SUBSTITUTED NUCLEOTIDE ANALOGS

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

1. Field


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


2. Description


Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, have been the subject of widespread research for the treatment of viral infections and cancer. Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active anti-metabolites, which, in turn, may inhibit polymerases involved in viral or cell proliferation. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.


SUMMARY

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


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


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


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


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


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


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


Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, 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 mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable salt of the foregoing, a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, 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 mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable salt of the foregoing, a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of Formula (I), 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 mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable salt of the foregoing, a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. In some embodiments, the agent can be a compound, or a pharmaceutically acceptable salt thereof, selected from Compound 1001-1014, 2001-2010, 3001-3008, 4001-4005, 5001-5002, 7000-7077, 8000-8012 or 9000, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or pharmaceutically acceptable salt thereof. In some embodiments, the method can 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 mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable salt of the foregoing, a compound of Formula (BB), or a pharmaceutically acceptable salt thereof and a compound of Formula (DD), or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is HCV.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 illustrates four chromatograms, labeled A, B, C and D, from the results of a hepatocyte activation assay.



FIGS. 2A-2B shows example HCV protease inhibitors.



FIG. 3 shows example nucleoside HCV polymerase inhibitors.



FIG. 4 shows example non-nucleoside HCV polymerase inhibitors.



FIG. 5 shows example NS5A inhibitors.



FIG. 6 shows example other antivirals.



FIGS. 7A-7M show example compounds of Formula (I).



FIGS. 8A-8O show example compounds of Formula (AA), and triphosphates thereof.



FIGS. 9A-9B show example compounds of Formula (BB).



FIG. 10 shows Formula (DD).





DETAILED DESCRIPTION

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


As used herein, any “R” group(s) such as, without limitation, R, R1, R2, R3a, R3b, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R1A, R2A, R3A, R3B, R4A, R5A, R6A, R7A, R8A, R9A and R″ represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R1a and R1b of an NR1aR1b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:




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


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


As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.


As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.


As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.


As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.


As used herein, “cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.


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


As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.


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


As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).


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


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


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


“Lower alkylene groups” are straight-chained —CH2— tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), and butylene (—CH2CH2CH2CH2—). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.”


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


As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.


As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.


As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


An “S-sulfonamido” group refers to a “—SO2N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.


An “N-sulfonamido” group refers to a “RSO2N(RA)—” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.


An “O-carbamyl” group refers to a “—OC(═O)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.


An “N-carbamyl” group refers to an “ROC(═O)N(RA)—” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.


An “O-thiocarbamyl” group refers to a “—OC(═S)—N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.


An “N-thiocarbamyl” group refers to an “ROC(═S)N(RA)—” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.


A “C-amido” group refers to a “—C(═O)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. A C-amido may be substituted or unsubstituted.


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


The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.


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


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


The term “nucleoside” is used herein in its ordinary sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer thereof via a N-glycosidic bond, such as attached via the 9-position of a purine-base or the 1-position of a pyrimidine-base. Examples include, but are not limited to, a ribonucleoside comprising a ribose moiety and a deoxyribonucleoside comprising a deoxyribose moiety. A modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a carbon has been replaced with a sulfur or an oxygen atom. A “nucleoside” is a monomer that can have a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.


As used herein, the term “heterocyclic base” refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety. In some embodiments, the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidine-base and an optionally substituted triazole-base (for example, a 1,2,4-triazole). The term “purine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term “pyrimidine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. A non-limiting list of optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, uric acid and isoguanine. Examples of pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). An example of an optionally substituted triazole-base is 1,2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo-N6-alkyladenine (e.g., 8-oxo-N6-methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N4,N4-ethanocytosin, N6,N6-ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Pat. Nos. 5,432,272 and 7,125,855, which are incorporated herein by reference for the limited purpose of disclosing additional heterocyclic bases. In some embodiments, a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).


The term “—N-linked amino acid” refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group. When the amino acid is attached in an —N-linked amino acid, one of the hydrogens that is part of the main-chain amino or mono-substituted amino group is not present and the amino acid is attached via the nitrogen. As used herein, the term “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and ε-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine. N-linked amino acids can be substituted or unsubstituted.


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


The terms “protecting group” and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes, and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); 4,4′,4″-trimethoxytrityl (TMTr); and those described herein).


“Leaving group” as used herein refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates and halogens. Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171; and Organic Chemistry, 5th ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.


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


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


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


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


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




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


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


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


It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.


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


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




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wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R1 can be selected from O, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R2 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and




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wherein R19, R20 and R21 can be independently absent or hydrogen, and n can be 0 or 1; provided that when R1 is Oor OH, then R2 is




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R3a and R3b can be independently selected from hydrogen, deuterium, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and aryl(C1-6 alkyl); or R3a and R3b can be taken together to form an optionally substituted C3-6 cycloalkyl; R4 can be selected from hydrogen, azido, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl; R5 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR10 and —OC(═O)R11; R6 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR12 and —OC(═O)R13; R7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR14 and —OC(═O)R′5; or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR16 and —OC(═O)R′7; R9 can be selected from hydrogen, azido, cyano, an optionally substituted C1-6 alkyl and —OR18; R10, R12, R14, R16 and R18 can be independently selected from hydrogen and an optionally substituted C1-6 alkyl; and R11, R13, R15 and R17 can be independently selected from an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl; with the proviso that when R3a, R3b, R4, R5, R7, R8, and R9 are all hydrogen, then R6 cannot be azido.


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




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wherein R19, R20 and R21 can be independently absent or hydrogen, and n can be 0 or 1. In some embodiments, n can be 0. In other embodiments, n can be 1. Those skilled in the art understand when n is 0, R2 can be an α-thiodiphosphate. Similarly, those skilled in the art understand when n is 1, R2 can be an α-thiotriphosphate. In some embodiments, at least one of R19, R20 and R21 can be absent. In other embodiments, at least one of R19, R20 and R21 can be hydrogen. In some embodiments, R20 and R21 can be absent. In other embodiments, R20 and R21 can be hydrogen. In some embodiments, R19, R20 and R21 can be absent. In some embodiments, R19, R20 and R21 can be hydrogen. Those skilled in the art understand that when any of R19, R20 and R21 are absent the oxygen atom to which R19, R20 and R21 are associated with can have a negative charge. For example, when R20 is absent, the oxygen atom to which R20 is associated with can be O. Depending upon the substituents attached to each phosphorus atoms, one or more the phosphorus atoms can be a chiral center. For example, when n is 1, the alpha-phosphorus (the phosphorus nearest to the pentose ring) can be a chiral center. In some embodiments, the alpha-phosphorus can be a (R)-stereocenter. In other embodiments, the alpha-phosphorus can be a (S)-stereocenter.


In some embodiments, R1 can be absent. In other embodiments, R1 can be hydrogen. In still other embodiments, R1 can be an optionally substituted N-linked α-amino acid. In yet still other embodiments, R1 can be an optionally substituted N-linked α-amino acid ester derivative. Various amino acids and amino acid ester derivatives can be used, including those described herein. Suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional suitable amino acids include, but are not limited to, alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine. Examples of an N-linked amino acid ester derivatives include, but are not limited to, an ester derivatives of any of the following amino acids: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of N-linked amino acid ester derivatives include, but are not limited to, an ester derivative of any of the following amino acids: alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine.


In an embodiment, R1 can be an ester derivative of alanine. In an embodiment, R1 can be selected from alanine methyl ester, alanine ethyl ester, alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester derivative can be in the L-configuration. In other embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester derivative can be in the D-configuration.


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


In some embodiments, R1 can have the structure




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wherein R22 can be selected from hydrogen, an optionally substituted C1-6-alkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C1-6 alkyl) and an optionally substituted C1-6 haloalkyl; and R23 can be selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C6 aryl, an optionally substituted C10 aryl and an optionally substituted aryl(C1-6 alkyl); and R24 can be hydrogen or an optionally substituted C1-4-alkyl; or R23 and R24 can be taken together to form an optionally substituted C3-6 cycloalkyl.


When R1 has the structure shown above, R23 can be an optionally substituted C1-6-alkyl. Examples of suitable optionally substituted C1-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). When R23 is substituted, R23 can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiment, R23 can be an unsubstituted C1-6-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In an embodiment, R23 can be methyl.


As to R22, in some embodiments, R22 can be an optionally substituted C1-6 alkyl. Examples of optionally substituted C1-6-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, R22 can be methyl or isopropyl. In some embodiments, R22 can be ethyl or neopentyl. In other embodiments, R22 can be an optionally substituted C3-6 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R22 can be an optionally substituted cyclohexyl. In still other embodiments, R22 can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R22 can be an optionally substituted aryl(C1-6 alkyl). In some embodiments, R22 can be an optionally substituted benzyl. In some embodiments, R22 can be an optionally substituted C1-6 haloalkyl, for example, CF3.


In some embodiments, R24 can be hydrogen. In other embodiments, R24 can be an optionally substituted C1-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R24 can be methyl. In some embodiments, R23 and R24 can be taken together to form an optionally substituted C3-6 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R23 and R24, the carbon to which R23 and R24 are attached may be a chiral center. In some embodiment, the carbon to which R23 and R24 are attached may be a (R)-chiral center. In other embodiments, the carbon to which R23 and R24 are attached may be a (S)-chiral center.


As example of a suitable




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groups include the following:




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The substituents attached to the 5′-position of a compound of Formula (I) can vary. In some embodiments, R3a and R3b can be the same. In other embodiments, R3a and R3b can be different. In some embodiments, R3a and R3b can be both hydrogen. In some embodiments, at least one of R3a and R3b can be an optionally substituted C1-6-alkyl; and the other of R3a and R3b can be hydrogen. Examples of suitable optionally substituted C1-6 alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In an embodiment, at least one of R3a and R3b can be methyl, and the other of R3a and R3b can be hydrogen. In other embodiments, at least one of R3a and R3b can be an optionally substituted C1-6-haloalkyl, and the other of R3a and R3b can be hydrogen. One example of a suitable optionally substituted C1-6-haloalkyl is CF3. In other still embodiments, R3a and R3b can be taken together to form an optionally substituted C3-6 cycloalkyl. When the substituents attached to the 5′-carbon make the 5′-carbon chiral, in some embodiments, the 5′-carbon can be a (R)-stereocenter. In other embodiments, the 5′-carbon can be an (S)-stereocenter.


The substituents attached to the 4′-carbon can vary. In some embodiments, R4 can be hydrogen. In other embodiments, R4 can be azido. In still other embodiments, R4 can be an optionally substituted C1-6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R4 can be an optionally substituted C2-6 alkenyl. In some embodiments, R4 can be an optionally substituted C2-6 alkynyl.


The substituents attached to the 2′-carbon and the 3′-carbon can also vary. In some embodiments, R5 can be hydrogen. In other embodiments, R5 can be halogen. In still other embodiments, R5 can be azido. In yet still other embodiments, R5 can be cyano. In some embodiments, R5 can be an optionally substituted C1-6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In other embodiments, R5 can be —OR10, wherein R10 can be hydrogen. In still other embodiments, R5 can be —OR10, wherein R10 can be an optionally substituted C1-6 alkyl. In yet still other embodiments, R5 can be —OC(═O)R11, wherein R11 can be an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl. Examples of suitable C1-6 alkyls and C3-6 cycloalkyls are described herein.


In some embodiments, R6 can be hydrogen. In other embodiments, R6 can be halogen. In still other embodiments, R6 can be azido. In yet still other embodiments, R6 can be cyano. In some embodiments, R6 can be an optionally substituted C1-6 alkyl. In other embodiments, R6 can be —OR12, wherein R12 can be hydrogen. In still other embodiments, R6 can be —OR12, wherein R12 can be an optionally substituted C1-6 alkyl. A non-limiting list of examples of R6 being —OR12, wherein R12 can be an optionally substituted C1-6 alkyl are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched). In yet still other embodiments, R6 can be —OC(═O)R13, wherein R13 can be an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl. Examples of suitable optionally substituted C1-6 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). Examples of suitable optionally substituted C3-6 cycloalkyls include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.


In some embodiments, R7 can be hydrogen. In other embodiments, R7 can be halogen. In still other embodiments, R7 can be azido. In yet still other embodiments, R7 can be cyano. In some embodiments, R7 can be an optionally substituted C1-6 alkyl. In other embodiments, R7 can be —OR14. In an embodiment, when R14 is hydrogen, R7 can be a hydroxy group. In still other embodiments, when R14 is an optionally substituted C1-6 alkyl, R7 can be an optionally substituted C1-6 alkoxy. Examples, of R7 being —OR14, wherein R14 can be an optionally substituted C1-6 alkyl include, but are not limited to, are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched). In yet still other embodiments, R7 can be —OC(═O)R15, wherein R15 can be an optionally substituted C1-6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R7 can be —OC(═O)R15, wherein R15 can be an optionally substituted C3-6 cycloalkyl


In some embodiments, R8 can be hydrogen. In other embodiments, R8 can be halogen. In still other embodiments, R8 can be azido. In yet still other embodiments, R8 can be cyano. In some embodiments, R8 can be —OR16. When R16 is hydrogen, R8 can be hydroxy. Alternatively, when R16 is an optionally substituted C1-6 alkyl, R8 can be an optionally substituted C1-6 alkoxy. Suitable alkoxy groups are described herein. In other embodiments, R8 can be an optionally substituted C1-6 alkyl. In still other embodiments, R8 can be —OC(═O)R17 in which R17 is an optionally substituted C1-6 alkyl. In yet still other embodiments, R8 can be —OC(═O)R17 in which R17 is an optionally substituted C3-6 cycloalkyl. Examples of suitable C1-6 alkyl and C3-6 cycloalkyl groups are described herein.


In some embodiments, R6 and R7 can both be hydroxy. In still other embodiments, R6 and R7 can both be both oxygen atoms and linked together by a carbonyl group, for example, —O—C(═O)—O—. In some embodiments, at least one of R7 and R8 can be a halogen. In some embodiments, R7 and R8 can both be a halogen. In other embodiments, R7 can be a halogen and R8 can be an optionally substituted C1-6 alkyl, such as those described herein. In other embodiments, R7 can be hydrogen and R8 can be a halogen. In still other embodiments, at least one of R6 and R7 can be a hydroxy and R8 can be an optionally substituted C1-6 alkyl. In yet still other embodiments, R6 can be hydroxy, R7 can be hydroxy, H or halogen, and R8 can be an optionally substituted C1-6 alkyl. In some embodiments, R3a, R3b, R4, R5 and R9 can be hydrogen in any of the embodiments described in this paragraph. In some embodiments, B1 can be an optionally substituted adenine, an optionally substituted guanine, and optionally substituted thymine, optionally substituted cytosine, or an optionally substituted uracil in any of the embodiments described in this paragraph.


In some embodiments, R9 can be hydrogen. In other embodiments, R9 can be azido. In still other embodiments, R9 can be cyano. In yet still other embodiments, R9 can be an optionally substituted C1-6 alkyl, such as those described herein. In some embodiments, R9 can be —OR18. In some embodiments, when R9 is —OR18, R9 can be a hydroxy group. In other embodiments, when R9 is —OR18, R9 can be an optionally substituted C1-6 alkoxy. Examples of optionally substituted C1-6 alkoxy include the following: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), and hexoxy (branched and straight-chained).


