purified using silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give 66-13 (50 g, yield 5%) as a yellow solid.

A mixture of PPh₃ (35 g, 133.5 mol) and I₂ (31.75 g, 125 mmol) in anhydrous pyridine (600 mL) was stirred for 30 mins, and then a solution of 66-13 (50 g, 83.3 mmol) in pyridine (100 mL) was added at 0° C. The mixture was stirred overnight at R.T. and monitored by TLC (DCM:MeOH=50:1). The reaction was quenched with a sat. NaHCO₃ solution, and extracted with DCM (3×50 mL). The organic phase was dried over anhydrous MgSO₄, and evaporated at low pressure. The residue was purified using silica gel column chromatography (DCM:MeOH=200:1 to 50:1) to give 66-14 (50 g, 84.7%).

To a solution of 66-14 (37 g, 52.1 mmol) in dry THF (400 mL) was added DBU (16 g, 105 mmol). The mixture was heated to reflux and stirred for 3 h. The reaction was monitored by LCMS. The reaction was quenched with a sat. NaHCO₃ solution, and extracted with EA. The combined organic layers were dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified using silica gel column chromatography (PE:EA=10:1 to 5:1) to give 66-15 (25 g, 61.1%) as a white solid.

To an ice-cold solution of 66-15 (26 g, 44.6 mmol) in dry MeCN (300 mL) was added NIS (12.68 g, 56 mmol) and NEt₃.3HF (10.6 g, 67 mmol) at 0° C. The reaction was stirred at R.T. for 2 h. and monitored by LCMS. After the reaction was completed, the reaction was quenched with a sat Na₂SO₃ and sat. NaHCO₃ solution, and extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified using silica gel column chromatography (PE:EA=8:1 to 1:1) to give 66-16 (21 g, 64.4%) as a white solid.

To a solution of 66-16 (21 g, 28.8 mol) in CH₂Cl₂ (150 mL) was added AgNO₃ (9.8 g, 59.6 mmol) and collidine (7 g, 59.8 mmol) and MMTrCl (13.1 g, 42.5 mmol) in small portions under N₂ at 0° C. The mixture was stirred at R.T., and the reaction was monitored by TLC (PE:EA=2:1). After filtration, the solution was washed with sat. aq. NaHCO₃ and brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by a silica gel column to give 66-17 (25 g, yield 86.5%).

To a solution of 66-17 (22 g, 22 mmol) in dry DMF (500 mL) was added NaOBz (31.9 g, 220 mmol) and 15-crown-5 (48.4 g, 220 mmol), and the mixture was stirred for 72 h. at 95° C. The mixture was diluted with EA, washed with water and brine, and dried over MgSO₄. The organic layer was evaporated at low pressure, and the residue was purified using a silica gel column chromatography to give 66-18 (15 g, 68.8%) as a white solid.

Compound 66-18 (15.2 g, 15.3 mmol) was co-evaporated with anhydrous toluene 3 times to remove H₂O. The compound was treated with NH₃ in MeOH (7 N, 200 mL) at R.T. The mixture was stirred for 18 h at R.T., and the reaction was monitored by LCMS. The residue was concentrated at low pressure, and purified using silica gel column chromatography to give 66-19 (11 g, 81%) as a white solid.

To a stirred solution of 66-20 (14 g, 15.73 mmol) in anhydrous CH₃CN (150 mL) was added N-methylimidazole (23.5 g, 283.9 mmol) at 0 to 5° C. (ice/water bath) followed by a solution of phenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (16.33 g, 47.2 mmol, dissolved in 50 mL of CH₃CN). The solution was stirred at 0 to 5° C. for 12 h and then diluted with EA. The solution was washed 50% aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO₄ and filtered. The filtrate was concentrated at low pressure, and the residue was purified on silica gel with PE:EA=5:1 as the eluent to give 66-20 (17.62 g, 93.4%) as a white solid.

Compound 66-20 (17.62 g, 14.7 mmol) was dissolved in 80% AcOH (200 mL), and the mixture was stirred overnight at R.T. After removal of the solvents, the reside was purified on silica gel using PE:EA=2:1 to eluent to give the crude product, which was purified on via reverse-phase HPLC using acetonitrile and water to give compound 66 (5.25 g, yield 66%) as a white solid. ESI-LCMS: m/z 655 [M+H]⁺.

Example 49

Compound 67

To a solution of the nucleoside (300 mg, 1.09 mmol) and proton-sponge (467 mg, 2.18 mmol) in anhydrous CH₃CN (5 mL) at 0° C. under N₂ was added dropwise a solution of phosphorus oxychloride (330 mg, 2.18 mmol) in anhydrous CH₃CN (1 mL). The mixture was stirred at 0° C. for 30 mins, and the hydrogen chloride salt of (S)-ethyl 2-aminopropanoate (998 mg, 6.52 mmol) and triethylamine (1.5 mL, 10.87 mmol) at 0° C. were added. The mixture was stirred overnight at 30° C. The reaction was quenched with water, and extracted with EA (3×20 mL). The organic layer was concentrated at low pressure, and the residue was purified by reverse phase HPLC to give compound 67 (20 mg, 3%) as a white solid. ESI-LCMS: m/z 535 [M−F]⁺.

Example 50

Compound 59

To a solution of sodium hydrosulfide (4.26 g, 76.0 mmol) in EtOH (100 mL) was added t-butyryl chloride (76.2 mmol; 9.35 mL) dropwise at 0° C., and the mixture was stirred at R.T. for 1 h. A solution of 2-(2-chloroethoxy)ethanol (57 mmol; 6.0 mL) and TEA (21 mL, 120 mmol) was added, and the mixture was heated at reflux for 60 h. The mixture was filtered, and then concentrated to a small volume. The residue was dissolved in EA, and then washed with water, sat. aq. NaHCO₃ and brine. The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (10.0 g) was isolated and 5 grams were purified by silica gel flash column chromatography using a gradient of 0 to 100% EA in hexane to give 59-3 (4.5 g, 22 mmol) as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.70-3.74 (m, 2H), 3.5-3.65 (m, 4H), 3.1 (t, 2H), 1.25 (s, 9H).

A solution 59-3 (4.5 g; 21.8 mmol) and triethylamine (6.7 mL, 87.2 mmol) in tetrahydrofuran (50 mL) was added dropwise over 1 h to a stirred solution of N,N-diisopropylphosphorodichloridite (2.0 mL, 10.9 mmol) in THF (50 mL) under argon at −78° C. The mixture was stirred at R.T. for 2 h, and then diluted with EA (200 mL). The mixture was washed with sat. aq. NaCl and dried over Na₂SO₄. After filtration, the filtrate was evaporated under reduced pressure to give a pale yellow oil. Purification by flash column chromatography using a gradient of EA (0-5%) in hexane containing 5% triethylamine afforded 59-4 (2.5 g, 4.25 mmol) as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.70-3.82 (m, 4H), 3.57-3.65 (m, 10H), 3.1 (t, 4H), 1.25 (s, 18H), 1.17 (t, 12H); ³¹P-NMR (CDCl₃): 148.0 ppm.