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




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wherein: RA2 can be selected from hydrogen, halogen and NHRJ2, wherein RJ2 can be selected from hydrogen, —C(═O)RK2 and —C(═O)ORL2; RB2 can be halogen or NHRW2, wherein RW2 is selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-8 cycloalkyl, —C(═O)RM2 and —C(═O)ORN2; RC2 can be hydrogen or NHRO2, wherein RO2 can be selected from hydrogen, —C(═O)RP2 and —C(═O)ORQ2; RD2 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl; RE2 can be selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-8 cycloalkyl, —C(═O)RR2 and —C(═O)ORS2; RF2 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl; Y2 can be N (nitrogen) or CRI2, wherein RI2 can be selected from hydrogen, halogen, an optionally substituted C1-6-alkyl, an optionally substituted C2-6-alkenyl and an optionally substituted C2-6-alkynyl; RO2 can be an optionally substituted C1-6 alkyl; RH2 can be hydrogen or NHRT2, wherein RT2 can be independently selected from hydrogen, —C(═O)RU2 and —C(═O)ORV2, and RK2, RL2, RM2, RN2, RP2, RQ2RR2, can be independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 cycloalkynyl, C6-10 aryl, heteroaryl, heteroalicyclyl, aryl(C1-6 alkyl), heteroaryl(C1-6 alkyl) and heteroalicyclyl(C1-6 alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the definition of “substituted.” Suitable optionally substituted C1-6 alkyl groups that can be present on an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups are described herein, and include, optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).


In some embodiments, B1 can be selected from adenine, guanine, thymine, cytosine and uracil. In some embodiments, RB2 can be NH2. In other embodiments, RE2 can be hydrogen. In some embodiments, B1 can be




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In other embodiments, B1 can be




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In some embodiments, B1 can be




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In some embodiments, B1 can be




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In still other embodiments, B1 can be




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In yet still other embodiments, B1 can be




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In some embodiments, B1 can be




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




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




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




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then at least one of R5 and R6 cannot be hydroxy.


In some embodiments, when R1 is Oor OH, then R2 cannot be




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In some embodiments, at least one of R3a and R3b cannot be hydrogen. In some embodiments, R4 is not azido. In some embodiments, when R4 is not azido, then R7 and R8 are not both halogen. In some embodiments, when R4 is azido, then B1 is not an optionally substituted uracil, optionally substituted uracil with one or more protected amino groups, an optionally substituted cytosine or optionally substituted cytosine with one or more protected amino groups. In some embodiments, R6 cannot be azido. In some embodiments, when R1 is a methyl ester of glycine, alanine, valine, or phenylalanine; R2 is p-chlorophenyl or p-nitrophenyl; B1 is thymine; and R3a, R3b, R4, R5, R7, R8, and R9 are all hydrogen; then R6 cannot be azido. In some embodiments, at least one of R6 and R7 cannot be hydroxy. For example, R6 cannot be hydroxy, R7 cannot be hydroxy, or both of R6 and R7 cannot be hydroxy.


Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: B1 can be an optionally substituted heterocyclic base as described in paragraph [0106]; R1 can be selected from O, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R2 can be selected from an optionally substituted aryl and




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wherein R19, R20 and R21 can be independently absent or hydrogen, and n can be 0 or 1; provided that when R1 is Oor OH, then R2 is




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R3a and R3b can be hydrogen; R4 can be hydrogen; R5 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl and —OR10; R6 can be selected from hydrogen, halogen, optionally substituted C1-6 alkyl, —OR12 and —OC(═O)R13; R7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR14 and —OC(═O)R15; or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl and —OR16; R9 can be hydrogen; R10, R12, R14 and R16 can be independently selected from hydrogen and an optionally substituted C1-6 alkyl; and R13 and R15 can be independently selected from an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl.


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




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R1 can be selected from O, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R2 can be selected from an optionally substituted aryl and




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wherein R19, R20 and R21 can be independently absent or hydrogen, and n can be 0 or 1; provided that when R1 is Oor OH, then R2 is




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R3a and R3b can be hydrogen; R4 can be hydrogen; R5 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl and —OR10; R6 can be selected from hydrogen, halogen, optionally substituted C1-6 alkyl, —OR12 and —OC(═O)R13; R7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR14 and —OC(═O)R15; or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl and —OR16; R9 can be hydrogen; R10, R12, R14 and R16 can be independently selected from hydrogen and an optionally substituted C1-6 alkyl; and R13 and R15 can be independently selected from an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl.


In some embodiments, Formula (I) can be a compound of Formula (Iα), wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group selected from cytosine, uridine, thymidine, guanine and adenine; R1 can be selected from O, OH, and an optionally substituted N-linked amino acid ester derivative of alanine, valine, or leucine; R2 can be selected from an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted pyridyl, an optionally substituted quinolyl, and




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wherein R19, R20 and R21 independently can be hydrogen or absent, and n can be 0 or 1; provided that when R1 is Oor OH, then R2 is




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R3a and R3b can be hydrogen; R4 can be hydrogen; R5 can be hydrogen; R6 can be —OR12 or —OC(═O)R13; R7 can be selected from halogen, —OR14 and —OC(═O)R15; R8 can be an optionally substituted C1-6 alkyl; R9 can be hydrogen; R12 and R14 can be independently hydrogen or an optionally substituted C1-6 alkyl; and R13 and R15 can be independently an optionally substituted C1-6 alkyl.


Some embodiments relate to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R1 can be selected from O, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R2 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and




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wherein R19, R20 and R21 can be independently absent or hydrogen, and n can be 0 or 1; provided that when R1 is Oor OH, then R2 is




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R3a and R3b can be independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and aryl(C1-6 alkyl); or R3a and R3b can be taken together to form an optionally substituted C3-6 cycloalkyl; R4 can be selected from hydrogen, azido, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl; R5 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR10 and —OC(═O)R11; R6 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR12 and —OC(═O)R13; R7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR14 and —OC(═O)R′5; or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR16 and —OC(═O)R′7; R9 can be selected from hydrogen, azido, cyano, an optionally substituted C1-6 alkyl and —OR18; R10, R12, R14, R16 and R18 can be independently selected from hydrogen and an optionally substituted C1-6 alkyl; and R11, R13, R15 and R17 can be independently an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl.


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


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




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and R1 is



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TABLE 1





R2, R1, Rα







bb01,aa01,es01


bb01,aa01,es02


bb01,aa01,es03


bb01,aa01,es04


bb01,aa01,es05


bb01,aa01,es06


bb01,aa01,es07


bb01,aa01,es08


bb01,aa01,es09


bb01,aa01,es10


bb01,aa01,es11


bb01,aa01,es12


bb01,aa02,es01


bb01,aa02,es02


bb01,aa02,es03


bb01,aa02,es04


bb01,aa02,es05


bb01,aa02,es06


bb01,aa02,es07


bb01,aa02,es08


bb01,aa02,es09


bb01,aa02,es10


bb01,aa02,es11


bb01,aa02,es12


bb01,aa03,es01


bb01,aa03,es02


bb01,aa03,es03


bb01,aa03,es04


bb01,aa03,es05


bb01,aa03,es06


bb01,aa03,es07


bb01,aa03,es08


bb01,aa03,es09


bb01,aa03,es10


bb01,aa03,es11


bb01,aa03,es12


bb01,aa04,es01


bb01,aa04,es02


bb01,aa04,es03


bb01,aa04,es04


bb01,aa04,es05


bb01,aa04,es06


bb01,aa04,es07


bb01,aa04,es08


bb01,aa04,es09


bb01,aa04,es10


bb01,aa04,es11


bb01,aa04,es12


bb01,aa05,es01


bb01,aa05,es02


bb01,aa05,es03


bb01,aa05,es04


bb01,aa05,es05


bb01,aa05,es06


bb01,aa05,es07


bb01,aa05,es08


bb01,aa05,es09


bb01,aa05,es10


bb01,aa05,es11


bb01,aa05,es12


bb01,aa06,es01


bb01,aa06,es02


bb01,aa06,es03


bb01,aa06,es04


bb01,aa06,es05


bb01,aa06,es06


bb01,aa06,es07


bb01,aa06,es08


bb01,aa06,es09


bb01,aa06,es10


bb01,aa06,es11


bb01,aa06,es12


bb01,aa07,es01


bb01,aa07,es02


bb01,aa07,es03


bb01,aa07,es04


bb01,aa07,es05


bb01,aa07,es06


bb01,aa07,es07


bb01,aa07,es08


bb01,aa07,es09


bb01,aa07,es10


bb01,aa07,es11


bb01,aa07,es12


bb01,aa08,es01


bb01,aa08,es02


bb01,aa08,es03


bb01,aa08,es04


bb01,aa08,es05


bb01,aa08,es06


bb01,aa08,es07


bb01,aa08,es08


bb01,aa08,es09


bb01,aa08,es10


bb01,aa08,es11


bb01,aa08,es12


bb01,aa09,es01


bb01,aa09,es02


bb01,aa09,es03


bb01,aa09,es04


bb01,aa09,es05


bb01,aa09,es06


bb01,aa09,es07


bb01,aa09,es08


bb01,aa09,es09


bb01,aa09,es10


bb01,aa09,es11


bb01,aa09,es12


bb01,aa10,es01


bb01,aa10,es02


bb01,aa10,es03


bb01,aa10,es04


bb01,aa10,es05


bb01,aa10,es06


bb01,aa10,es07


bb01,aa10,es08


bb01,aa10,es09


bb01,aa10,es10


bb01,aa10,es11


bb01,aa10,es12


bb02,aa01,es01


bb02,aa01,es02


bb02,aa01,es03


bb02,aa01,es04


bb02,aa01,es05


bb02,aa01,es06


bb02,aa01,es07


bb02,aa01,es08


bb02,aa01,es09


bb02,aa01,es10


bb02,aa01,es11


bb02,aa01,es12


bb02,aa02,es01


bb02,aa02,es02


bb02,aa02,es03


bb02,aa02,es04


bb02,aa02,es05


bb02,aa02,es06


bb02,aa02,es07


bb02,aa02,es08


bb02,aa02,es09


bb02,aa02,es10


bb02,aa02,es11


bb02,aa02,es12


bb02,aa03,es01


bb02,aa03,es02


bb02,aa03,es03


bb02,aa03,es04


bb02,aa03,es05


bb02,aa03,es06


bb02,aa03,es07


bb02,aa03,es08


bb02,aa03,es09


bb02,aa03,es10


bb02,aa03,es11


bb02,aa03,es12


bb02,aa04,es01


bb02,aa04,es02


bb02,aa04,es03


bb02,aa04,es04


bb02,aa04,es05


bb02,aa04,es06


bb02,aa04,es07


bb02,aa04,es08


bb02,aa04,es09


bb02,aa04,es10


bb02,aa04,es11


bb02,aa04,es12


bb02,aa05,es01


bb02,aa05,es02


bb02,aa05,es03


bb02,aa05,es04


bb02,aa05,es05


bb02,aa05,es06


bb02,aa05,es07


bb02,aa05,es08


bb02,aa05,es09


bb02,aa05,es10


bb02,aa05,es11


bb02,aa05,es12


bb02,aa06,es01


bb02,aa06,es02


bb02,aa06,es03


bb02,aa06,es04


bb02,aa06,es05


bb02,aa06,es06


bb02,aa06,es07


bb02,aa06,es08


bb02,aa06,es09


bb02,aa06,es10


bb02,aa06,es11


bb02,aa06,es12


bb02,aa07,es01


bb02,aa07,es02


bb02,aa07,es03


bb02,aa07,es04


bb02,aa07,es05


bb02,aa07,es06


bb02,aa07,es07


bb02,aa07,es08


bb02,aa07,es09


bb02,aa07,es10


bb02,aa07,es11


bb02,aa07,es12


bb02,aa08,es01


bb02,aa08,es02


bb02,aa08,es03


bb02,aa08,es04


bb02,aa08,es05


bb02,aa08,es06


bb02,aa08,es07


bb02,aa08,es08


bb02,aa08,es09


bb02,aa08,es10


bb02,aa08,es11


bb02,aa08,es12


bb02,aa09,es01


bb02,aa09,es02


bb02,aa09,es03


bb02,aa09,es04


bb02,aa09,es05


bb02,aa09,es06


bb02,aa09,es07


bb02,aa09,es08


bb02,aa09,es09


bb02,aa09,es10


bb02,aa09,es11


bb02,aa09,es12


bb02,aa10,es01


bb02,aa10,es02


bb02,aa10,es03


bb02,aa10,es04


bb02,aa10,es05


bb02,aa10,es06


bb02,aa10,es07


bb02,aa10,es08


bb02,aa10,es09


bb02,aa10,es10


bb02,aa10,es11


bb02,aa10,es12


bb03,aa03,es01


bb03,aa03,es02


bb03,aa03,es03


bb03,aa03,es04


bb03,aa03,es05


bb03,aa03,es06


bb03,aa03,es07


bb03,aa03,es08


bb03,aa03,es09


bb03,aa03,es10


bb03,aa03,es11


bb03,aa03,es12


bb03,aa04,es01


bb03,aa04,es02


bb03,aa04,es03


bb03,aa04,es04


bb03,aa04,es05


bb03,aa04,es06


bb03,aa04,es07


bb03,aa04,es08


bb03,aa04,es09


bb03,aa04,es10


bb03,aa04,es11


bb03,aa04,es12


bb03,aa05,es01


bb03,aa05,es02


bb03,aa05,es03


bb03,aa05,es04


bb03,aa05,es05


bb03,aa05,es06


bb03,aa05,es07


bb03,aa05,es08


bb03,aa05,es09


bb03,aa05,es10


bb03,aa05,es11


bb03,aa05,es12


bb03,aa06,es01


bb03,aa06,es02


bb03,aa06,es03


bb03,aa06,es04


bb03,aa06,es05


bb03,aa06,es06


bb03,aa06,es07


bb03,aa06,es08


bb03,aa06,es09


bb03,aa06,es10


bb03,aa06,es11


bb03,aa06,es12


bb03,aa07,es01


bb03,aa07,es02


bb03,aa07,es03


bb03,aa07,es04


bb03,aa07,es05


bb03,aa07,es06


bb03,aa07,es07


bb03,aa07,es08


bb03,aa07,es09


bb03,aa07,es10


bb03,aa07,es11


bb03,aa07,es12


bb03,aa08,es01


bb03,aa08,es02


bb03,aa08,es03


bb03,aa08,es04


bb03,aa08,es05


bb03,aa08,es06


bb03,aa08,es07


bb03,aa08,es08


bb03,aa08,es09


bb03,aa08,es10


bb03,aa08,es11


bb03,aa08,es12


bb03,aa09,es01


bb03,aa09,es02


bb03,aa09,es03


bb03,aa09,es04


bb03,aa09,es05


bb03,aa09,es06


bb03,aa09,es07


bb03,aa09,es08


bb03,aa09,es09


bb03,aa09,es10


bb03,aa09,es11


bb03,aa09,es12


bb03,aa10,es01


bb03,aa10,es02


bb03,aa10,es03


bb03,aa10,es04


bb03,aa10,es05


bb03,aa10,es06


bb03,aa10,es07


bb03,aa10,es08


bb03,aa10,es09


bb03,aa10,es10


bb03,aa10,es11


bb03,aa10,es12


bb04,aa01,es01


bb04,aa01,es02


bb04,aa01,es03


bb04,aa01,es04


bb04,aa01,es05


bb04,aa01,es06


bb04,aa01,es07


bb04,aa01,es08


bb04,aa01,es09


bb04,aa01,es10


bb04,aa01,es11


bb04,aa01,es12


bb04,aa02,es01


bb04,aa02,es02


bb04,aa02,es03


bb04,aa02,es04


bb04,aa02,es05


bb04,aa02,es06


bb04,aa02,es07


bb04,aa02,es08


bb04,aa02,es09


bb04,aa02,es10


bb04,aa02,es11


bb04,aa02,es12


bb04,aa03,es01


bb04,aa03,es02


bb04,aa03,es03


bb04,aa03,es04


bb04,aa03,es05


bb04,aa03,es06


bb04,aa03,es07


bb04,aa03,es08


bb04,aa03,es09


bb04,aa03,es10


bb04,aa03,es11


bb04,aa03,es12


bb04,aa04,es01


bb04,aa04,es02


bb04,aa04,es03


bb04,aa04,es04


bb04,aa04,es05


bb04,aa04,es06


bb04,aa04,es07


bb04,aa04,es08


bb04,aa04,es09


bb04,aa04,es10


bb04,aa04,es11


bb04,aa04,es12


bb04,aa05,es01


bb04,aa05,es02


bb04,aa05,es03


bb04,aa05,es04


bb04,aa05,es05


bb04,aa05,es06


bb04,aa05,es07


bb04,aa05,es08


bb04,aa05,es09


bb04,aa05,es10


bb04,aa05,es11


bb04,aa05,es12


bb04,aa06,es01


bb04,aa06,es02


bb04,aa06,es03


bb04,aa06,es04


bb04,aa06,es05


bb04,aa06,es06


bb04,aa06,es07


bb04,aa06,es08


bb04,aa06,es09


bb04,aa06,es10


bb04,aa06,es11


bb04,aa06,es12


bb04,aa07,es01


bb04,aa07,es02


bb04,aa07,es03


bb04,aa07,es04


bb04,aa07,es05


bb04,aa07,es06


bb04,aa07,es07


bb04,aa07,es08


bb04,aa07,es09


bb04,aa07,es10


bb04,aa07,es11


bb04,aa07,es12


bb04,aa08,es01


bb04,aa08,es02


bb04,aa08,es03


bb04,aa08,es04


bb04,aa08,es05


bb04,aa08,es06


bb04,aa08,es07


bb04,aa08,es08


bb04,aa08,es09


bb04,aa08,es10


bb04,aa08,es11


bb04,aa08,es12


bb04,aa09,es01


bb04,aa09,es02


bb04,aa09,es03


bb04,aa09,es04


bb04,aa09,es05


bb04,aa09,es06


bb04,aa09,es07


bb04,aa09,es08


bb04,aa09,es09


bb04,aa09,es10


bb04,aa09,es11


bb04,aa09,es12


bb04,aa10,es01


bb04,aa10,es02


bb04,aa10,es03


bb04,aa10,es04


bb04,aa10,es05


bb04,aa10,es06


bb04,aa10,es07


bb04,aa10,es08


bb04,aa10,es09


bb04,aa10,es10


bb04,aa10,es11


bb04,aa10,es12


bb05,aa01,es01


bb05,aa01,es02


bb05,aa01,es03


bb05,aa01,es04


bb05,aa01,es05


bb05,aa01,es06


bb05,aa01,es07


bb05,aa01,es08


bb05,aa01,es09


bb05,aa01,es10


bb05,aa01,es11


bb05,aa01,es12


bb05,aa02,es01


bb05,aa02,es02


bb05,aa02,es03


bb05,aa02,es04


bb05,aa02,es05


bb05,aa02,es06


bb05,aa02,es07


bb05,aa02,es08


bb05,aa02,es09


bb05,aa02,es10


bb05,aa02,es11


bb05,aa02,es12


bb05,aa03,es01


bb05,aa03,es02


bb05,aa03,es03


bb05,aa03,es04


bb05,aa03,es05


bb05,aa03,es06


bb05,aa03,es07


bb05,aa03,es08


bb05,aa03,es09


bb05,aa03,es10


bb05,aa03,es11


bb05,aa03,es12


bb05,aa04,es01


bb05,aa04,es02


bb05,aa04,es03


bb05,aa04,es04


bb05,aa04,es05


bb05,aa04,es06


bb05,aa04,es07


bb05,aa04,es08


bb05,aa04,es09


bb05,aa04,es10


bb05,aa04,es11


bb05,aa04,es12


bb05,aa05,es01


bb05,aa05,es02


bb05,aa05,es03


bb05,aa05,es04


bb05,aa05,es05


bb05,aa05,es06


bb05,aa05,es07


bb05,aa05,es08


bb05,aa05,es09


bb05,aa05,es10


bb05,aa05,es11


bb05,aa05,es12


bb05,aa06,es01


bb05,aa06,es02


bb05,aa06,es03


bb05,aa06,es04


bb05,aa06,es05


bb05,aa06,es06


bb05,aa06,es07


bb05,aa06,es08


bb05,aa06,es09


bb05,aa06,es10


bb05,aa06,es11


bb05,aa06,es12


bb05,aa07,es01


bb05,aa07,es02


bb05,aa07,es03


bb05,aa07,es04


bb05,aa07,es05


bb05,aa07,es06


bb05,aa07,es07


bb05,aa07,es08


bb05,aa07,es09


bb05,aa07,es10


bb05,aa07,es11


bb05,aa07,es12


bb05,aa08,es01


bb05,aa08,es02


bb05,aa08,es03


bb05,aa08,es04


bb05,aa08,es05


bb05,aa08,es06


bb05,aa08,es07


bb05,aa08,es08


bb05,aa08,es09


bb05,aa08,es10


bb05,aa08,es11


bb05,aa08,es12


bb05,aa09,es01


bb05,aa09,es02


bb05,aa09,es03


bb05,aa09,es04


bb05,aa09,es05


bb05,aa09,es06


bb05,aa09,es07


bb05,aa09,es08


bb05,aa09,es09


bb05,aa09,es10


bb05,aa09,es11


bb05,aa09,es12


bb05,aa10,es01


bb05,aa10,es02


bb05,aa10,es03


bb05,aa10,es04


bb05,aa10,es05


bb05,aa10,es06


bb05,aa10,es07


bb05,aa10,es08


bb05,aa10,es09


bb05,aa10,es10


bb05,aa10,es11


bb05,aa10,es12


bb06,aa01,es01


bb06,aa01,es02


bb06,aa01,es03


bb06,aa01,es04


bb06,aa01,es05


bb06,aa01,es06


bb06,aa01,es07


bb06,aa01,es08


bb06,aa01,es09


bb06,aa01,es10


bb06,aa01,es11


bb06,aa01,es12


bb06,aa02,es01


bb06,aa02,es02


bb06,aa02,es03


bb06,aa02,es04


bb06,aa02,es05


bb06,aa02,es06


bb06,aa02,es07


bb06,aa02,es08


bb06,aa02,es09


bb06,aa02,es10


bb06,aa02,es11


bb06,aa02,es12


bb06,aa03,es01


bb06,aa03,es02


bb06,aa03,es03


bb06,aa03,es04


bb06,aa03,es05


bb06,aa03,es06


bb06,aa03,es07


bb06,aa03,es08


bb06,aa03,es09


bb06,aa03,es10


bb06,aa03,es11


bb06,aa03,es12


bb06,aa04,es01


bb06,aa04,es02


bb06,aa04,es03


bb06,aa04,es04


bb06,aa04,es05


bb06,aa04,es06


bb06,aa04,es07


bb06,aa04,es08


bb06,aa04,es09


bb06,aa04,es10


bb06,aa04,es11


bb06,aa04,es12


bb06,aa05,es01


bb06,aa05,es02


bb06,aa05,es03


bb06,aa05,es04


bb06,aa05,es05


bb06,aa05,es06


bb06,aa05,es07


bb06,aa05,es08


bb06,aa05,es09


bb06,aa05,es10


bb06,aa05,es11


bb06,aa05,es12


bb06,aa06,es01


bb06,aa06,es02


bb06,aa06,es03


bb06,aa06,es04


bb06,aa06,es05


bb06,aa06,es06


bb06,aa06,es07


bb06,aa06,es08


bb06,aa06,es09


bb06,aa06,es10


bb06,aa06,es11


bb06,aa06,es12


bb06,aa07,es01


bb06,aa07,es02


bb06,aa07,es03


bb06,aa07,es04


bb06,aa07,es05


bb06,aa07,es06


bb06,aa07,es07


bb06,aa07,es08


bb06,aa07,es09


bb06,aa07,es10


bb06,aa07,es11


bb06,aa07,es12


bb06,aa08,es01


bb06,aa08,es02


bb06,aa08,es03


bb06,aa08,es04


bb06,aa08,es05


bb06,aa08,es06


bb06,aa08,es07


bb06,aa08,es08


bb06,aa08,es09


bb06,aa08,es10


bb06,aa08,es11


bb06,aa08,es12


bb06,aa09,es01


bb06,aa09,es02


bb06,aa09,es03


bb06,aa09,es04


bb06,aa09,es05


bb06,aa09,es06


bb06,aa09,es07


bb06,aa09,es08


bb06,aa09,es09


bb06,aa09,es10


bb06,aa09,es11


bb06,aa09,es12


bb06,aa10,es01


bb06,aa10,es02


bb06,aa10,es03


bb06,aa10,es04


bb06,aa10,es05


bb06,aa10,es06


bb06,aa10,es07


bb06,aa10,es08


bb06,aa10,es09


bb06,aa10,es10


bb06,aa10,es11


bb06,aa10,es12


bb07,aa01,es01


bb07,aa01,es02


bb07,aa01,es03


bb07,aa01,es04


bb07,aa01,es05


bb07,aa01,es06


bb07,aa01,es07


bb07,aa01,es08


bb07,aa01,es09


bb07,aa01,es10


bb07,aa01,es11


bb07,aa01,es12


bb07,aa02,es01


bb07,aa02,es02


bb07,aa02,es03


bb07,aa02,es04


bb07,aa02,es05


bb07,aa02,es06


bb07,aa02,es07


bb07,aa02,es08


bb07,aa02,es09


bb07,aa02,es10


bb07,aa02,es11


bb07,aa02,es12


bb07,aa03,es01


bb07,aa03,es02


bb07,aa03,es03


bb07,aa03,es04


bb07,aa03,es05


bb07,aa03,es06


bb07,aa03,es07


bb07,aa03,es08


bb07,aa03,es09


bb07,aa03,es10


bb07,aa03,es11


bb07,aa03,es12


bb07,aa04,es01


bb07,aa04,es02


bb07,aa04,es03


bb07,aa04,es04


bb07,aa04,es05


bb07,aa04,es06


bb07,aa04,es07


bb07,aa04,es08


bb07,aa04,es09


bb07,aa04,es10


bb07,aa04,es11


bb07,aa04,es12


bb07,aa05,es01


bb07,aa05,es02


bb07,aa05,es03


bb07,aa05,es04


bb07,aa05,es05


bb07,aa05,es06


bb07,aa05,es07


bb07,aa05,es08


bb07,aa05,es09


bb07,aa05,es10


bb07,aa05,es11


bb07,aa05,es12


bb07,aa06,es01


bb07,aa06,es02


bb07,aa06,es03


bb07,aa06,es04


bb07,aa06,es05


bb07,aa06,es06


bb07,aa06,es07


bb07,aa06,es08


bb07,aa06,es09


bb07,aa06,es10


bb07,aa06,es11


bb07,aa06,es12


bb07,aa07,es01


bb07,aa07,es02


bb07,aa07,es03


bb07,aa07,es04


bb07,aa07,es05


bb07,aa07,es06


bb07,aa07,es07


bb07,aa07,es08


bb07,aa07,es09


bb07,aa07,es10


bb07,aa07,es11


bb07,aa07,es12


bb07,aa08,es01


bb07,aa08,es02


bb07,aa08,es03


bb07,aa08,es04


bb07,aa08,es05


bb07,aa08,es06


bb07,aa08,es07


bb07,aa08,es08


bb07,aa08,es09


bb07,aa08,es10


bb07,aa08,es11


bb07,aa08,es12


bb07,aa09,es01


bb07,aa09,es02


bb07,aa09,es03


bb07,aa09,es04


bb07,aa09,es05


bb07,aa09,es06


bb07,aa09,es07


bb07,aa09,es08


bb07,aa09,es09


bb07,aa09,es10


bb07,aa09,es11


bb07,aa09,es12


bb07,aa10,es01


bb07,aa10,es02


bb07,aa10,es03


bb07,aa10,es04


bb07,aa10,es05


bb07,aa10,es06


bb07,aa10,es07


bb07,aa10,es08


bb07,aa10,es09


bb07,aa10,es10


bb07,aa10,es11


bb07,aa10,es12


bb08,aa01,es01


bb08,aa01,es02


bb08,aa01,es03


bb08,aa01,es04


bb08,aa01,es05


bb08,aa01,es06


bb08,aa01,es07


bb08,aa01,es08


bb08,aa01,es09


bb08,aa01,es10


bb08,aa01,es11


bb08,aa01,es12


bb08,aa02,es01


bb08,aa02,es02


bb08,aa02,es03


bb08,aa02,es04


bb08,aa02,es05


bb08,aa02,es06


bb08,aa02,es07


bb08,aa02,es08


bb08,aa02,es09


bb08,aa02,es10


bb08,aa02,es11


bb08,aa02,es12


bb08,aa03,es01


bb08,aa03,es02


bb08,aa03,es03


bb08,aa03,es04


bb08,aa03,es05


bb08,aa03,es06


bb08,aa03,es07


bb08,aa03,es08


bb08,aa03,es09


bb08,aa03,es10


bb08,aa03,es11


bb08,aa03,es12


bb08,aa04,es01


bb08,aa04,es02


bb08,aa04,es03


bb08,aa04,es04


bb08,aa04,es05


bb08,aa04,es06


bb08,aa04,es07


bb08,aa04,es08


bb08,aa04,es09


bb08,aa04,es10


bb08,aa04,es11


bb08,aa04,es12


bb08,aa05,es01


bb08,aa05,es02


bb08,aa05,es03