Compound 59-5 (285 mg, 0.9 mmol) and DCI (175 mg, 1.5 mmol) were coevaporated twice with ACN and then dissolved in ACN (5 mL). Compound 59-4 (790 mg, 1.35 mmol) in ACN (4 mL) was added, and the reaction was monitored by TLC. After 15 mins, tert-butylhydroperoxide (0.5 mL of 5.5M solution in decane) was added, and the mixture was stirred for 10 mins. The mixture was diluted with EA (25 mL), washed with sat. aq. NaHCO₃ and sat. aq. NaCl solution, dried over Na₂SO₄, filtered and concentrated. Purification by flash column chromatography using a gradient of EA (0-100%) in hexane afforded 59-6 (0.17 g, 0.22 mmol) as a white solid. Compound 59-6 was dissolved in 80% aq. HCOOH (5 mL). After 30 mins at R.T., the solvent was removed and coevaporated twice with toluene. The residue was dissolved in methanol (10 mL) and TEA (0.2 mL) was added. After 2 mins at R.T., the solvent was removed in vacuo. Purification by flash column chromatography using a gradient of methanol (0-15%) in DCM afforded compound 59 (90 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.70-3.82 (m, 4H), 3.57-3.65 (m, 4H), 3.1 (t, 4H) 1.61 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹P-NMR (CDCl₃): −1.55 ppm.

Example 51

Compound 60

Compound 60-1 (6.0 g, 31.6 mmol) was prepared using a similar procedure to the one used to prepared 59-3 using 4-chlorobutanol. Compound 60-1 was obtained as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.67 (s, 2H), 2.86 (m, 2H), 1.65 (m, 4H), 1.25 (s, 9H).

Compound 60-2 (2.14 g, 4.0 mmol) was prepared using a similar procedure to the one used to prepared 59-4. Compound 60-2 was obtained as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.67 (m, 6H), 2.86 (t, 4H), 1.65 (m, 8H), 1.25 (s, 18H), 1.17 (t, 12H). ³¹P-NMR (CDCl₃): 143.7 ppm.

Compound 60-3 (0.23 g, 0.22 mmol) was prepared using a similar procedure to the one used to prepared 59-6 using 59-5 and 60-2. Compound 60-3 was obtained as a white solid. Using a similar procedure to the one used to prepared compound 59, 60-3 was used to prepare compound 60 (170 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 2.8 (t, 4H), 1.78 (m, 4H), 1.69 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹P-NMR (CDCl₃): −1.56 ppm.

Example 52

Compound 58

Compound 58-1 was prepared according to the procedure described in Lefebre et al. J. Med. Chem. (1995) 38:3941-3950, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 58-1.

Compound 58-2 (0.33 g, 0.5 mmol) was prepared using a similar procedure to the one used to prepared 59-6 using 59-5 and 58-1. Compound 58-2 was obtained as a white solid. Using a similar procedure to the one used to prepared compound 59, 58-2 was used to prepare compound 58 (130 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.2 (t, 4H), 1.69 (s, 4H), 1.3 (s, 3H), 1.23 (s, 18H); ³¹P-NMR (CDCl₃): −2.4 ppm.

Example 53

Compound 47

Compound 47-1 (1.0 g, 3.53 mmol) was coevaporated with anhydrous pyridine 3 times to remove H₂O. To an ice-cold solution of 47-1 in anhydrous pyridine (9 mL) was added TsCl (808 mg, 4.24 mmol) in pyridine (3 mL) drop-wise at 0° C., and the mixture was stirred for 18 h. at 0° C. The reaction was monitored by LCMS, and then quenched with H₂O. After concentration at low pressure, the residue was dissolved in EA (50 mL). The solution was washed with sat. NaHCO₃ solution and brine. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-2 (980 mg, 63%) as a white solid.

To a solution of 47-2 (980 mg, 2.24 mmol) in acetone (10 mL) was added NaI (1.01 g, 6.73 mmol), and the mixture was heated to reflux overnight. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated at low pressure. The residue was dissolved in EA (50 mL). The solution was washed with brine, and dried over anhydrous Na₂SO₄. The solution was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-3 (700 mg, 79%) as a solid.

To a solution of 47-3 (700 mg, 1.78 mmol) in dry THF (9 mL) was added DBU (817 mg, 5.34 mmol), and the mixture was heated to 60° C. The mixture was stirred overnight, and monitored by LCMS. The reaction was quenched with sat. NaHCO₃ and extracted with EA (3×50 mL). The organic phase was dried over anhydrous Na₂SO₄, and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-4 (250 mg, 53%) as a white solid.

To an ice-clod solution of 47-4 (250 mg, 0.94 mmol) in dry MeCN (5 mL) was added NEt₃.3HF (151 mg, 0.94 mmol) and NIS (255 mg, 1.13 mmol). The mixture was stirred at R.T., for 3 h., and checked by LCMS. The reaction was quenched with sat Na₂S₂O₃ and sat. NaHCO₃ solution, and extracted with EA (3×50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (2% acetone in DCM) to give 47-5 (170 mg, 44%).

To a solution of 47-5 (270 mg, 0.65 mmol) in dry DCM (4 mL) was added DMAP (158.6 mg, 1.3 mmol), and BzCl (137 mg, 0.98 mmol). The mixture was stirred for 4-5 h. at R.T., and checked by LCMS. The mixture was diluted with CH₂Cl₂, and washed with sat. NaHCO₃ solution and brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-6 (290 mg, 86%) as a solid.

To a solution of 47-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (4.5 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100° C. The mixture was diluted with EA (100 mL), and washed with brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-7 (500 mg, 56%) as a solid.

To a solution of 47-7 (500 mg, 0.98 mmol) in anhydrous CH₃CN (5 mL) was added TPSCl (741 mg, 2.45 mmol), DMAP (299.6 mg, 2.45 mmol) and NEt₃ (248 mg, 2.45 mmol) at R.T., and the mixture was stirred overnight. The mixture was then treated with NH₃ in THF (5 mL) and then stirred for another 30 mins. The mixture was diluted with EA (100 mL). The solution was washed with 0.5% AcOH solution. The organic solvent was dried over anhydrous MgSO4, and concentrated at low pressure. The crude product was purified by silica gel column chromatography (2% Acetone in DCM) to give 47-8 (257 mg, 51.6%) as a white solid. ESI-MS: m/z 509 [M+H]⁺.

Compound 47-8 (80 mg, 0.16 mmol) was dissolved in n-butylamine (3 mL). The mixture was kept overnight at R.T. and evaporated. The residue was crystallized from methanol to give compound 47 (30 mg). The mother liquor was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer to yield additional compound 47 (13 mg). Compound 47 (total yield 43 mg, 73%). MS: m/z 299.7 [M−1]⁻.

Example 54

Compound 83

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added 1-naphthol (1.88 g, 13 mmol) at −70° C., and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed to R.T. and stirred for 1 h. Crude 83-1 was obtained.

To a stirred solution of (S)-isopropyl 2-aminopropanoate hydrochloride (2.17 g, 13 mmol) in DCM (10 mL) was added crude 83-1 at −70° C. TEA (2.63 g, 26 mmol) was added to the stirred solution dropwise at −70° C. The mixture was gradually warmed to R.T. and stirred for 2 h. The reaction was monitored by LCMS and quenched with n-propylamine. The mixture was concentrated at low pressure, and the residue was purified by a silica gel column (PE:MTBE=5:1˜1:1) to give pure 83-2 (1.6 g, 35%).

To a solution of 83-(A) (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol) in anhydrous CH₃CN (4 mL) was added 83-2 (240 mg, 0.674 mol, in DCM (5 mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction was monitored by LCMS. The reaction was quenched with water, and extracted with CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by sil-gel (PE:EA=5:1˜2:1) to give 83-3 (380 mg, 93%).

Compound 83-3 (380 mg, 0.314 mmol) was dissolved in CH₃COOH (80%, 8 mL), and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMS. The mixture was concentrated at low pressure, and the residue was purified by chromatography (PE:EA=1:1˜EA) to give crude compound 83. The crude product was purified by prep-HPLC (neutral system, NH₄HCO₃) to give pure compound 83 (70 mg, 80%) as a white solid. ESI-MS: m/z 665.1 [M+H]⁺.

Example 55

Compound 79

A solution of 79-1 (16.70 g, 0.363 mol) and TEA (36.66 g, 0.363 mol) in CH₂Cl₂ (150 mL) was added dropwise to a stirred solution of POCl₃ (55.65 g, 0.363 mol) in DCM (100 mL) over 25 mins at −78° C. After the mixture was stirred for 2 h. at R.T., the triethylamine hydrochloride salt was filtered, and washed with CH₂Cl₂ (100 mL). The filtrate was concentrated at low pressure, and the residue was distilled under high vacuum (˜10 mm Hg) with a cow-head fraction collector. The product was collected between 45° C. (distillation head temperature) as a colorless liquid (30.5 g, 50% yield). ¹H-NMR (400 MHz, CDCl₃) δ=4.44 (dq, J=10.85, 7.17 Hz, 2H), 1.44-1.57 (m, 3H); ³¹P-NMR (162 MHz, CDCl₃) δ=6.75 (br. s., 1 P).

To a stirred suspension of 83-A (93 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) was added TEA (61 mg, 0.15 mmol) at R.T. The mixture was cooled to −20° C., and then was treated with a 79-2 (35 mg, 0.21 mmol) solution dropwise over a period of 10 mins. The mixture was stirred at this temperature for 15 min., and then was treated with NMI (27 mg, 0.33 mmol). The mixture was stirred at −20° C., and then slowly warmed to R.T. The mixture was stirred overnight. The mixture was suspended in EA (15 mL), washed with brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated at low pressure, and the residue was purified by chromatography (DCM:MeOH=100:1) to give 79-3 (60 mg, yield: 56%) as a solid.

A solution of 79-3 (60 mg, 0.085 mmol) in 80% AcOH aqueous (2 mL) was stirred at R.T. for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column eluting DCM/MeOH=50/1 and prep-HPLC to give compound 79 (23 mg, 62%) as a white solid. ESI-MS: m/z 436.3 [M+H]⁺.

Example 56

Compound 80

Compound 80-2 was prepared using a similar procedure as for the preparation of 79-2 using a solution of iso-butanol (23.9 g, 322.98 mmol) and POCl₃ (49.5 g, 322.98 mmol). Compound 80-2 (26 g, 42% yield) was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.10 (dd, J=9.04, 6.39 Hz, 2H), 2.09 (dq, J=13.24, 6.67, 6.67, 6.67, 6.67 Hz, 1H), 1.01 (d, J=6.62 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=7.06 (br. s., 1 P).

To a stirred suspension of 83-A (310 mg, 0.5 mmol) in CH₂Cl₂ (3 mL) was added TEA (202 mg, 2 mmol) at R.T. The mixture was cooled to −20° C., and then was treated with 80-2 (134 mg, 0.7 mmol). The mixture was stirred at this temperature for 15 mins and then was treated with NMI (90 mg, 1.1 mmol). The mixture was stirred at −20° C. for 1 h., and then slowly warmed to R.T. overnight. The mixture was suspended in EA (15 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated at low pressure, and the residue was purified by silica column gel (DCM:MeOH=100:1) to give 80-3 (310 mg, yield: 84%) as a solid.

A solution of 80-3 (310 mg, 0.43 mmol) in 80% AcOH aqueous (4 mL) was stirred at R.T. for 2 h. The mixture was concentrated at low pressure, and the residue was purified by a silica gel column eluting DCM/MeOH=50/1 and prep-HPLC to give compound 80 (79 mg, 50%) as a white solid. ESI-MS: m/z 464.0 [M+H]⁺.

Example 57

Compound 81

Compound 81-2 was prepared using a similar procedure as for the preparation of 79-2 using a solution of isopropyl alcohol (21 g, 350 mmol) and POCl₃ (53.6 g, 350 mmol). Compound 81-2 (40.5 g, 65% yield) was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.94-5.10 (m, 1H), 1.48 (d, J=6.17 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=5.58 (br. s., 1 P).

Compound 81-3 was prepared using a similar procedure as for the preparation of 80-3 using 81-2 (124 mg, 0.7 mmol) and 83-A (310 mg, 0.5 mmol). Compound 81-3 (300 mg, 83%) was obtained as a solid.

Compound 81 was prepared using a similar procedure as for the preparation of compound 80 using 81-3 (300 mg, 0.41 mmol) in 80% AcOH aqueous (4 mL). Compound 81 (80 mg, 43%) was obtained as a white solid. ESI-MS: m/z 450.0 [M+H]⁺.

Example 58

Compound 82

To an ice cooled solution of 82-1 (50 g, 204.9 mmol) in dry Py (400 mL) was added TIPDSCl (70.78 g, 225.4 mmol) dropwise. The mixture was stirred at R.T. for 16 h, and then concentrated at low pressure. The residue was purified by chromatography using 20% EA in PE to generate 82-2 (111.5 g, 100%) as a white solid.

To a solution of 82-2 (50 g, 103 mmol) in anhydrous CH₃CN (400 mL) was added IBX (43 g, 153 mmol) at R.T. The mixture was refluxed overnight and monitored by TLC (PE:EA=1:1). The precipitate was filtered off, and the filtrate was concentrated to give the crude 82-3 (50 g, 99%) as a white solid.