bb08,aa05,es04


bb08,aa05,es05


bb08,aa05,es06


bb08,aa05,es07


bb08,aa05,es08


bb08,aa05,es09


bb08,aa05,es10


bb08,aa05,es11


bb08,aa05,es12


bb08,aa06,es01


bb08,aa06,es02


bb08,aa06,es03


bb08,aa06,es04


bb08,aa06,es05


bb08,aa06,es06


bb08,aa06,es07


bb08,aa06,es08


bb08,aa06,es09


bb08,aa06,es10


bb08,aa06,es11


bb08,aa06,es12


bb08,aa07,es01


bb08,aa07,es02


bb08,aa07,es03


bb08,aa07,es04


bb08,aa07,es05


bb08,aa07,es06


bb08,aa07,es07


bb08,aa07,es08


bb08,aa07,es09


bb08,aa07,es10


bb08,aa07,es11


bb08,aa07,es12


bb08,aa08,es01


bb08,aa08,es02


bb08,aa08,es03


bb08,aa08,es04


bb08,aa08,es05


bb08,aa08,es06


bb08,aa08,es07


bb08,aa08,es08


bb08,aa08,es09


bb08,aa08,es10


bb08,aa08,es11


bb08,aa08,es12


bb08,aa09,es01


bb08,aa09,es02


bb08,aa09,es03


bb08,aa09,es04


bb08,aa09,es05


bb08,aa09,es06


bb08,aa09,es07


bb08,aa09,es08


bb08,aa09,es09


bb08,aa09,es10


bb08,aa09,es11


bb08,aa09,es12


bb08,aa10,es01


bb08,aa10,es02


bb08,aa10,es03


bb08,aa10,es04


bb08,aa10,es05


bb08,aa10,es06


bb08,aa10,es07


bb08,aa10,es08


bb08,aa10,es09


bb08,aa10,es10


bb08,aa10,es11


bb08,aa10,es12


bb09,aa01,es01


bb09,aa01,es02


bb09,aa01,es03


bb09,aa01,es04


bb09,aa01,es05


bb09,aa01,es06


bb09,aa01,es07


bb09,aa01,es08


bb09,aa01,es09


bb09,aa01,es10


bb09,aa01,es11


bb09,aa01,es12


bb09,aa02,es01


bb09,aa02,es02


bb09,aa02,es03


bb09,aa02,es04


bb09,aa02,es05


bb09,aa02,es06


bb09,aa02,es07


bb09,aa02,es08


bb09,aa02,es09


bb09,aa02,es10


bb09,aa02,es11


bb09,aa02,es12


bb09,aa03,es01


bb09,aa03,es02


bb09,aa03,es03


bb09,aa03,es04


bb09,aa03,es05


bb09,aa03,es06


bb09,aa03,es07


bb09,aa03,es08


bb09,aa03,es09


bb09,aa03,es10


bb09,aa03,es11


bb09,aa03,es12


bb09,aa04,es01


bb09,aa04,es02


bb09,aa04,es03


bb09,aa04,es04


bb09,aa04,es05


bb09,aa04,es06


bb09,aa04,es07


bb09,aa04,es08


bb09,aa04,es09


bb09,aa04,es10


bb09,aa04,es11


bb09,aa04,es12


bb09,aa05,es01


bb09,aa05,es02


bb09,aa05,es03


bb09,aa05,es04


bb09,aa05,es05


bb09,aa05,es06


bb09,aa05,es07


bb09,aa05,es08


bb09,aa05,es09


bb09,aa05,es10


bb09,aa05,es11


bb09,aa05,es12


bb09,aa06,es01


bb09,aa06,es02


bb09,aa06,es03


bb09,aa06,es04


bb09,aa06,es05


bb09,aa06,es06


bb09,aa06,es07


bb09,aa06,es08


bb09,aa06,es09


bb09,aa06,es10


bb09,aa06,es11


bb09,aa06,es12


bb09,aa07,es01


bb09,aa07,es02


bb09,aa07,es03


bb09,aa07,es04


bb09,aa07,es05


bb09,aa07,es06


bb09,aa07,es07


bb09,aa07,es08


bb09,aa07,es09


bb09,aa07,es10


bb09,aa07,es11


bb09,aa07,es12


bb09,aa08,es01


bb09,aa08,es02


bb09,aa08,es03


bb09,aa08,es04


bb09,aa08,es05


bb09,aa08,es06


bb09,aa08,es07


bb09,aa08,es08


bb09,aa08,es09


bb09,aa08,es10


bb09,aa08,es11


bb09,aa08,es12


bb09,aa09,es01


bb09,aa09,es02


bb09,aa09,es03


bb09,aa09,es04


bb09,aa09,es05


bb09,aa09,es06


bb09,aa09,es07


bb09,aa09,es08


bb09,aa09,es09


bb09,aa09,es10


bb09,aa09,es11


bb09,aa09,es12


bb09,aa10,es01


bb09,aa10,es02


bb09,aa10,es03


bb09,aa10,es04


bb09,aa10,es05


bb09,aa10,es06


bb09,aa10,es07


bb09,aa10,es08


bb09,aa10,es09


bb09,aa10,es10


bb09,aa10,es11


bb09,aa10,es12


bb10,aa01,es01


bb10,aa01,es02


bb10,aa01,es03


bb10,aa01,es04


bb10,aa01,es05


bb10,aa01,es06


bb10,aa01,es07


bb10,aa01,es08


bb10,aa01,es09


bb10,aa01,es10


bb10,aa01,es11


bb10,aa01,es12


bb10,aa02,es01


bb10,aa02,es02


bb10,aa02,es03


bb10,aa02,es04


bb10,aa02,es05


bb10,aa02,es06


bb10,aa02,es07


bb10,aa02,es08


bb10,aa02,es09


bb10,aa02,es10


bb10,aa02,es11


bb10,aa02,es12


bb10,aa03,es01


bb10,aa03,es02


bb10,aa03,es03


bb10,aa03,es04


bb10,aa03,es05


bb10,aa03,es06


bb10,aa03,es07


bb10,aa03,es08


bb10,aa03,es09


bb10,aa03,es10


bb10,aa03,es11


bb10,aa03,es12


bb10,aa04,es01


bb10,aa04,es02


bb10,aa04,es03


bb10,aa04,es04


bb10,aa04,es05


bb10,aa04,es06


bb10,aa04,es07


bb10,aa04,es08


bb10,aa04,es09


bb10,aa04,es10


bb10,aa04,es11


bb10,aa04,es12


bb10,aa05,es01


bb10,aa05,es02


bb10,aa05,es03


bb10,aa05,es04


bb10,aa05,es05


bb10,aa05,es06


bb10,aa05,es07


bb10,aa05,es08


bb10,aa05,es09


bb10,aa05,es10


bb10,aa05,es11


bb10,aa05,es12


bb10,aa06,es01


bb10,aa06,es02


bb10,aa06,es03


bb10,aa06,es04


bb10,aa06,es05


bb10,aa06,es06


bb10,aa06,es07


bb10,aa06,es08


bb10,aa06,es09


bb10,aa06,es10


bb10,aa06,es11


bb10,aa06,es12


bb10,aa07,es01


bb10,aa07,es02


bb10,aa07,es03


bb10,aa07,es04


bb10,aa07,es05


bb10,aa07,es06


bb10,aa07,es07


bb10,aa07,es08


bb10,aa07,es09


bb10,aa07,es10


bb10,aa07,es11


bb10,aa07,es12


bb10,aa08,es01


bb10,aa08,es02


bb10,aa08,es03


bb10,aa08,es04


bb10,aa08,es05


bb10,aa08,es06


bb10,aa08,es07


bb10,aa08,es08


bb10,aa08,es09


bb10,aa08,es10


bb10,aa08,es11


bb10,aa08,es12


bb10,aa09,es01


bb10,aa09,es02


bb10,aa09,es03


bb10,aa09,es04


bb10,aa09,es05


bb10,aa09,es06


bb10,aa09,es07


bb10,aa09,es08


bb10,aa09,es09


bb10,aa09,es10


bb10,aa09,es11


bb10,aa09,es12


bb10,aa10,es01


bb10,aa10,es02


bb10,aa10,es03


bb10,aa10,es04


bb10,aa10,es05


bb10,aa10,es06


bb10,aa10,es07


bb10,aa10,es08


bb10,aa10,es09


bb10,aa10,es10


bb10,aa10,es11


bb10,aa10,es12



















TABLE 2











embedded image


bb01









embedded image


bb02









embedded image


bb03









embedded image


bb04









embedded image


bb05









embedded image


bb06









embedded image


bb07









embedded image


bb08









embedded image


bb09









embedded image


bb10




















TABLE 3











embedded image


aa01









embedded image


aa02









embedded image


aa03









embedded image


aa04









embedded image


aa05









embedded image


aa06









embedded image


aa07









embedded image


aa08









embedded image


aa09









embedded image


aa10



















TABLE 4







es01 Rα = methyl
es02 Rα = ethyl
es03 Rα = isopropyl


es04 Rα = propyl
es05 Rα = cyclohexyl
es06 Rα = cyclopentyl


es07 Rα = cyclobutyl
es08 Rα = cyclopropyl
es09 Rα = benzyl


es11 Rα = neopentyl
es10 Rα = t-butyl
es12 Rα = hydrogen









In some embodiments, R3a, R3b, R4, R5 and R9 can be all hydrogens in any of the embodiments described in Table 1. In some embodiments, at least one of R6 and R7 can be OH in any of the embodiments described in Table 1. In some embodiments, R8 can be a C1-6 alkyl in any of the embodiments described in Table 1. In some embodiments, B1 can be adenine, guanine, uracil, thymine or cystine in any of the embodiments described in Table 1. In some embodiments, R3a, R3b, R4, R5, R6, R7, R8, R9 and B1 can be the groups provided with respect to Formula (Iα) in any of the embodiments described in Table 1.


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




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




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In some embodiments, the compound of Formula (I) can be the following:




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




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In some embodiments, neutralizing the charge on the thiophosphate group may facilitate the penetration of the cell membrane by a compound of Formula (I) (including a compound of Formula (Iα)) by making the compound more lipophilic compared to a thionucleotide having a comparable structure with one or more charges present on the phosphate. Once absorbed and taken inside the cell, the groups attached to the thiophosphate can be easily removed by esterases, proteases, or other enzymes. In some embodiments, the groups attached to the thiophosphate can be removed by simple hydrolysis. Inside the cell, the thio-monophosphate thus released may then be metabolized by cellular enzymes to the thio-diphosphate or the active thio-triphosphate. 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) (including a compound of Formula (Iα)) 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) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can act as a chain terminator of HCV replication. For example, incorporation of a compound of Formula (I) containing a moiety at the 2′-carbon position can terminate further elongation of the RNA chain of HCV. For example, a compound of Formula (I) can contain a 2′-carbon modification when R8 is a non-hydrogen group selected from halogen, azido, cyano, an optionally substituted C1-6 alkyl, —OR16 and —OC(═O)R17.


In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can have increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can 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 phosphate attached to the 5′-carbon of the ribose ring. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can have improved properties. In previous studies, replacing a sulfur with an oxygen on the alpha-phosphate of a nucleotide phosphoramidate has resulted in more than a 1000-fold decrease in potency. See Venkatachalam et al. European Journal of Medicinal Chemistry (2004) 39:665-683. 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 in the range of about 40 hours to about 46 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 has a phosphate attached to the 5′-carbon of the ribose ring (for example, a compound that is identical in structure but for having a phosphate attached to the 5′-carbon of the ribose ring). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have more potent antiviral activity (for example, a lower IC50 in an HCV replicon assay) as compared to the current standard of care.


Synthesis

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




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One method for forming a compound of Formula (I) is shown in Scheme 1. In Scheme 1, R3A, R3B, R4A, R5A, R6A, R7A, R8A, R9A and B1A can be the same as R3a, R3b, R4, R5, R6, R7, R8, R9 and B1 as described herein for Formula (I); and R1 and R2 can be the same as described herein for Formula (I). As shown in Scheme 1, a compound of Formula (A) can be reacted with a compound having the formula R2O—P(═S)(R1)—Cl to form a compound of Formula (I).


To reduce the formation of side products, one or more the groups attached to the pentose ring can be protected with one or more suitable protecting groups. As an example, if R6A and/or R7A is/are hydroxy group(s), the hydroxy group(s) can be protected with suitable protecting groups, such as triarylmethyl and/or silyl groups. Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy)trityl (TBTr), 4,4′,4″-tris(4,5-dichlorophthalimido)trityl (CPTr), 4,4′,4″-tris(levulinyloxy)trityl (TLTr), p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl, p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl, 9-(4-octadecyloxyphenyl) xanthen-9-yl, 1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl, 4,4′,4″-tris-(tert-butylphenyl) methyl (TTTr) and 4,4′-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups are described herein. Alternatively, R6A and/or R7A can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2-oxacyclopentylidene orthoester, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylidene orthoester, and alpha-methoxybenzylidene orthoester; suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3-(benzyloxy)propyl acetal, benzylidene acetal, 3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; and suitable cyclic ketals include 1-t-butylethylidene ketal, 1-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal and 1-(4-methoxyphenyl)ethylidene ketal.


If desired, any —NH and/or NH2 groups present on the B1A can also be protected with one or more suitable protecting groups. Examples of suitable protecting groups include triarylmethyl groups and silyl groups. Examples of silyl groups include, but are not limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.


Suitable thiophosphorochloridates can be commercially obtained or prepared by a synthetic method described herein. An example of a general structure of a thiophosphorochloridate is shown in Scheme 1. In some embodiments, the thiophosphorochloridate can be coupled to a compound of Formula (A). In some embodiments, to facilitate the coupling, a Grignard reagent can be used. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnesium bromides. In other embodiments, the thiophosphorochloridate can be added to a compound of Formula (A) using a base. Suitable bases are known to those skilled in the art. Examples of bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidzoles (e.g., N-methylimidazole)).


When at least one of R3a and R3b is an optionally substituted C1-6 alkyl or an optionally substituted C1-6 haloalkyl, the optionally substituted C1-6 alkyl or the optionally substituted C1-6 haloalkyl can be added to the 5′-position using methods known to those skilled in the art. In some embodiments, the hydroxy attached to the 5′-carbon can be oxidized to an aldehyde. Suitable oxidation conditions include, but are not limited to, DMSO in combination with an activating agent (usually an acylating agent or an acid) and an amine base, Moffatt oxidation, Swern oxidation and Corey-Kim oxidation, and suitable oxidizing agents include, but are not limited to, Dess-Martin periodinane, TPAP/NMO (tetrapropylammonium perruthenate/N-methylmorpholine N-oxide), Swern oxidation reagent, PCC (pyridinium chlorochromate), and/or PDC (pyridinium dichromate), sodium periodate, Collin's reagent, ceric ammonium nitrate CAN, Na2Cr2O7 in water, Ag2CO3 on celite, hot HNO3 in aqueous glyme, O2-pyridine CuCl, Pb(OAc)4-pyridine and benzoyl peroxide-NiBr2. The resulting aldehyde compound can be reacted with a Grignard reagent, an organolithium reagent or trialkylaluminum (e.g., trimethylaluminum) to form a compound of Formula (A) where at least one of R3A and R3B is an optionally substituted C1-6 alkyl or an optionally substituted C1-6 haloalkyl. Optionally, the alkylating reagents can be in the presence of a Lewis acid. Suitable Lewis acids are known to those skilled in the art.


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


As described herein, in some embodiments, R6 and R7 can be both oxygen atoms linked together by a carbonyl groups. The —O—C(═O)—O— group can be formed using methods known to those skilled in the art. For example, a compound of Formula (I), wherein R6 and R7 are both hydroxy groups, can be treated with 1,1′-carbonyldiimidazole (CDI).


In some embodiments, R6 and/or R7 can be —OC(═O)R13 and —OC(═O)R15, respectively. The —OC(═O)R13 and —OC(═O)R15 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 R6 and R7 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)R13 and —OC(═O)R15 groups can be formed at the 2′- and 3′-positions by reacting an alkyl acid (e.g. acetic acid and propionic acid) in the presences of a carbodiimide or a coupling reagent. Examples of carbodiimides include, but are not limited to, N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).