To a solution of trimethylsilylacetylene (20 g, 200 mmol) in anhydrous THF (400 mL) was added dropwise n-BuLi (80 mL, 200 mL) at −78° C. The mixture was stirred at −78° C. for 30 mins, and then warmed to R.T for 10 mins. Compound 82-3 (30 g, 60 mmol) in THF (100 mL) was added to the mixture dropwise at −78° C. The mixture was stirred at −78° C. for 1 h and then slowly warmed to R.T. The mixture was stirred for 20 mins, and then the reaction was quenched with a sat. NH₄Cl solution at −78° C. The mixture was diluted with EA. The organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (15% EA in PE) to give 82-4 as a white solid (14 g, 50%).

Compound 82-4 (14 g, 24 mmol) was dissolved in anhydrous toluene (100 mL) under N₂ and cooled to −78° C. DAST (19 g, 120 mmol) was added dropwise at −78° C. and stirring was continued for 1.5 h. The mixture was diluted with EA and poured into a sat. NaHCO₃ solution. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel chromatography (20% EA in PE) to give 82-5 as a white solid (12 g, 81%).

A mixture of 82-5 (12 g, 20 mmol) and NH₄F (11 g, 30 mmol) in MeOH (150 mL) was refluxed for 2 h. After cooling to R.T, the mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% MeOH in DCM) to give 82-6 (3.1 g, 58%) as a white solid.

To a solution of 82-6 (3.1 g, 11.6 mmol) in dry Py (50 mL) was added imidazole (3.1 g, 46.4 mmol) and TBSCl (5.2 g, 34.8 mmol). The mixture was stirred at 50-60° C. for 3 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (100 mL). The solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel chromatography (20% EA in PE) to give 82-7 as a white solid (5 g, 86%).

To a solution of 82-7 (4.5 g, 9 mmol) in 1,4-dioxane (45 mL) was added CuBr (643 mg, 4.5 mmol), dicyclohexylamine (3.3 g, 18 mmol) and paraformaldehyde (675 mg, 22.5 mmol). The mixture was refluxed for 24 h and then cooled to R.T. The reaction was quenched with a sat. NH₄Cl solution. The mixture was extracted with EA (3×100 mL). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (15% EA in PE) to give 82-8 as a white solid (2.0 g, 43%).

A mixture of 82-8 (2 g, 4 mmol) and NH₄F (2.2 g, 60 mmol) in MeOH (20 mL) was refluxed overnight. After cooling to R.T., the mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% MeOH in DCM) to give 82-9 (946 mg, 83%) as a white solid.

To a stirred suspension of 82-9 (946 mg, 3.33 mmol), PPh₃ (1.3 g, 5 mmol), imidazole (453 mg, 6.66 mmol) and pyridine (3 mL) in anhydrous THF (12 mL) was added a solution of I₂ (1 g, 4.33 mmol) in THF (4 mL) dropwise at 0° C. The mixture was warmed to R.T. and stirred for 16 h. The reaction was quenched with a sat. Na₂S₂O₃ aq. solution and extracted with EA (3×60 mL). The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified on a silica gel column (2% MeOH in DCM to 5% MeOH in DCM) to afford 82-10 (2.1 g, crude) as a white solid.

To a solution of 82-10 (2.1 g, 5.3 mmol) in THF (15 mL) was added DBU (15 g, 100 mmol) and the mixture stirred for 30 mins. The mixture was diluted with EA and neutralized with acetic acid. The solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (1.5% MeOH in DCM) to give 82-11 as a white solid (800 mg, 90%).

To an ice-cooled solution of 82-11 (800 mg, 3 mmol) in dry MeCN (1.5 mL) was added NEt₃.3HF (484 mg, 3 mmol) and NIS (1.68 g, 7.5 mmol). The mixture was stirred at R.T. for 30 mins., and the reaction was monitored by LCMS. The reaction was quenched with sat. Na₂S₂O₃ and sat. NaHCO₃ solution, and extracted with EA (3×50 mL). The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by a silica gel column (25% EA in PE) to afford 82-12 (850 mg, 68%) as a white solid.

To a solution of 82-12 (850 mg, 2 mmol) in dry DCM (10 mL) was added DMAP (488 mg, 4 mmol) and BzCl (422 mg, 3 mol). The mixture was stirred for 4-5 h at R.T., and the reaction was monitored by LCMS. The mixture was diluted with CH₂Cl₂ (40 mL), and washed with a sat. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 82-13 (900 mg, 87%) as a white foam.

Tetra-butylammonium hydroxide (21 mL as 54-56% aqueous solution, 42 mmol, 24 eq.) was adjusted with TFA to pH˜4 (˜3.5 mL), and the solution was treated with a solution of 82-13 (900 mg, 1.7 mmol) in DCM (21 mL). m-Chloroperbenzoic acid (2.1 g, 60-70%, ˜8.75 mmol, ˜5 eq.) was added portionwise under vigorous stirring, and the mixture was stirred overnight. The mixture was diluted with CH₂Cl₂ (30 mL), and washed with a saturated NaHCO₃ solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography in (40-70% EA in PE) to give 82-14 as an oil. The residue was purified by TLC (50% EA in PE) to give pure 82-14 (350 mg 50%).

Compound 82-14 (350 mg, 0.86 mg) was treated with 7N NH₃ in MeOH (15 mL). The mixture was stirred for 2-3 h and monitored by TLC. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% isopropanol in DCM) to give 82-15 (250 mg, 96%) as a white solid. ¹H NMR (CD₃OD, 400 M Hz) δ=7.75 (d, J=7.9 Hz, 1H), 6.60-6.35 (m, 1H), 5.72 (d, J=8.2 Hz, 1H), 5.37-5.25 (m, 1H), 5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 4.59-4.29 (m, 1H), 3.87-3.70 (m, 2H).

To a stirred solution of 82-16 (3.79 g, 18 mmol) and 82-17 (3 g, 18 mmol) in anhydrous DCM (60 mL) was added with a solution of TEA (4 g, 39 mmol) in DCM (40 mL) dropwise at −78° C., and the mixture was stirred for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was removed by filtration, and the filtrate was concentrated to give the crude product. The residue was purified by dry column chromatography (anhydrous DCM) to give pure 82-18 as a colorless oil (3 g, 54%).

Compound 82-15 (200 mg, 0.66 mmol) was coevaporated with toluene 3 times to remove H₂O. Compound 82-15 was treated with MeCN (1.5 mL) and NMI (541 mg, 6.6 mmol). The mixture was stirred at R.T., and then 82-18 (403 mg, 1.32 mmol) in MeCN (0.5 mL) was added. The residue was purified by a silica gel column (5% iPrOH in DCM) to give the crude product, which was purified by HPLC (0.1% HCOOH in water and MeCN) to give compound 82 (33 mg, 9%). ESI-LCMS: m/z 594 [M+Na]⁺.

Example 59

Compound 84

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added 1-naphthol (1.88 g, 13 mmol) at −70° C. and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed to R.T., and stirred for 1 h. A crude solution of 84-1 was obtained.

To a stirred solution of (S)-isobutyl 2-aminopropanoate hydrochloride (2.35 g, 13 mmol) in DCM (20 mL) was added TEA (2.63 g, 26 mmol) and a crude solution of 84-1 at −70° C. The mixture was gradually warmed to R.T., and stirred for 2 h. The reaction was monitored by LCMS and quenched with n-propylamine. The solvent was evaporated at low pressure, and the residue was purified by chromatography (PE:MTBE=5:1-1:1) to give pure 84-2 (1.8 g, 37%).

To a solution of 83-A (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol) in anhydrous CH₃CN (4 mL) was added 84-2 (249 mg, 0.674 mol, in DCM (5 mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction was monitored by LCMS, and then quenched with H₂O. The mixture was extracted with CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by chromatography using PE:EA=5:1˜2:1 as the eluent to give 84-3 (360 mg, 87%).

Compound 84-3 (360 mg, 0.294 mmol) was dissolved in CH₃COOH (80%, 8 mL), and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMS and then quenched with MeO. The mixture was concentrated at low pressure, and the residue was purified by chromatography using PE:EA=1:1 as the eluent to generate crude compound 84. The product purified by prep-HPLC (neutral system, NH₄HCO₃) to give compound 84 (70 mg, 75%) as a white solid. ESI-MS: m/z 679.2 [M+H]⁺.

Example 60

Compound 85

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added phenol (1.22 g, 13 mmol) at −70° C. and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed to R.T., and stirred for 1 h. A crude solution of 85-1 was obtained.

Compound 85 was prepared using a similar procedure as for the preparation of compound 84 using 85-2 (205 mg, 0.674 mol, in DCM (5 mL) obtained from (S)-isopropyl 2-aminopropanoate hydrochloride and 85-1) and 83-A (300 mg, 0.337 mmol). Compound 85 (50 mg, 74%) was obtained as a white solid. ESI-MS: m/z 615.2 [M+H]⁺.

Example 61

Compound 86

Compound 86 was prepared using a similar procedure as for the preparation of compound 84 using 86-2 (214 mg, 0.674 mol, in DCM (5 mL) obtained from (S)-isobutyl 2-aminopropanoate hydrochloride and 86-1) and 83-A (300 mg, 0.337 mmol). Compound 86 (70 mg, 87%) was obtained as a white solid. ESI-MS: m/z 629.2 [M+H]⁺.

Example 62

Compound 87

Compound 87 was prepared using a similar procedure as for the preparation of compound 84 using 87-2 (223 mg, 0.674 mol, DCM (5 mL) obtained from (S)-cyclopentyl 2-aminopropanoate hydrochloride and 87-1) and 83-A (300 mg, 0.337 mmol). Compound 87 (62 mg, 71%) was obtained as a white solid. ESI-MS: m/z 641.2 [M+H]⁺.

Example 63

Compound 88

Compound 88 was prepared using a similar procedure as for the preparation of compound 84 using 88-2 (223 mg, 0.674 mol, DCM (5 mL), obtained from (S)-3-pentyl 2-aminopropanoate hydrochloride and 88-1) and 83-A (300 mg, 0.337 mmol). Compound 88 (42 mg, 60%) was obtained as a white solid. ESI-MS: m/z 643.2 [M+H]⁺.

Example 64

Compound 89

A stirred solution of phosphoryl trichloride (1.00 g, 6.58 mmol) and 5-quinoline (955 mg, 6.58 mmol) in anhydrous DCM (50 mL) was treated with a solution of TEA (665 mg, 6.58 mmol) in DCM (10 mL) at −78° C. The mixture was gradually warmed to R.T., and stirred for 2 h. The solution was cooled to −78° C. and then treated with (S)-neopentyl 2-aminopropanoate hydrochloride (1.28 g, 6.58 mmol). TEA (1.33 g, 13.16 mmol) was added dropwise at −78° C. The mixture was gradually warmed to R.T., and stirred for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off, and the filtrate was concentrated at low pressure. The residue was purified by a silica gel column (pure AcOEt) to give 89-1 as colorless oil (500 mg, 20%).

To a solution of 89-2 (300 mg, 0.337 mmol) and NMI (276.6 mg, 3.37 mmol) in anhydrous CH₃CN (0.9 mL) was added 89-1 (388 mg, 1.011 mmol) in CH₃CN (0.3 mL) dropwise at 0° C. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and extracted with AcOEt. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by silica gel column (33% EA in PE) to give 89-3 as a yellow powder (300 mg, 71.9%).

Compound 89-3 (300 mg, 0.243 mmol) was dissolved in 80% CH₃COOH (3 mL), and the mixture was stirred at 60° C. for 2.5 h. The mixture was partitioned between AcOEt and water. The organic layer phase was washed by brine, dried over sodium sulfate and concentrated at low pressure. The residue was purified by silica gel column (50% EA in PE) to give compound 89 as a yellow powder (81 mg, crude product). The crude product (81 mg) was purified by RP HPLC to give compound 89 as a white solid. (28.7 mg, 17.1%). ESI-LCMS: m/z 694.1 [M+H]⁺.

Example 65

Compound 90

Compound 90-1 was prepared using a similar procedure as for the preparation of compound 89-1 using phosphoryl trichloride (2.00 g, 13.16 mmol), 1-naphthol (1.882 g, 13.16 mmol) and (S)-neopentyl 2-aminopropanoate hydrochloride (2.549 g, 13.16 mmol). Compound 90-1 (600 mg, 12%) was obtained as a colorless oil.

A solution of 90-2 (230 mg 0.26 mmol) and NMI (212 mg 2.60 mmol) in anhydrous CH₃CN (1 mL) was treated with a solution of 90-1 (300 mg 0.78 mmol) in anhydrous CH₃CN (0.5 mL) at R.T. The mixture was stirred at R.T. overnight. The reaction was quenched with water, and extracted with EA (3×20 mL). The organic layer was washed with brine, dried by anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) to give 90-3 (300 mg, 93%) as a white solid.

Compound 90-3 (300 mg, 0.24 mmol) was dissolved in CH₃COOH (80%, 5 mL). The mixture was stirred at 60° C. for 2.5 h. The mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) to give crude compound 90 (105 mg). The crude product was purified by HPLC (0.1% NH₄HCO₃ in water and CH₃CN) to give compound 90 (45 mg, 26%) as a white solid. ESI-LCMS: m/z 693.2 [M+H]⁺.

Example 66

Compound 91

A stirred solution of 91-1 (2.00 g, 13.99 mmol) and 91-2 (2.00 g, 13.99 mmol) in anhydrous DCM (8 mL) was treated with a solution of TEA (3.11 g, 30.8 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was stirred for 2 h. at −78° C. and then gradually warmed to R.T. The organic solvent was removed at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (dry DCM) to give 91-3 as colorless oil (1 g, 20.96%).