As described herein, B1A can include a carbamate and/or an amide. Those skilled in the art know methods for forming a carbamate and/or an amide on B1A. In some embodiments, the carbamate can be formed using 1,1′-carbonyldiimidazole and an alcohol.


B1A can be added to the pentose ring using various methods known to those skilled in the art. In some embodiments, a compound of Formula (B) can be reacted with a nitrogenous base. In some embodiments, R3A, R3B, R4A, R5A, R6A, R7A, R8A, R9A and B1A of a compound of Formula (B) can be the same as disclosed herein, with respect to R3a, R3b, R4, R5, R6, R7, R8, R9 and B1; and PG1 can be an appropriate protecting group. In some embodiments, PG1 can be p-nitrobenzyl group. In some embodiments, any hydroxy groups attached to the pentose ring can be protected with one or more suitable protecting groups. In some embodiments, any hydroxy groups attached to the pentose ring can be protected with benzoyl groups. Examples of nitrogenous bases include an optionally substituted heterocyclic bases described herein, wherein the nitrogen atom (—N) connected to the pentose ring is —NH. If desired, any —NH and/or NH2 groups present on the nitrogenous base can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. In some embodiments, the nitrogenous base can be added via a coupling reaction in the presence of a Lewis acid or TMSOTf. Suitable Lewis acids are known to those skilled in the art.




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Various methods can be used to make a compound of Formula (I), wherein R1 is




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For example, a thiophosphorochloridate having the general formula of (P(═S)Cl3) can be transformed into a phosphorus reagent having the general formula, P(═S)LG3, wherein each LG can be amine-based leaving group. In some embodiments, each LG can be a triazole. The phosphorus reagent having the general formula, P(═S)LG3, can be reacted with a compound of Formula (I). Using a suitable pyrophosphorylation reagent, the β and γ phosphates can be added. An example of a suitable pyrophosphorylation reagent is tris(tetrabutylammonium) hydrogen pyrophosphate.


During the synthesis of any of the compounds described herein, if desired, any hydroxy groups attached to the pentose ring, and any —NH and/or NH2 groups present on the B1A can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. Those skilled in the art will appreciate that groups attached to the pentose ring and any —NH and/or NH2 groups present on the B1A can be protected with various protecting groups, and any protecting groups present can be exchanged for other protecting groups. The selection and exchange of the protecting groups is within the skill of those of ordinary skill in the art. Any protecting group(s) can also be removed by methods known in the art, for example, with an acid (e.g., a mineral or an organic acid), a base or a fluoride source.


Pharmaceutical Compositions

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


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


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


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


As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.


As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.


The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.


The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.


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


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


The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.


Methods of Use

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


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


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


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


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


Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include contacting a cell infected with the virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for inhibiting replication of a virus that can include contacting a cell infected with the virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for inhibiting replication of a virus by contacting a cell infected with the virus with an effective amount of said compound(s). In some embodiments, the compound can be a compound of Formulae (I) and/or (Iα), or a pharmaceutical acceptable salt thereof. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of a compound of Formulae (I) and/or (Iα), or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the virus can be a HCV virus.


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


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


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


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


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


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


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


In some embodiments, an effective amount of a compound of Formula (I) and/or (Iα), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the subject's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.


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


Subjects who are clinically diagnosed with HCV infection include “naïve” subjects (e.g., subjects not previously treated for HCV, particularly those who have not previously received IFN-alpha-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV (“treatment failure” subjects). Treatment failure subjects include “non-responders” (i.e., subjects in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV (≦0.5 log IU/mL), for example, a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy); and “relapsers” (i.e., subjects who were previously treated for HCV, for example, who received a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).


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


After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject infected with an HCV strain that is resistant to one or more different anti-HCV agents. In some embodiments, development of resistant HCV strains is delayed when patients are treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of HCV strains resistant to other HCV drugs.


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


Some subjects being treated for HCV experience a viral load rebound. The term “viral load rebound” as used herein refers to a sustained ≧0.5 log IU/mL increase of viral load above nadir before the end of treatment, where nadir is a ≧0.5 log IU/mL decrease from baseline. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject experiencing viral load rebound, or can prevent such viral load rebound when used to treat the subject.


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


Table 5 provides some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the standard of care. Examples include the following: in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a percentage of non-responders that is 10% less than the percentage of non-responders receiving the standard of care; in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving the standard of care; and in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving the standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art.














TABLE 5








Percentage
Number
Severity


Percentage
Percentage
Percentage
of viral
of
of


of non-
of
of
load
side
side


responders
relapsers
resistance
rebound
effects
effects







10% less
10% less
10% less
10% less
10% less
10% less


25% less
25% less
25% less
25% less
25% less
25% less


40% less
40% less
40% less
40% less
40% less
40% less


50% less
50% less
50% less
50% less
50% less
50% less


60% less
60% less
60% less
60% less
60% less
60% less


70% less
70% less
70% less
70% less
70% less
70% less


80% less
80% less
80% less
80% less
80% less
80% less


90% less
90% less
90% less
90% less
90% less
90% less


about 10%
about 10%
about 10%
about 10%
about 10%
about 10%


to about
to about
to about
to about
to about
to about


30% less
30% less
30% less
30% less
30% less
30% less


about 20%
about 20%
about 20%
about 20%
about 20%
about 20%


to about
to about
to about
to about
to about
to about


50% less
50% less
50% less
50% less
50% less
50% less


about 30%
about 30%
about 30%
about 30%
about 30%
about 30%


to about
to about
to about
to about
to about
to about


70% less
70% less
70% less
70% less
70% less
70% less


about 20%
about 20%
about 20%
about 20%
about 20%
about 20%


to about
to about
to about
to about
to about
to about


80% less
80% less
80% less
80% less
80% less
80% less









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


As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.


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


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


As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.


The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can be administered less frequently compared to the frequency of administration of an agent within the standard of care. In some embodiments, a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can be administered one time per day. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered one time per day to a subject suffering from a HCV infection. In some embodiments, the total time of the treatment regime with a compound of Formula (I) (including a compound of Formula (Iα)), or a pharmaceutically acceptable salt thereof, can less compared to the total time of the treatment regime with the standard of care.


In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.


In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.


Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.


It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.


Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.


Combination Therapies

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


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


In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be substituted for an agent currently used in a conventional standard of care therapy. For example, for the treatment of HCV, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in place of ribavirin.


In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with an interferon, such as a pegylated interferon. Examples of suitable interferons include, but are not limited to, Pegylated interferon-alpha-2a (brand name PEGASYS®), Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferon alfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or a combination thereof.


In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a HCV protease inhibitor. A non-limiting list of example HCV protease inhibitors include the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH 503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof. A non-limiting list of example HCV protease inhibitors includes the compounds numbered 1001-1014 in FIG. 2.


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-184, PSI-352938, PSI-661, 4′-azidouridine (including known prodrugs of 4′-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinations thereof. A non-limiting list of example nucleoside inhibitors includes compounds numbered 2001-2010 in FIG. 3. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof. A non-limiting list of example non-nucleoside inhibitors includes the compounds numbered 3001-3008 in FIG. 4.


In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a NS5A inhibitor. A non-limiting list of example NS5A inhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A non-limiting list of example NS5A inhibitors includes the compounds numbered 4001-4005 in FIG. 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 other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122 and/or combinations thereof. A non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5002 in FIG. 6.


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), mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition that includes a compound of Formula (AA), mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable salt of the foregoing (see, U.S. Provisional Application Nos. 61/385,425, filed Sep. 22, 2010, and 61/426,467, filed Dec. 22, 2010, the contents of which are incorporated by reference in its entirety):




embedded image


wherein BAA1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; RAA1 can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; RAA2 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; RAA3a and RAA3b can be independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and aryl(C1-6 alkyl), provided that at least one of RAA3a and RAA3b is not hydrogen; or RAA3a and RAA3b can be taken together to form a group selected from an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted C3-6 aryl, and an optionally substituted C3-6 heteroaryl; RAA4 can be hydrogen; RAA5 be selected from hydrogen, —ORAA9 and —OC(═O)RAA10; RAA6 can be selected from hydrogen, halogen, —ORAA11 and —OC(═O)RAA12; or RAA5 and RAA6 can be both oxygen atoms and linked together by a carbonyl group; RAA7 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl, —ORAA13 and —OC(═O)RAA14; RAA8 can be hydrogen or an optionally substituted C1-6 alkyl; RAA9, RAA11 and RAA13 can be independently selected from hydrogen and an optionally substituted C1-6 alkyl; and RAA10, RAA12 and RAA14 can be independently selected from an optionally substituted C1-6 alkyl and an optionally substituted C3-6 cycloalkyl. A non-limiting list of examples of compounds of Formula (AA), and phosphates thereof, includes the compounds numbered 7000-7077 in FIGS. 8A-8I. In some embodiments, Formula (AA) cannot be compound 7044, 7045, 7046, 7047, 7048, 7049, 7050, 7072, 7073, 7074, 7075, 7076 or 7077.


In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (BB), or a pharmaceutically acceptable salt thereof (see, U.S. Provisional Application No. 61/426,471, filed Dec. 22, 2010, the contents of which are incorporated by reference in its entirety):




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wherein BBB1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; XBB can be O (oxygen) or S (sulfur); RBB1 can be selected from —ZBB—RBB9, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; ZBB can be selected from O (oxygen), S (sulfur) and N(RBB10); RBB2 and RBB3 can be independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and an optionally substituted aryl(C1-6 alkyl); or RBB2 and RBB3 can be taken together to form a group selected from an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted C3-6 aryl and an optionally substituted C3-6 heteroaryl; RBB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted allenyl; RBB5 can be hydrogen or an optionally substituted C1-6 alkyl; RBB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C1-6 alkyl, —ORBB11 and —OC(═O)RBB12; RBB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB13 and —OC(═O)RBB14; RBB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB15 and —OC(═O)RBB16; RBB9 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(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB10 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(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB11, RBB13 and RBB15 can be independently hydrogen or an optionally substituted C1-6 alkyl; and RBB12, RBB14 and RBB16 can be independently an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl. In some embodiments, at least one of RBB2 and RBB3 is not hydrogen. A non-limiting list of example compounds of Formula (BB) includes the compound numbered 8000-8012 in FIGS. 9A-9B.


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




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wherein each custom-character

can be independently a double or single bond; ADD1 can be selected from C (carbon), O (oxygen) and S (sulfur); BDD1 can be an optionally substituted heterocyclic base or a derivative thereof; DDD1 can be selected from C═CH2, CH2, O (oxygen), S (sulfur), CHF, and CF2; RDD1 can be hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aralkyl, dialkylaminoalkylene, alkyl-C(═O)—, aryl-C(═O)—, alkoxyalkyl-C(═O)—, aryloxyalkyl-C(═O)—, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,




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an —O-linked amino acid, diphosphate, triphosphate or derivatives thereof; RDD2 and RDD3 can be each independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C1-6 haloalkyl, provided that at least one of RDD2 and RDD3 cannot be hydrogen; or RDD2 and RDD3 are taken together to form a group selected from among C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 aryl, and a C3-6 heteroaryl; RDD4 and RDD9 can be independently selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(—O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)NRDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; RDD5, RDD6 and RDD7 can be independently absent or selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1—C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; or RDD6 and RDD7 taken together form —O—C(═O)—O—; RDD8 can be absent or selected from the group consisting of hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)NRDDa1RDDb1, N(RDDc1)—ORDDa1, S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, N(RDDc1) C(═O)NRDDa1RDDb1, S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, N(RDDc1) S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted haloalkyl, an optionally substituted hydroxyalkyl and an —O-linked amino acid, or when the bond to RDD7 indicated by custom-character is a double bond, then RDD7 is a C2-6 alkylidene and RDD8 is absent; RDDa1, RDDb1 and RDDc1 can be each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and an optionally substituted heteroaryl(C1-6 alkyl); RDD10 can be selected from O, —OH, an optionally substituted aryloxy or aryl-O—,




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alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; RDD11 can be selected from O, —OH, an optionally substituted aryloxy or aryl-O—,




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alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; each RDD12 and each RDD13 can be independently —C≡N or an optionally substituted substituent selected from C1-8 organylcarbonyl, C1-8 alkoxycarbonyl and C1-8 organylaminocarbonyl; each RDD14 can be hydrogen or an optionally substituted C1-6-alkyl; each mDD can be independently 1 or 2, and if both RDD10 and RDD11 are




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each RDD12, each RDD13, each RDD14 and each mDD can be the same or different. In some embodiments, RDD8 can be halogen, —ORDDa1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C1-6 haloalkyl.


Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a compound of Formula (I) (including a compound of Formula (Iα)), 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 mono-, di, and/or tri-phosphate thereof, a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.


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


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


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


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


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


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


The dosing amount(s) and dosing schedule(s) when using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agents are within the knowledge of those skilled in the art. For example, when performing a conventional standard of care therapy using art-recognized dosing amounts and dosing schedules, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective amounts and dosing protocols as described herein.


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


In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 2-6 and 8-10 (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. 2-6 and 8-10 (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. 2-6 and 8-10 (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. 2-6 and 8-10 (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. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) may be a reduction in the required amount(s) of one or more compounds of FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, HCV), as compared to the amount required to achieve same therapeutic result when one or more compounds of FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound in FIGS. 2-6 and 8-10 (including a pharmaceutically acceptable salt and prodrug thereof), can be less compared to the amount of the compound in FIGS. 2-6 and 8-10 (including a pharmaceutically acceptable salt and prodrug thereof), needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.


Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) in FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) thereof; different routes for elimination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) in FIGS. 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof).


A non-limiting list of example combination of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, with one or more additional agent(s) are provided in Tables A, B, C and D. Each numbered X and Y compound in Tables A, B, C and D has a corresponding name and/or structure provided in FIGS. 2 to 10. The numbered compounds in Tables A, B, C and D includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions containing the compounds or a pharmaceutically acceptable salt thereof. For example, 1001 includes the compound corresponding to 1001, pharmaceutically acceptable salts thereof, and pharmaceutical compositions that include compound 1001 and/or a pharmaceutically acceptable salt thereof. The combinations exemplified in Tables A, B, C and D are designated by the formula X:Y, which represents a combination of a compound X with a compound Y. For example, the combination designated as 1001:6001 in Table A represents a combination of compound 1001 with compound 6001, including pharmaceutically acceptable salts of compound 1001 and/or 6001, and pharmaceutical compositions including compound 1001 and 6001 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 6001). Thus, the combination designated as 1001:6001 in Table A represents the combination of Telaprevir (compound 1001, as shown in FIG. 2) and




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(compound 6001, as shown in FIG. 7A), including pharmaceutically acceptable salts of compound 1001 and/or 6001, and pharmaceutical compositions including compound 1001 and 6001 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 6001). Each of the combinations provided in Tables A, B, C and D can be used with one, two, three or more additional agents described herein. In some embodiments, embodiments described herein, the combination of agents can be used to treat, amerliorate and/or inhibit a virus and/or a viral infection, wherein the virus can be HCV and the viral infection can be an HCV viral infection.









TABLE A







Example combinations of a compound X with a compound Y.













X:Y
X:Y
X:Y
X:Y
X:Y
X:Y
X:Y





1001:6000
1001:6001
1001:6002
1001:6003
1001:6004
1001:6005
1001:6006


1002:6000
1002:6001
1002:6002
1002:6003
1002:6004
1002:6005
1002:6006


1003:6000
1003:6001
1003:6002
1003:6003
1003:6004
1003:6005
1003:6006


1004:6000
1004:6001
1004:6002
1004:6003
1004:6004
1004:6005
1004:6006


1005:6000
1005:6001
1005:6002
1005:6003
1005:6004
1005:6005
1005:6006


1006:6000
1006:6001
1006:6002
1006:6003
1006:6004
1006:6005
1006:6006


1007:6000
1007:6001
1007:6002
1007:6003
1007:6004
1007:6005
1007:6006


1008:6000
1008:6001
1008:6002
1008:6003
1008:6004
1008:6005
1008:6006


1009:6000
1009:6001
1009:6002
1009:6003
1009:6004
1009:6005
1009:6006


1010:6000
1010:6001
1010:6002
1010:6003
1010:6004
1010:6005
1010:6006


1011:6000
1011:6001
1011:6002
1011:6003
1011:6004
1011:6005
1011:6006


1012:6000
1012:6001
1012:6002
1012:6003
1012:6004
1012:6005
1012:6006


1013:6000
1013:6001
1013:6002
1013:6003
1013:6004
1013:6005
1013:6006


1014:6000
1014:6001
1014:6002
1014:6003
1014:6004
1014:6005
1014:6006


2001:6000
2001:6001
2001:6002
2001:6003
2001:6004
2001:6005
2001:6006


2002:6000
2002:6001
2002:6002
2002:6003
2002:6004
2002:6005
2002:6006


2003:6000
2003:6001
2003:6002
2003:6003
2003:6004
2003:6005
2003:6006


2004:6000
2004:6001
2004:6002
2004:6003
2004:6004
2004:6005
2004:6006


2005:6000
2005:6001
2005:6002
2005:6003
2005:6004
2005:6005
2005:6006


2006:6000
2006:6001
2006:6002
2006:6003
2006:6004
2006:6005
2006:6006


2007:6000
2007:6001
2007:6002
2007:6003
2007:6004
2007:6005
2007:6006


2008:6000
2008:6001
2008:6002
2008:6003
2008:6004
2008:6005
2008:6006


2009:6000
2009:6001
2009:6002
2009:6003
2009:6004
2009:6005
2009:6006


2010:6000
2010:6001
2010:6002
2010:6003
2010:6004
2010:6005
2010:6006


3001:6000
3001:6001
3001:6002
3001:6003
3001:6004
3001:6005
3001:6006


3002:6000
3002:6001
3002:6002
3002:6003
3002:6004
3002:6005
3002:6006


3003:6000
3003:6001
3003:6002
3003:6003
3003:6004
3003:6005
3003:6006


3004:6000
3004:6001
3004:6002
3004:6003
3004:6004
3004:6005
3004:6006


3005:6000
3005:6001
3005:6002
3005:6003
3005:6004
3005:6005
3005:6006


3006:6000
3006:6001
3006:6002
3006:6003
3006:6004
3006:6005
3006:6006


3007:6000
3007:6001
3007:6002
3007:6003
3007:6004
3007:6005
3007:6006


3008:6000
3008:6001
3008:6002
3008:6003
3008:6004
3008:6005
3008:6006


4001:6000
4001:6001
4001:6002
4001:6003
4001:6004
4001:6005
4001:6006


4002:6000
4002:6001
4002:6002
4002:6003
4002:6004
4002:6005
4002:6006


4003:6000
4003:6001
4003:6002
4003:6003
4003:6004
4003:6005
4003:6006


4004:6000
4004:6001
4004:6002
4004:6003
4004:6004
4004:6005
4004:6006


4005:6000
4005:6001
4005:6002
4005:6003
4005:6004
4005:6005
4005:6006


5001:6000
5001:6001
5001:6002
5001:6003
5001:6004
5001:6005
5001:6006


5002:6000
5002:6001
5002:6002
5002:6003
5002:6004
5002:6005
5002:6006


1001:6007
1001:6008
1001:6009
1001:6010
1001:6011
1001:6012
1001:6013


1002:6007
1002:6008
1002:6009
1002:6010
1002:6011
1002:6012
1002:6013


1003:6007
1003:6008
1003:6009
1003:6010
1003:6011
1003:6012
1003:6013


1004:6007
1004:6008
1004:6009
1004:6010
1004:6011
1004:6012
1004:6013


1005:6007
1005:6008
1005:6009
1005:6010
1005:6011
1005:6012
1005:6013


1006:6007
1006:6008
1006:6009
1006:6010
1006:6011
1006:6012
1006:6013


1007:6007
1007:6008
1007:6009
1007:6010
1007:6011
1007:6012
1007:6013


1008:6007
1008:6008
1008:6009
1008:6010
1008:6011
1008:6012
1008:6013


1009:6007
1009:6008
1009:6009
1009:6010
1009:6011
1009:6012
1009:6013


1010:6007
1010:6008
1010:6009
1010:6010
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1010:6012
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1011:6007
1011:6008
1011:6009
1011:6010
1011:6011
1011:6012
1011:6013


1012:6007
1012:6008
1012:6009
1012:6010
1012:6011
1012:6012
1012:6013


1013:6007
1013:6008
1013:6009
1013:6010
1013:6011
1013:6012
1013:6013


1014:6007
1014:6008
1014:6009
1014:6010
1014:6011
1014:6012
1014:6013


2001:6007
2001:6008
2001:6009
2001:6010
2001:6011
2001:6012
2001:6013


2002:6007
2002:6008
2002:6009
2002:6010
2002:6011
2002:6012
2002:6013


2003:6007
2003:6008
2003:6009
2003:6010
2003:6011
2003:6012
2003:6013


2004:6007
2004:6008
2004:6009
2004:6010
2004:6011
2004:6012
2004:6013


2005:6007
2005:6008
2005:6009
2005:6010
2005:6011
2005:6012
2005:6013


2006:6007
2006:6008
2006:6009
2006:6010
2006:6011
2006:6012
2006:6013


2007:6007
2007:6008
2007:6009
2007:6010
2007:6011
2007:6012
2007:6013


2008:6007
2008:6008
2008:6009
2008:6010
2008:6011
2008:6012
2008:6013


2009:6007
2009:6008
2009:6009
2009:6010
2009:6011
2009:6012
2009:6013


2010:6007
2010:6008
2010:6009
2010:6010
2010:6011
2010:6012
2010:6013


3001:6007
3001:6008
3001:6009
3001:6010
3001:6011
3001:6012
3001:6013


3002:6007
3002:6008
3002:6009
3002:6010
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3002:6012
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3003:6007
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3003:6009
3003:6010
3003:6011
3003:6012
3003:6013


3004:6007
3004:6008
3004:6009
3004:6010
3004:6011
3004:6012
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3005:6007
3005:6008
3005:6009
3005:6010
3005:6011
3005:6012
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3006:6007
3006:6008
3006:6009
3006:6010
3006:6011
3006:6012
3006:6013


3007:6007
3007:6008
3007:6009
3007:6010
3007:6011
3007:6012
3007:6013


3008:6007
3008:6008
3008:6009
3008:6010
3008:6011
3008:6012
3008:6013


4001:6007
4001:6008
4001:6009
4001:6010
4001:6011
4001:6012
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4002:6007
4002:6008
4002:6009
4002:6010
4002:6011
4002:6012
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4003:6007
4003:6008
4003:6009
4003:6010
4003:6011
4003:6012
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4004:6007
4004:6008
4004:6009
4004:6010
4004:6011
4004:6012
4004:6013


4005:6007
4005:6008
4005:6009
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4005:6012
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5001:6007
5001:6008
5001:6009
5001:6010
5001:6011
5001:6012
5001:6013