Compound 91-4 (260 mg, 0.29 mmol) was coevaporated with toluene 3 times to remove H₂O. Dried 91-4 was treated with MeCN (0.8 mL) and NMI (240 mg, 2.9 mmol) and then stirred for 10 mins. The mixture was treated with a solution of 91-3 (291 mg, 0.87 mmol) in MeCN (0.4 mL), and then concentrated at low pressure. The residue was purified on a silica gel column (75% EA in PE)) to give 91-5 (300 mg, 86%) as a white solid.

Compound 91-5 (300 mg, 0.25 mmol) was treated with CH₃COOH (5 mL, 80%), and stirred at 50° C. for 3 h. The mixture was diluted with EA. The solution was washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by silica gel column chromatography (67% EA in PE) to give crude compound 91, which was purified by HPLC. The product was dried by lyophilization to give compound 91 (30 mg, 18.5%) as a white solid. ESI-LCMS: m/z 643 [M+H]⁺.

Example 67

Compound 77

To a solution of 1,1-dimethoxycyclopentane (19.3 g, 148.52 mmol) and 77-1 (10.0 g, 37.13 mmol) in DCE (100 mL) was added TsOH.H₂O (0.7 g, 3.71 mmol). The mixture was stirred at 50° C. for 12 h. The mixture was neutralized with Et₃N, and concentrated at low pressure. The residue was purified by silica gel column chromatography (1-10% MeOH in DCM) to give 77-2 (8.7 g, 70.1%) as a white solid.

Compound 77-2 (20.0 g, 0.06 mol) was coevaporated with anhydrous pyridine 3 times to remove H₂O. To an ice-cold solution of 77-2 in anhydrous pyridine (100 mL) was added TsCl (22.8 g, 0.12 mol) at 0° C., and the mixture was stirred overnight. The reaction was monitored by LCMS and TLC. The reaction was quenched with H₂O, and the mixture extracted with EA (3×200 mL). The solution was dried over anhydrous Na₂SO₄ and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 77-3 (20.0 g, 69.0%) as a white solid.

To a solution of 77-3 (20.0 g, 0.04 mol) in acetone (200 mL) was added NaI (31.0 g, 0.2 mol), and the mixture was heated to reflux overnight. The reaction was monitored by LCMS. The reaction was quenched with a sat. Na₂S₂O₃ solution. The solution was extracted with EA (3×200 mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 77-4 (15.0 g, 83.3%) as a white solid.

Compound 77-4 (13.4 g, 30.16 mmol) was treated with HCOOH (80%) in H₂O at R.T. The solution was stirred at 60° C. for 2 h. The mixture was concentrated at low pressure. The residue was purified by column chromatography (1%-10% MeOH in DCM) to give 77-5 (9.1 g, 80.0%) as a white solid.

To a solution of 77-5 (5.0 g, 13.22 mmol) in anhydrous CH₃CN/THF (50 mL, 1:1, v:v) was added DBU (6.0 g, 39.66 mmol) at R.T. The solution was stirred at 50° C. for 1.5 h. The reaction was quenched with HCOOH at 0° C., and then concentrated at low pressure. The residue was purified by column chromatography (50%-70% EA in PE) to give 77-6 (3.3 g, 48.1%) as a white solid.

To an ice-cold solution of 77-6 (2.1 g, 8.39 mmol) in anhydrous MeCN (21 mL) was added NIS (2.4 g, 10.49 mmol) and TEA.3HF (1.0 g, 6.29 mmol) under N₂. The mixture was stirred at R.T. for 1 h. The reaction was quenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extracted with EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (30%-50% EA in PE) to give 77-7 (1.3 g, 39.3%) as a light yellow solid.

To a stirred solution of 77-7 (3.2 g, 8.08 mmol) in anhydrous DCM (32 mL) was added DMAP (2.5 g, 20.20 mmol) and Et₃N (2.5 g, 24.24 mmol) at R.T. The mixture was treated with BzCl (3.7 g, 26.66 mmol) at 0° C. and then stirred at R.T. overnight. The reaction was quenched with water, and extracted with EA (3×60 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography (20%-30% EA in PE) to give 77-8 (1.8 g, 31.6%) as a white solid.

Bu₄NOH (8.0 g, 13.74 mL, 55% in H₂O) was adjusted to pH=3-4 with TFA, and then cooled to R.T. To a solution of 77-8 (600 mg, 0.85 mmol) in DCM (10 mL) was added the Bu₄NOH solution and m-CPBA (917 mg, 4.25 mmol, 80%) at R.T. The mixture was stirred at 25° C. for 48 h and then washed with a sat. NaHCO₃ solution. The organic layer was directly passed through basic Al₂O₃ column, and the solvent was concentrated at low pressure. The residue was purified by a silica gel column (20%-30% EA in PE) to give 77-9 (123 mg, 24.3%) as a white solid.

To a solution of 77-9 (300 mg, 0.50 mmol) in EA/hexane (20 mL, 1:1, v:v) was added Lindlar catalyst (200 mg) under N₂. The mixture was stirred under H₂ (40 Psi) at 2° C. for 1.5 h. The suspension was filtered, and the filtrate was treated with Lindlar catalyst (200 mg) under N₂, and stirred under H2 (40 Psi) at 25° C. for 1.5 h. The mixture was filtered, and the filtrate was concentrated at low pressure to give crude 77-10 (287 mg) as a white solid.

Compound 77-10 (287 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7 M). The mixture was stirred at R.T. for 24 h under N₂ and then concentrated at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give 77-11 (50 mg, 34.7% over two steps) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=7.86 (d, J=8.0 Hz 1H), 6.26 (s, 1H), 5.62-5.86 (m, 1H), 5.49 (d, J=17.1 Hz, 1H), 5.30 (d, J=10.5 Hz, 1H), 4.41 (d, J=19.3 Hz, 1H), 3.71-3.86 (m, 1H).

Compound 77-11 (113 mg, 0.39 mmol) was co-evaporated with toluene 3 times to remove H₂O. To a stirred solution of 77-11 (113 mg, 0.39 mmol) in a mixture of MeCN (0.5 mL) and NMI (320 mg, 3.90 mmol) was added a solution of 73-C (256 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight and then concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to give crude compound 77, which purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 77 (45 mg, 20.1%) as a white solid. ESI-MS: m/z 538.2 [M−F]⁺ ESI-MS: m/z 580.2 [M+Na]⁺.

Example 68

Compound 78

To a solution of 77-9 (300 mg, 0.50 mmol) in MeOH (30 mL) was added wet Pd/C (300 mg, 10%) under N₂. The mixture was stirred under H₂ (1 atm) at 25° C. for 1.5 h. The suspension was filtered, and then concentrated at low pressure to give crude 78-1 (307 mg) as a white solid.

Compound 78-1 (307 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7 M). The mixture was stirred at R.T. for 24 h under N₂ then concentrated at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give 78-2 (30 mg, 21% over two steps) as a white solid.

Compound 78-2 (91 mg, 0.31 mmol) was co-evaporated with toluene 3 times to remove H₂O. To a stirred solution of 78-2 (91 mg, 0.31 mmol) in a mixture of MeCN (0.5 mL) and NMI (254 mg, 3.90 mmol) was added a solution 73-C (203 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixture was stirred at R.T. overnight and then concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to the crude compound 78, which purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 78 (30 mg, 17%) as a white solid. ESI-MS: m/z 540.1 [M−F]⁺.

Example 69

Additional Compounds of Formula (I)

The foregoing syntheses are exemplary and can be used as a starting point to prepare a large number of additional compounds. Examples of compounds of Formula (I) that can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

Example 70

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 h. At 72 h, 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.

Compounds of Formula (I) are active in the replicon assay. The antiviral activity of exemplary compounds is shown in Table 2, where ‘A’ indicates an EC₅₀<1 μM, ‘B’ indicates an EC₅₀≥1 μM and <10 μM, and ‘C’ indicates an EC₅₀≥10 μM and <100 μM.

TABLE 2
Compound # EC50
2          A
3          A
5          A
11         A
13         B
14         A
16         A
17         A
18         A
19         A
20         A
21         A
22         A
27         C
28         A
29         C
30         A
31         A
32         A
33         A
34         A
35         A
36         A
37         A
40         B
41         B
42         A
43         A
49         A
51         B
52         A
53         A
54         A
55         A
56         A
57         A
58         A
59         C
60         C
61         A
62         A
66         A
67         B
70         B
73         B
77         B
79         A
80         B
81         A
83         A
84         A
85         A
86         A
87         A
88         A
89         A
90         A
91         A

Example 71

NS5B Inhibition Assay

The enzyme activity of NS5B570-Con1 (Delta-21) was measured as an incorporation of tritiated NMP into acid-insoluble RNA products. The complementary IRES (cIRES) RNA sequence was used as a template, corresponding to 377 nucleotides from the 3′-end of HCV (−) strand RNA of the Con-1 strain, with a base content of 21% Ade, 23% Ura, 28% Cyt, and 28% Gua. The cIRES RNA was transcribed in vitro using a T7 transcription kit (Ambion, Inc.) and purified using the Qiagen RNeasy maxi kit. HCV polymerase reactions contained 50 nM NS5B570-Con1, 50 nM cIRES RNA, about 0.5 μLCi tritiated NTP, 1 μM of competing cold NTP, 20 mM NaCl, 40 mM Tris-HCl (pH 8.0), 4 mM dithiothreitol, and 4 mM MgCl₂. Standard reactions were incubated for 2 h at 37° C., in the presence of increasing concentration of inhibitor. At the end of the reaction, RNA was precipitated with 10% TCA, and acid-insoluble RNA products were filtered on a size exclusion 96-well plate. After washing of the plate, scintillation liquid was added and radio labeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The compound concentration at which the enzyme-catalyzed rate was reduced by 50% (IC₅₀) was calculated by fitting the data to a non-linear regression (sigmoidal). The IC₅₀ values were derived from the mean of several independent experiments and are shown in Table 3. Compounds of Formula (I) showed activity in this assay. A value of ‘A’ in the table below indicates an IC₅₀ of <1 μM, a value of ‘B’ indicates an IC₅₀≥1 μM and <10 μM, and a value of ‘C’ indicates an IC₅₀ value of ≥10 μM and <100 μM.

TABLE 3
Compound # IC50
6          A
7a         A
7b         B
9          A
12         A
15         A
26         A
28         A
38         A
44         A
46         A
50         A
63         A
64         A
69         A
76         A

Example 72

Assessment of Inhibition of Mitochondrial Function

Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in patients treated with antiviral nucleoside/nucleotides. For this reason, evaluation of compounds for their potential to inhibit mitochondrial function is useful. To assess the potential for nucleotide/nucleoside analogs to interfere with normal mitochondrial functions and exhibit mitochondrial toxicity, the following were measured: (1) the ability of nucleotides to be incorporated by human mitochondrial RNA polymerase in vitro and (2) the cellular inhibition of the synthesis of the mitochondrial DNA (mtDNA)-encoded protein, cytochrome c oxidase (COX-I), relative to the nuclear DNA (nDNA)-encoded mitochondrial protein succinate dehydrogenase subunit A (SDH-A) in HepG2 cells. Control compounds and compounds of Formula (I) were studied in these assays.

Biochemical Assay

Arnold et al. “Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides” PLoS Pathog (2012) 8(11): e1003030. doi:10.1371/journal.ppat.1003030, which is hereby incorporated by reference in its entirety.

Assessment of Incorporation of Nucleotides by Human Mitochondrial RNA Polymerase (HMRP)

DdRp Assay with Human Mitochondrial RNA Polymerase

The DdRp assay with human mitochondrial RNA polymerase was performed under single turnover conditions where enzyme concentration is in excess of the primer/template. The ³³P-RNA/DNA primer/template was used at a concentration of 100 nM, together with 320 nM enzyme. The standard 10-μL reactions were carried out at 30° C. for 1 minute with 100 μM of each nucleotide 5′-triphosphate (NTP), 10 mM MgCl₂, 50 mM NaCl, 40 mM Tris, pH 7.5, and 1 mM DTT. The reaction was stopped by adding 20 μL of formamide loading dye containing 50 mM EDTA. RNA products were resolved by electrophoresis on 22.5% TBE Urea polyacrylamide sequencing gels that were scanned using a TYPHOON PhosphorImager.

Results

As shown in both FIGS. 10 and 11, the appropriate natural nucleotides were shown to be good substrates for incorporation by HMRP in each template. The template in FIG. 10 was designed to measure incorporation of UTP analogs. Primer/Template: (SEQ ID NO: 1) UUUUGCCGCGCC and (SEQ ID NO: 2) GGGAATGCTAGGCGCGGC. In the control water lanes, wherein no nucleotides were added, no incorporation was observed as indicated by the lack of product band. As shown in FIG. 10, UTP and 3′-deoxy-UTP were efficient substrates for incorporation as indicated by the prominent product band. The potential for misincorporation was assessed using the control nucleotide CTP. As provided in FIG. 10, CTP was incorporated to a lesser extent relative to UTP. In contrast to UTP and 3′-deoxy-UTP, compounds of Formula (I) and 2′-Me-2′-F-UTP were not efficient substrates for incorporation by HMRP as demonstrated by the lack of product band.

The template strand shown in FIG. 11 was designed to measure the incorporation of GTP analogs. Primer/Template: (SEQ ID NO: 3) UUUUGCCGCGCC and (SEQ ID NO: 4) GGGAATGCACGGCGCGGC. In the control water lanes, no incorporation was observed as indicated by the lack of product band. GTP and 3′-deoxy-GTP were found to be efficient substrates for incorporation as demonstrated by the significant product bands. The potential for misincorporation was assessed using the control nucleotide ATP. As shown by the lack of product band in FIG. 11, control ATP was a poor substrate for incorporation. Nucleotide analog 2′-Me-GTP (the nucleotide metabolite of monophosphate prodrug INX-0189/BMS-986094) was tested and found to be a good substrate for incorporation by HMRP as indicated by the product band. Nucleotide analog 2′-Me-2′-F-GTP (nucleotide metabolite of monophosphate prodrug GS-938) was tested and also found to be incorporated by HMRP. In contrast, compounds of Formula (I) were not efficient substrates for incorporation into the template strand by HMRP as indicated by the lack of product bands in FIG. 11.