5002:6007
5002:6008
5002:6009
5002:6010
5002:6011
5002:6012
5002:6013


1001:6014
1001:6015
1001:6016
1001:6017
1001:6018
1001:6019
1001:6020


1002:6014
1002:6015
1002:6016
1002:6017
1002:6018
1002:6019
1002:6020


1003:6014
1003:6015
1003:6016
1003:6017
1003:6018
1003:6019
1003:6020


1004:6014
1004:6015
1004:6016
1004:6017
1004:6018
1004:6019
1004:6020


1005:6014
1005:6015
1005:6016
1005:6017
1005:6018
1005:6019
1005:6020


1006:6014
1006:6015
1006:6016
1006:6017
1006:6018
1006:6019
1006:6020


1007:6014
1007:6015
1007:6016
1007:6017
1007:6018
1007:6019
1007:6020


1008:6014
1008:6015
1008:6016
1008:6017
1008:6018
1008:6019
1008:6020


1009:6014
1009:6015
1009:6016
1009:6017
1009:6018
1009:6019
1009:6020


1010:6014
1010:6015
1010:6016
1010:6017
1010:6018
1010:6019
1010:6020


1011:6014
1011:6015
1011:6016
1011:6017
1011:6018
1011:6019
1011:6020


1012:6014
1012:6015
1012:6016
1012:6017
1012:6018
1012:6019
1012:6020


1013:6014
1013:6015
1013:6016
1013:6017
1013:6018
1013:6019
1013:6020


1014:6014
1014:6015
1014:6016
1014:6017
1014:6018
1014:6019
1014:6020


2001:6014
2001:6015
2001:6016
2001:6017
2001:6018
2001:6019
2001:6020


2002:6014
2002:6015
2002:6016
2002:6017
2002:6018
2002:6019
2002:6020


2003:6014
2003:6015
2003:6016
2003:6017
2003:6018
2003:6019
2003:6020


2004:6014
2004:6015
2004:6016
2004:6017
2004:6018
2004:6019
2004:6020


2005:6014
2005:6015
2005:6016
2005:6017
2005:6018
2005:6019
2005:6020


2006:6014
2006:6015
2006:6016
2006:6017
2006:6018
2006:6019
2006:6020


2007:6014
2007:6015
2007:6016
2007:6017
2007:6018
2007:6019
2007:6020


2008:6014
2008:6015
2008:6016
2008:6017
2008:6018
2008:6019
2008:6020


2009:6014
2009:6015
2009:6016
2009:6017
2009:6018
2009:6019
2009:6020


2010:6014
2010:6015
2010:6016
2010:6017
2010:6018
2010:6019
2010:6020


3001:6014
3001:6015
3001:6016
3001:6017
3001:6018
3001:6019
3001:6020


3002:6014
3002:6015
3002:6016
3002:6017
3002:6018
3002:6019
3002:6020


3003:6014
3003:6015
3003:6016
3003:6017
3003:6018
3003:6019
3003:6020


3004:6014
3004:6015
3004:6016
3004:6017
3004:6018
3004:6019
3004:6020


3005:6014
3005:6015
3005:6016
3005:6017
3005:6018
3005:6019
3005:6020


3006:6014
3006:6015
3006:6016
3006:6017
3006:6018
3006:6019
3006:6020


3007:6014
3007:6015
3007:6016
3007:6017
3007:6018
3007:6019
3007:6020


3008:6014
3008:6015
3008:6016
3008:6017
3008:6018
3008:6019
3008:6020


4001:6014
4001:6015
4001:6016
4001:6017
4001:6018
4001:6019
4001:6020


4002:6014
4002:6015
4002:6016
4002:6017
4002:6018
4002:6019
4002:6020


4003:6014
4003:6015
4003:6016
4003:6017
4003:6018
4003:6019
4003:6020


4004:6014
4004:6015
4004:6016
4004:6017
4004:6018
4004:6019
4004:6020


4005:6014
4005:6015
4005:6016
4005:6017
4005:6018
4005:6019
4005:6020


5001:6014
5001:6015
5001:6016
5001:6017
5001:6018
5001:6019
5001:6020


5002:6014
5002:6015
5002:6016
5002:6017
5002:6018
5002:6019
5002:6020


1001:6021
1001:6022
1001:6023
1001:6024
1001:6025
1001:6026
1001:6027


1002:6021
1002:6022
1002:6023
1002:6024
1002:6025
1002:6026
1002:6027


1003:6021
1003:6022
1003:6023
1003:6024
1003:6025
1003:6026
1003:6027


1004:6021
1004:6022
1004:6023
1004:6024
1004:6025
1004:6026
1004:6027


1005:6021
1005:6022
1005:6023
1005:6024
1005:6025
1005:6026
1005:6027


1006:6021
1006:6022
1006:6023
1006:6024
1006:6025
1006:6026
1006:6027


1007:6021
1007:6022
1007:6023
1007:6024
1007:6025
1007:6026
1007:6027


1008:6021
1008:6022
1008:6023
1008:6024
1008:6025
1008:6026
1008:6027


1009:6021
1009:6022
1009:6023
1009:6024
1009:6025
1009:6026
1009:6027


1010:6021
1010:6022
1010:6023
1010:6024
1010:6025
1010:6026
1010:6027


1011:6021
1011:6022
1011:6023
1011:6024
1011:6025
1011:6026
1011:6027


1012:6021
1012:6022
1012:6023
1012:6024
1012:6025
1012:6026
1012:6027


1013:6021
1013:6022
1013:6023
1013:6024
1013:6025
1013:6026
1013:6027


1014:6021
1014:6022
1014:6023
1014:6024
1014:6025
1014:6026
1014:6027


2001:6021
2001:6022
2001:6023
2001:6024
2001:6025
2001:6026
2001:6027


2002:6021
2002:6022
2002:6023
2002:6024
2002:6025
2002:6026
2002:6027


2003:6021
2003:6022
2003:6023
2003:6024
2003:6025
2003:6026
2003:6027


2004:6021
2004:6022
2004:6023
2004:6024
2004:6025
2004:6026
2004:6027


2005:6021
2005:6022
2005:6023
2005:6024
2005:6025
2005:6026
2005:6027


2006:6021
2006:6022
2006:6023
2006:6024
2006:6025
2006:6026
2006:6027


2007:6021
2007:6022
2007:6023
2007:6024
2007:6025
2007:6026
2007:6027


2008:6021
2008:6022
2008:6023
2008:6024
2008:6025
2008:6026
2008:6027


2009:6021
2009:6022
2009:6023
2009:6024
2009:6025
2009:6026
2009:6027


2010:6021
2010:6022
2010:6023
2010:6024
2010:6025
2010:6026
2010:6027


3001:6021
3001:6022
3001:6023
3001:6024
3001:6025
3001:6026
3001:6027


3002:6021
3002:6022
3002:6023
3002:6024
3002:6025
3002:6026
3002:6027


3003:6021
3003:6022
3003:6023
3003:6024
3003:6025
3003:6026
3003:6027


3004:6021
3004:6022
3004:6023
3004:6024
3004:6025
3004:6026
3004:6027


3005:6021
3005:6022
3005:6023
3005:6024
3005:6025
3005:6026
3005:6027


3006:6021
3006:6022
3006:6023
3006:6024
3006:6025
3006:6026
3006:6027


3007:6021
3007:6022
3007:6023
3007:6024
3007:6025
3007:6026
3007:6027


3008:6021
3008:6022
3008:6023
3008:6024
3008:6025
3008:6026
3008:6027


4001:6021
4001:6022
4001:6023
4001:6024
4001:6025
4001:6026
4001:6027


4002:6021
4002:6022
4002:6023
4002:6024
4002:6025
4002:6026
4002:6027


4003:6021
4003:6022
4003:6023
4003:6024
4003:6025
4003:6026
4003:6027


4004:6021
4004:6022
4004:6023
4004:6024
4004:6025
4004:6026
4004:6027


4005:6021
4005:6022
4005:6023
4005:6024
4005:6025
4005:6026
4005:6027


5001:6021
5001:6022
5001:6023
5001:6024
5001:6025
5001:6026
5001:6027


5002:6021
5002:6022
5002:6023
5002:6024
5002:6025
5002:6026
5002:6027


1001:6028
1001:6029
1001:6030
1001:6031
1001:6032
1001:6033
1001:6034


1002:6028
1002:6029
1002:6030
1002:6031
1002:6032
1002:6033
1002:6034


1003:6028
1003:6029
1003:6030
1003:6031
1003:6032
1003:6033
1003:6034


1004:6028
1004:6029
1004:6030
1004:6031
1004:6032
1004:6033
1004:6034


1005:6028
1005:6029
1005:6030
1005:6031
1005:6032
1005:6033
1005:6034


1006:6028
1006:6029
1006:6030
1006:6031
1006:6032
1006:6033
1006:6034


1007:6028
1007:6029
1007:6030
1007:6031
1007:6032
1007:6033
1007:6034


1008:6028
1008:6029
1008:6030
1008:6031
1008:6032
1008:6033
1008:6034


1009:6028
1009:6029
1009:6030
1009:6031
1009:6032
1009:6033
1009:6034


1010:6028
1010:6029
1010:6030
1010:6031
1010:6032
1010:6033
1010:6034


1011:6028
1011:6029
1011:6030
1011:6031
1011:6032
1011:6033
1011:6034


1012:6028
1012:6029
1012:6030
1012:6031
1012:6032
1012:6033
1012:6034


1013:6028
1013:6029
1013:6030
1013:6031
1013:6032
1013:6033
1013:6034


1014:6028
1014:6029
1014:6030
1014:6031
1014:6032
1014:6033
1014:6034


2001:6028
2001:6029
2001:6030
2001:6031
2001:6032
2001:6033
2001:6034


2002:6028
2002:6029
2002:6030
2002:6031
2002:6032
2002:6033
2002:6034


2003:6028
2003:6029
2003:6030
2003:6031
2003:6032
2003:6033
2003:6034


2004:6028
2004:6029
2004:6030
2004:6031
2004:6032
2004:6033
2004:6034


2005:6028
2005:6029
2005:6030
2005:6031
2005:6032
2005:6033
2005:6034


2006:6028
2006:6029
2006:6030
2006:6031
2006:6032
2006:6033
2006:6034


2007:6028
2007:6029
2007:6030
2007:6031
2007:6032
2007:6033
2007:6034


2008:6028
2008:6029
2008:6030
2008:6031
2008:6032
2008:6033
2008:6034


2009:6028
2009:6029
2009:6030
2009:6031
2009:6032
2009:6033
2009:6034


2010:6028
2010:6029
2010:6030
2010:6031
2010:6032
2010:6033
2010:6034


3001:6028
3001:6029
3001:6030
3001:6031
3001:6032
3001:6033
3001:6034


3002:6028
3002:6029
3002:6030
3002:6031
3002:6032
3002:6033
3002:6034


3003:6028
3003:6029
3003:6030
3003:6031
3003:6032
3003:6033
3003:6034


3004:6028
3004:6029
3004:6030
3004:6031
3004:6032
3004:6033
3004:6034


3005:6028
3005:6029
3005:6030
3005:6031
3005:6032
3005:6033
3005:6034


3006:6028
3006:6029
3006:6030
3006:6031
3006:6032
3006:6033
3006:6034


3007:6028
3007:6029
3007:6030
3007:6031
3007:6032
3007:6033
3007:6034


3008:6028
3008:6029
3008:6030
3008:6031
3008:6032
3008:6033
3008:6034


4001:6028
4001:6029
4001:6030
4001:6031
4001:6032
4001:6033
4001:6034


4002:6028
4002:6029
4002:6030
4002:6031
4002:6032
4002:6033
4002:6034


4003:6028
4003:6029
4003:6030
4003:6031
4003:6032
4003:6033
4003:6034


4004:6028
4004:6029
4004:6030
4004:6031
4004:6032
4004:6033
4004:6034


4005:6028
4005:6029
4005:6030
4005:6031
4005:6032
4005:6033
4005:6034


5001:6028
5001:6029
5001:6030
5001:6031
5001:6032
5001:6033
5001:6034


5002:6028
5002:6029
5002:6030
5002:6031
5002:6032
5002:6033
5002:6034


1001:6035
1001:6036
1001:6037
1001:6038
1001:6039
1001:6040
1001:6041


1002:6035
1002:6036
1002:6037
1002:6038
1002:6039
1002:6040
1002:6041


1003:6035
1003:6036
1003:6037
1003:6038
1003:6039
1003:6040
1003:6041


1004:6035
1004:6036
1004:6037
1004:6038
1004:6039
1004:6040
1004:6041


1005:6035
1005:6036
1005:6037
1005:6038
1005:6039
1005:6040
1005:6041


1006:6035
1006:6036
1006:6037
1006:6038
1006:6039
1006:6040
1006:6041


1007:6035
1007:6036
1007:6037
1007:6038
1007:6039
1007:6040
1007:6041


1008:6035
1008:6036
1008:6037
1008:6038
1008:6039
1008:6040
1008:6041


1009:6035
1009:6036
1009:6037
1009:6038
1009:6039
1009:6040
1009:6041


1010:6035
1010:6036
1010:6037
1010:6038
1010:6039
1010:6040
1010:6041


1011:6035
1011:6036
1011:6037
1011:6038
1011:6039
1011:6040
1011:6041


1012:6035
1012:6036
1012:6037
1012:6038
1012:6039
1012:6040
1012:6041


1013:6035
1013:6036
1013:6037
1013:6038
1013:6039
1013:6040
1013:6041


1014:6035
1014:6036
1014:6037
1014:6038
1014:6039
1014:6040
1014:6041


2001:6035
2001:6036
2001:6037
2001:6038
2001:6039
2001:6040
2001:6041


2002:6035
2002:6036
2002:6037
2002:6038
2002:6039
2002:6040
2002:6041


2003:6035
2003:6036
2003:6037
2003:6038
2003:6039
2003:6040
2003:6041


2004:6035
2004:6036
2004:6037
2004:6038
2004:6039
2004:6040
2004:6041


2005:6035
2005:6036
2005:6037
2005:6038
2005:6039
2005:6040
2005:6041


2006:6035
2006:6036
2006:6037
2006:6038
2006:6039
2006:6040
2006:6041


2007:6035
2007:6036
2007:6037
2007:6038
2007:6039
2007:6040
2007:6041


2008:6035
2008:6036
2008:6037
2008:6038
2008:6039
2008:6040
2008:6041


2009:6035
2009:6036
2009:6037
2009:6038
2009:6039
2009:6040
2009:6041


2010:6035
2010:6036
2010:6037
2010:6038
2010:6039
2010:6040
2010:6041


3001:6035
3001:6036
3001:6037
3001:6038
3001:6039
3001:6040
3001:6041


3002:6035
3002:6036
3002:6037
3002:6038
3002:6039
3002:6040
3002:6041


3003:6035
3003:6036
3003:6037
3003:6038
3003:6039
3003:6040
3003:6041


3004:6035
3004:6036
3004:6037
3004:6038
3004:6039
3004:6040
3004:6041


3005:6035
3005:6036
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3001:6056
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1001:6063
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1002:6063
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1003:6063
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1004:6063
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1008:6063
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1009:6063
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1010:6063
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1011:6063
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1012:6063
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1013:6063
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1014:6063
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2001:6063
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2002:6063
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2008:6063
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2009:6063
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2010:6063
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3001:6063
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3002:6063
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3006:6063
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3007:6063
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3008:6063
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4001:6063
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1001:6070
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1002:6070
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1003:6070
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1004:6070
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1008:6070
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1009:6070
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1010:6070
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1011:6070
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1011:6075
1011:6076


1012:6070
1012:6071
1012:6072
1012:6073
1012:6074
1012:6075
1012:6076


1013:6070
1013:6071
1013:6072
1013:6073
1013:6074
1013:6075
1013:6076


1014:6070
1014:6071
1014:6072
1014:6073
1014:6074
1014:6075
1014:6076


2001:6070
2001:6071
2001:6072
2001:6073
2001:6074
2001:6075
2001:6076


2002:6070
2002:6071
2002:6072
2002:6073
2002:6074
2002:6075
2002:6076


2003:6070
2003:6071
2003:6072
2003:6073
2003:6074
2003:6075
2003:6076


2004:6070
2004:6071
2004:6072
2004:6073
2004:6074
2004:6075
2004:6076


2005:6070
2005:6071
2005:6072
2005:6073
2005:6074
2005:6075
2005:6076


2006:6070
2006:6071
2006:6072
2006:6073
2006:6074
2006:6075
2006:6076


2007:6070
2007:6071
2007:6072
2007:6073
2007:6074
2007:6075
2007:6076


2008:6070
2008:6071
2008:6072
2008:6073
2008:6074
2008:6075
2008:6076


2009:6070
2009:6071
2009:6072
2009:6073
2009:6074
2009:6075
2009:6076


2010:6070
2010:6071
2010:6072
2010:6073
2010:6074
2010:6075
2010:6076


3001:6070
3001:6071
3001:6072
3001:6073
3001:6074
3001:6075
3001:6076


3002:6070
3002:6071
3002:6072
3002:6073
3002:6074
3002:6075
3002:6076


3003:6070
3003:6071
3003:6072
3003:6073
3003:6074
3003:6075
3003:6076


3004:6070
3004:6071
3004:6072
3004:6073
3004:6074
3004:6075
3004:6076


3005:6070
3005:6071
3005:6072
3005:6073
3005:6074
3005:6075
3005:6076


3006:6070
3006:6071
3006:6072
3006:6073
3006:6074
3006:6075
3006:6076


3007:6070
3007:6071
3007:6072
3007:6073
3007:6074
3007:6075
3007:6076


3008:6070
3008:6071
3008:6072
3008:6073
3008:6074
3008:6075
3008:6076


4001:6070
4001:6071
4001:6072
4001:6073
4001:6074
4001:6075
4001:6076


4002:6070
4002:6071
4002:6072
4002:6073
4002:6074
4002:6075
4002:6076


4003:6070
4003:6071
4003:6072
4003:6073
4003:6074
4003:6075
4003:6076


4004:6070
4004:6071
4004:6072
4004:6073
4004:6074
4004:6075
4004:6076


4005:6070
4005:6071
4005:6072
4005:6073
4005:6074
4005:6075
4005:6076


5001:6070
5001:6071
5001:6072
5001:6073
5001:6074
5001:6075
5001:6076


5002:6070
5002:6071
5002:6072
5002:6073
5002:6074
5002:6075
5002:6076


1001:6077
1014:6077
3003:6077
1001:6078
1014:6078
3003:6078



1002:6077
2001:6077
3004:6077
1002:6078
2001:6078
3004:6078


1003:6077
2002:6077
3005:6077
1003:6078
2002:6078
3005:6078


1004:6077
2003:6077
3006:6077
1004:6078
2003:6078
3006:6078


1005:6077
2004:6077
3007:6077
1005:6078
2004:6078
3007:6078


1006:6077
2005:6077
3008:6077
1006:6078
2005:6078
3008:6078


1007:6077
2006:6077
4001:6077
1007:6078
2006:6078
4001:6078


1008:6077
2007:6077
4002:6077
1008:6078
2007:6078
4002:6078


1009:6077
2008:6077
4003:6077
1009:6078
2008:6078
4003:6078


1010:6077
2009:6077
4004:6077
1010:6078
2009:6078
4004:6078


1011:6077
2010:6077
4005:6077
1011:6078
2010:6078
4005:6078


1012:6077
3001:6077
5001:6077
1012:6078
3001:6078
5001:6078


1013:6077
3002:6077
5002:6077
1013:6078
3002:6078
5002:6078
















TABLE B







Example combinations of a compound X with a compound Y.