Assessment of Inhibition of Mitochondrial Protein Synthesis—Cell Based Assay

Assay Principle

MitoBiogenesis™ In Cell ELISA kits (Cat. # MS643) were obtained from Mitosciences, OR, USA. The MitoBiogenesis™ In Cell ELISA kit is a duplexing 96 well assay that ratios both an mtDNA and an nDNA encoded mitochondrial protein. Cells were seeded in 96 microplates and after exposure to compounds for several cell doublings, the levels of the two mitochondrial proteins were measured simultaneously in each well. The two proteins assayed were each subunits of different oxidative phosphorylation enzyme complexes, one protein being subunit I of Complex IV (cytochrome c oxidase; COX I) that is mtDNA encoded and the other being the 70 kDa subunit of Complex II (succinate dehydrogenase subunit A; SDH A) that is nDNA encoded. Complex IV includes several proteins that are encoded by the mtDNA while the proteins of Complex II are entirely encoded by nDNA. To control for the density of cells present at the end of the culture period, the number of cells were assessed by staining with Janus Green and the levels of COX I/SDH A normalized to the final cell density.

96 Well Plate Assay Format for HepG2 Cells

On the first day, 1000 HepG2 cells per well were plated in a 96 well plate. On the following day, compounds to be tested were solubilized in 100% DMSO to 100× the desired final testing concentration. Each compound was serially diluted (1:3) up to 9 distinct concentrations. Compounds in 100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cell culture media. A 10 μL aliquot of the compounds diluted to 10% (v/v) DMSO with cell culture media was used to dose the cells in duplicate. The final DMSO concentration was 1% (v/v). Untreated cells and wells containing no cells were included on the plate to serve as controls. Cells were then incubated with compounds and observed for 8 days at 37° C. and 5% CO₂. Plates were processed as described below in the assay procedure.

Batch Assay Format for HepG2 Cells

An alternate cell culture procedure was employed to test the potential to mediate mitochondrial toxicity at higher concentrations than achievable in the 96 well plate format. HepG2 cells were grown either in media/DMSO alone or in a series of compound concentrations in 15 cm² dishes or 6 well plates at an initial cell seeding density of 5×10⁶ and 5×10⁴ cells/mL, respectively. Cells were then incubated and observed for 8 days at 37° C. and 5% CO₂. After 8 days, the cells were harvested by trypsinization, counted, and seeded in 96 well plates at a density of 25,000 cells/well in 16 replicate wells. Cells were allowed to adhere overnight and then the plates were processed as described below in the assay procedure.

Assay Procedure

The assay was performed according to the manufacturer's instructions. Briefly, after the end of the culture period the cell culture media was gently aspirated from the wells of the plate and replaced with 100 μL of 4% (v/v) paraformaldehyde solution in phosphate buffered saline (PBS, Electron Microscopy Sciences Cat. #15713). After a 20 mins incubation at R.T., the solution was removed and the wells washed 3× with 300 μL of PBS. After the final wash, the PBS was removed and the wells overlayed with 100 μL PBS. The plates were then sealed and stored at 4° C. until used. To perform the assay, the PBS overlay was removed by blotting on a paper towel and 100 μL of 0.5% (v/v) acetic acid added to each well to block endogenous alkaline phosphatase activity. After a 5 mins incubation at R.T., the acetic acid solution was removed and the cells washed once with 200 L PBS. Then, 100 μL of permeabilization buffer (0.1% (v/v) Triton X 100) was added to each well. After 30 mins incubation at R.T., the permeabilization buffer was removed and each well was blocked with 200 μL of 2× blocking solution for 2 h at R.T. The 2× blocking solution was then removed and 100 μL of primary antibody solution containing anti COX I and anti SDH A antibodies in 1× blocking solution was added to each well. Plates were then sealed and incubated overnight at 4° C. The primary antibody/blocking solution was removed and the plate washed 3× with 250 μL 0.05% (v/v) Tween 20 in PBS. Then, 100 μL of secondary antibody solution containing alkaline phosphatase (AP) labeled anti SDH A antibody and horseradish peroxidase (HRP) labeled anti COX I antibody was added and incubated for 1 h at R.T. The plate was then washed 4× with 250 μL 0.05% (v/v) Tween 20 in PBS. After blotting the plate dry 100 μL of AP detection reagent was added to each well, and the plate incubated in the dark for 30 mins at R.T. The optical density of each well was then measured at 405 nm. The AP detection reagent was then removed and replaced with 100 μL of HRP detection reagent, and the plate incubated in the dark for a further 30 mins at R.T. The optical density of each well was then measured at 600 nm. The HRP detection reagent was then removed and each well was then stained with 50 μL of 1× Janus Green Stain for 5 mins at R.T. After removal of the dye, the plates were washed 5× in ultrapure water to remove any remaining dye. The Janus Green stain was then solubilized by the addition of 100 μL of 0.5 M HCl and incubated for 10 mins. The optical density of each well was then measured at 595 nm.

Data Analysis

The average of all replicate background measurements from each experimental condition was calculated and subtracted from the experimental values of the same condition. The SDH A and COX I signals were then plotted as a ratio (COX I/SDH A) and normalized to the Janus Green staining intensity to correct for differences in cell density.

Results

Control compound d4T was tested and found not to inhibit mitochondrial protein synthesis at concentrations up to 100 μM as shown in FIGS. 12A-D. Control compound ddC was tested and found to strongly inhibit mitochondrial protein synthesis. See FIGS. 12A-D. As demonstrated in FIG. 12A, nucleoside monophosphate prodrug INX-08189/BMS-986094 (which delivers 2′-Me-GTP) was tested in the assay and found to strongly inhibit mitochondrial protein synthesis. In contrast, compounds of Formula (I) were tested and found to not inhibit mitochondrial protein synthesis at concentrations up to 100 μM as shown in FIGS. 12B-D.

Example 73

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 18 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 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 synergy volume results for the combinations are provided in Table 4.

TABLE 4
Combination Compound	Synergy Volume (μM2 %)	Determination
ANA-598 (3002)	29.46	Synergistic
HCV-796 (3004)	81.72	Synergistic
Ribavirin (5012)	6.77	Additive
Filibuvir (3007)	23.51	Additive
VX-222 (3003)	32.35	Synergistic
BMS-790052 (4001)	38.01	Synergistic
VX-950 (1001)	32.28	Synergistic
TMC-435 (1013)	97.17	Synergistic

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 having the structure

3. The compound of claim 1 having the structure

4. The compound of claim 1 having the structure

5. The compound of claim 1 having the structure

6. The compound of claim 1 having the structure