X:Y
X:Y
X:Y
X:Y
X:Y
X:Y
X:Y





6000:7000
6000:7001
6000:7002
6000:7003
6000:7004
6000:7005
6000:7006


6001:7000
6001:7001
6001:7002
6001:7003
6001:7004
6001:7005
6001:7006


6002:7000
6002:7001
6002:7002
6002:7003
6002:7004
6002:7005
6002:7006


6003:7000
6003:7001
6003:7002
6003:7003
6003:7004
6003:7005
6003:7006


6004:7000
6004:7001
6004:7002
6004:7003
6004:7004
6004:7005
6004:7006


6005:7000
6005:7001
6005:7002
6005:7003
6005:7004
6005:7005
6005:7006


6006:7000
6006:7001
6006:7002
6006:7003
6006:7004
6006:7005
6006:7006


6007:7000
6007:7001
6007:7002
6007:7003
6007:7004
6007:7005
6007:7006


6008:7000
6008:7001
6008:7002
6008:7003
6008:7004
6008:7005
6008:7006


6009:7000
6009:7001
6009:7002
6009:7003
6009:7004
6009:7005
6009:7006


6010:7000
6010:7001
6010:7002
6010:7003
6010:7004
6010:7005
6010:7006


6011:7000
6011:7001
6011:7002
6011:7003
6011:7004
6011:7005
6011:7006


6012:7000
6012:7001
6012:7002
6012:7003
6012:7004
6012:7005
6012:7006


6013:7000
6013:7001
6013:7002
6013:7003
6013:7004
6013:7005
6013:7006


6014:7000
6014:7001
6014:7002
6014:7003
6014:7004
6014:7005
6014:7006


6015:7000
6015:7001
6015:7002
6015:7003
6015:7004
6015:7005
6015:7006


6016:7000
6016:7001
6016:7002
6016:7003
6016:7004
6016:7005
6016:7006


6017:7000
6017:7001
6017:7002
6017:7003
6017:7004
6017:7005
6017:7006


6018:7000
6018:7001
6018:7002
6018:7003
6018:7004
6018:7005
6018:7006


6019:7000
6019:7001
6019:7002
6019:7003
6019:7004
6019:7005
6019:7006


6020:7000
6020:7001
6020:7002
6020:7003
6020:7004
6020:7005
6020:7006


6000:7007
6000:7008
6000:7009
6000:7010
6000:7011
6000:7012
6000:7013


6001:7007
6001:7008
6001:7009
6001:7010
6001:7011
6001:7012
6001:7013


6002:7007
6002:7008
6002:7009
6002:7010
6002:7011
6002:7012
6002:7013


6003:7007
6003:7008
6003:7009
6003:7010
6003:7011
6003:7012
6003:7013


6004:7007
6004:7008
6004:7009
6004:7010
6004:7011
6004:7012
6004:7013


6005:7007
6005:7008
6005:7009
6005:7010
6005:7011
6005:7012
6005:7013


6006:7007
6006:7008
6006:7009
6006:7010
6006:7011
6006:7012
6006:7013


6007:7007
6007:7008
6007:7009
6007:7010
6007:7011
6007:7012
6007:7013


6008:7007
6008:7008
6008:7009
6008:7010
6008:7011
6008:7012
6008:7013


6009:7007
6009:7008
6009:7009
6009:7010
6009:7011
6009:7012
6009:7013


6010:7007
6010:7008
6010:7009
6010:7010
6010:7011
6010:7012
6010:7013


6011:7007
6011:7008
6011:7009
6011:7010
6011:7011
6011:7012
6011:7013


6012:7007
6012:7008
6012:7009
6012:7010
6012:7011
6012:7012
6012:7013


6013:7007
6013:7008
6013:7009
6013:7010
6013:7011
6013:7012
6013:7013


6014:7007
6014:7008
6014:7009
6014:7010
6014:7011
6014:7012
6014:7013


6015:7007
6015:7008
6015:7009
6015:7010
6015:7011
6015:7012
6015:7013


6016:7007
6016:7008
6016:7009
6016:7010
6016:7011
6016:7012
6016:7013


6017:7007
6017:7008
6017:7009
6017:7010
6017:7011
6017:7012
6017:7013


6018:7007
6018:7008
6018:7009
6018:7010
6018:7011
6018:7012
6018:7013


6019:7007
6019:7008
6019:7009
6019:7010
6019:7011
6019:7012
6019:7013


6020:7007
6020:7008
6020:7009
6020:7010
6020:7011
6020:7012
6020:7013


6000:7014
6000:7015
6000:7016
6000:7017
6000:7018
6000:7019
6000:7020


6001:7014
6001:7015
6001:7016
6001:7017
6001:7018
6001:7019
6001:7020


6002:7014
6002:7015
6002:7016
6002:7017
6002:7018
6002:7019
6002:7020


6003:7014
6003:7015
6003:7016
6003:7017
6003:7018
6003:7019
6003:7020


6004:7014
6004:7015
6004:7016
6004:7017
6004:7018
6004:7019
6004:7020


6005:7014
6005:7015
6005:7016
6005:7017
6005:7018
6005:7019
6005:7020


6006:7014
6006:7015
6006:7016
6006:7017
6006:7018
6006:7019
6006:7020


6007:7014
6007:7015
6007:7016
6007:7017
6007:7018
6007:7019
6007:7020


6008:7014
6008:7015
6008:7016
6008:7017
6008:7018
6008:7019
6008:7020


6009:7014
6009:7015
6009:7016
6009:7017
6009:7018
6009:7019
6009:7020


6010:7014
6010:7015
6010:7016
6010:7017
6010:7018
6010:7019
6010:7020


6011:7014
6011:7015
6011:7016
6011:7017
6011:7018
6011:7019
6011:7020


6012:7014
6012:7015
6012:7016
6012:7017
6012:7018
6012:7019
6012:7020


6013:7014
6013:7015
6013:7016
6013:7017
6013:7018
6013:7019
6013:7020


6014:7014
6014:7015
6014:7016
6014:7017
6014:7018
6014:7019
6014:7020


6015:7014
6015:7015
6015:7016
6015:7017
6015:7018
6015:7019
6015:7020


6016:7014
6016:7015
6016:7016
6016:7017
6016:7018
6016:7019
6016:7020


6017:7014
6017:7015
6017:7016
6017:7017
6017:7018
6017:7019
6017:7020


6018:7014
6018:7015
6018:7016
6018:7017
6018:7018
6018:7019
6018:7020


6019:7014
6019:7015
6019:7016
6019:7017
6019:7018
6019:7019
6019:7020


6020:7014
6020:7015
6020:7016
6020:7017
6020:7018
6020:7019
6020:7020


6000:7021
6000:7022
6000:7023
6000:7024
6000:7025
6000:7026
6000:7027


6001:7021
6001:7022
6001:7023
6001:7024
6001:7025
6001:7026
6001:7027


6002:7021
6002:7022
6002:7023
6002:7024
6002:7025
6002:7026
6002:7027


6003:7021
6003:7022
6003:7023
6003:7024
6003:7025
6003:7026
6003:7027


6004:7021
6004:7022
6004:7023
6004:7024
6004:7025
6004:7026
6004:7027


6005:7021
6005:7022
6005:7023
6005:7024
6005:7025
6005:7026
6005:7027


6006:7021
6006:7022
6006:7023
6006:7024
6006:7025
6006:7026
6006:7027


6007:7021
6007:7022
6007:7023
6007:7024
6007:7025
6007:7026
6007:7027


6008:7021
6008:7022
6008:7023
6008:7024
6008:7025
6008:7026
6008:7027


6009:7021
6009:7022
6009:7023
6009:7024
6009:7025
6009:7026
6009:7027


6010:7021
6010:7022
6010:7023
6010:7024
6010:7025
6010:7026
6010:7027


6011:7021
6011:7022
6011:7023
6011:7024
6011:7025
6011:7026
6011:7027


6012:7021
6012:7022
6012:7023
6012:7024
6012:7025
6012:7026
6012:7027


6013:7021
6013:7022
6013:7023
6013:7024
6013:7025
6013:7026
6013:7027


6014:7021
6014:7022
6014:7023
6014:7024
6014:7025
6014:7026
6014:7027


6015:7021
6015:7022
6015:7023
6015:7024
6015:7025
6015:7026
6015:7027


6016:7021
6016:7022
6016:7023
6016:7024
6016:7025
6016:7026
6016:7027


6017:7021
6017:7022
6017:7023
6017:7024
6017:7025
6017:7026
6017:7027


6018:7021
6018:7022
6018:7023
6018:7024
6018:7025
6018:7026
6018:7027


6019:7021
6019:7022
6019:7023
6019:7024
6019:7025
6019:7026
6019:7027


6020:7021
6020:7022
6020:7023
6020:7024
6020:7025
6020:7026
6020:7027


6000:7028
6000:7029
6000:7030
6000:7031
6000:7032
6000:7033
6000:7034


6001:7028
6001:7029
6001:7030
6001:7031
6001:7032
6001:7033
6001:7034


6002:7028
6002:7029
6002:7030
6002:7031
6002:7032
6002:7033
6002:7034


6003:7028
6003:7029
6003:7030
6003:7031
6003:7032
6003:7033
6003:7034


6004:7028
6004:7029
6004:7030
6004:7031
6004:7032
6004:7033
6004:7034


6005:7028
6005:7029
6005:7030
6005:7031
6005:7032
6005:7033
6005:7034


6006:7028
6006:7029
6006:7030
6006:7031
6006:7032
6006:7033
6006:7034


6007:7028
6007:7029
6007:7030
6007:7031
6007:7032
6007:7033
6007:7034


6008:7028
6008:7029
6008:7030
6008:7031
6008:7032
6008:7033
6008:7034


6009:7028
6009:7029
6009:7030
6009:7031
6009:7032
6009:7033
6009:7034


6010:7028
6010:7029
6010:7030
6010:7031
6010:7032
6010:7033
6010:7034


6011:7028
6011:7029
6011:7030
6011:7031
6011:7032
6011:7033
6011:7034


6012:7028
6012:7029
6012:7030
6012:7031
6012:7032
6012:7033
6012:7034


6013:7028
6013:7029
6013:7030
6013:7031
6013:7032
6013:7033
6013:7034


6014:7028
6014:7029
6014:7030
6014:7031
6014:7032
6014:7033
6014:7034


6015:7028
6015:7029
6015:7030
6015:7031
6015:7032
6015:7033
6015:7034


6016:7028
6016:7029
6016:7030
6016:7031
6016:7032
6016:7033
6016:7034


6017:7028
6017:7029
6017:7030
6017:7031
6017:7032
6017:7033
6017:7034


6018:7028
6018:7029
6018:7030
6018:7031
6018:7032
6018:7033
6018:7034


6019:7028
6019:7029
6019:7030
6019:7031
6019:7032
6019:7033
6019:7034


6020:7028
6020:7029
6020:7030
6020:7031
6020:7032
6020:7033
6020:7034


6000:7035
6000:7036
6000:7037
6000:7038
6000:7039
6000:7040
6000:7041


6001:7035
6001:7036
6001:7037
6001:7038
6001:7039
6001:7040
6001:7041


6002:7035
6002:7036
6002:7037
6002:7038
6002:7039
6002:7040
6002:7041


6003:7035
6003:7036
6003:7037
6003:7038
6003:7039
6003:7040
6003:7041


6004:7035
6004:7036
6004:7037
6004:7038
6004:7039
6004:7040
6004:7041


6005:7035
6005:7036
6005:7037
6005:7038
6005:7039
6005:7040
6005:7041


6006:7035
6006:7036
6006:7037
6006:7038
6006:7039
6006:7040
6006:7041


6007:7035
6007:7036
6007:7037
6007:7038
6007:7039
6007:7040
6007:7041


6008:7035
6008:7036
6008:7037
6008:7038
6008:7039
6008:7040
6008:7041


6009:7035
6009:7036
6009:7037
6009:7038
6009:7039
6009:7040
6009:7041


6010:7035
6010:7036
6010:7037
6010:7038
6010:7039
6010:7040
6010:7041


6011:7035
6011:7036
6011:7037
6011:7038
6011:7039
6011:7040
6011:7041


6012:7035
6012:7036
6012:7037
6012:7038
6012:7039
6012:7040
6012:7041


6013:7035
6013:7036
6013:7037
6013:7038
6013:7039
6013:7040
6013:7041


6014:7035
6014:7036
6014:7037
6014:7038
6014:7039
6014:7040
6014:7041


6015:7035
6015:7036
6015:7037
6015:7038
6015:7039
6015:7040
6015:7041


6016:7035
6016:7036
6016:7037
6016:7038
6016:7039
6016:7040
6016:7041


6017:7035
6017:7036
6017:7037
6017:7038
6017:7039
6017:7040
6017:7041


6018:7035
6018:7036
6018:7037
6018:7038
6018:7039
6018:7040
6018:7041


6019:7035
6019:7036
6019:7037
6019:7038
6019:7039
6019:7040
6019:7041


6020:7035
6020:7036
6020:7037
6020:7038
6020:7039
6020:7040
6020:7041


6000:7042
6000:7043
6000:7044
6000:7045
6000:7046
6000:7047
6000:7048


6001:7042
6001:7043
6001:7044
6001:7045
6001:7046
6001:7047
6001:7048


6002:7042
6002:7043
6002:7044
6002:7045
6002:7046
6002:7047
6002:7048


6003:7042
6003:7043
6003:7044
6003:7045
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6078:7041
6078:7042
6078:7043
6078:7044
6078:7045


6061:7046
6061:7047
6061:7048
6061:7049
6061:7050
6061:7051
6061:7052


6062:7046
6062:7047
6062:7048
6062:7049
6062:7050
6062:7051
6062:7052


6063:7046
6063:7047
6063:7048
6063:7049
6063:7050
6063:7051
6063:7052


6064:7046
6064:7047
6064:7048
6064:7049
6064:7050
6064:7051
6064:7052


6065:7046
6065:7047
6065:7048
6065:7049
6065:7050
6065:7051
6065:7052


6066:7046
6066:7047
6066:7048
6066:7049
6066:7050
6066:7051
6066:7052


6067:7046
6067:7047
6067:7048
6067:7049
6067:7050
6067:7051
6067:7052


6068:7046
6068:7047
6068:7048
6068:7049
6068:7050
6068:7051
6068:7052


6069:7046
6069:7047
6069:7048
6069:7049
6069:7050
6069:7051
6069:7052


6070:7046
6070:7047
6070:7048
6070:7049
6070:7050
6070:7051
6070:7052


6071:7046
6071:7047
6071:7048
6071:7049
6071:7050
6071:7051
6071:7052


6072:7046
6072:7047
6072:7048
6072:7049
6072:7050
6072:7051
6072:7052


6073:7046
6073:7047
6073:7048
6073:7049
6073:7050
6073:7051
6073:7052


6074:7046
6074:7047
6074:7048
6074:7049
6074:7050
6074:7051
6074:7052


6075:7046
6075:7047
6075:7048
6075:7049
6075:7050
6075:7051
6075:7052


6076:7046
6076:7047
6076:7048
6076:7049
6076:7050
6076:7051
6076:7052


6077:7046
6077:7047
6077:7048
6077:7049
6077:7050
6077:7051
6077:7052


6078:7046
6078:7047
6078:7048
6078:7049
6078:7050
6078:7051
6078:7052


6061:7053
6061:7054
6061:7055
6061:7056
6061:7057
6061:7058
6061:7059


6062:7053
6062:7054
6062:7055
6062:7056
6062:7057
6062:7058
6062:7059


6063:7053
6063:7054
6063:7055
6063:7056
6063:7057
6063:7058
6063:7059


6064:7053
6064:7054
6064:7055
6064:7056
6064:7057
6064:7058
6064:7059


6065:7053
6065:7054
6065:7055
6065:7056
6065:7057
6065:7058
6065:7059


6066:7053
6066:7054
6066:7055
6066:7056
6066:7057
6066:7058
6066:7059


6067:7053
6067:7054
6067:7055
6067:7056
6067:7057
6067:7058
6067:7059


6068:7053
6068:7054
6068:7055
6068:7056
6068:7057
6068:7058
6068:7059


6069:7053
6069:7054
6069:7055
6069:7056
6069:7057
6069:7058
6069:7059


6070:7053
6070:7054
6070:7055
6070:7056
6070:7057
6070:7058
6070:7059


6071:7053
6071:7054
6071:7055
6071:7056
6071:7057
6071:7058
6071:7059


6072:7053
6072:7054
6072:7055
6072:7056
6072:7057
6072:7058
6072:7059


6073:7053
6073:7054
6073:7055
6073:7056
6073:7057
6073:7058
6073:7059


6074:7053
6074:7054
6074:7055
6074:7056
6074:7057
6074:7058
6074:7059


6075:7053
6075:7054
6075:7055
6075:7056
6075:7057
6075:7058
6075:7059


6076:7053
6076:7054
6076:7055
6076:7056
6076:7057
6076:7058
6076:7059


6077:7053
6077:7054
6077:7055
6077:7056
6077:7057
6077:7058
6077:7059


6078:7053
6078:7054
6078:7055
6078:7056
6078:7057
6078:7058
6078:7059


6061:7060
6061:7061
6061:7062
6061:7063
6061:7064
6061:7065
6061:7066


6062:7060
6062:7061
6062:7062
6062:7063
6062:7064
6062:7065
6062:7066


6063:7060
6063:7061
6063:7062
6063:7063
6063:7064
6063:7065
6063:7066


6064:7060
6064:7061
6064:7062
6064:7063
6064:7064
6064:7065
6064:7066


6065:7060
6065:7061
6065:7062
6065:7063
6065:7064
6065:7065
6065:7066


6066:7060
6066:7061
6066:7062
6066:7063
6066:7064
6066:7065
6066:7066


6067:7060
6067:7061
6067:7062
6067:7063
6067:7064
6067:7065
6067:7066


6068:7060
6068:7061
6068:7062
6068:7063
6068:7064
6068:7065
6068:7066


6069:7060
6069:7061
6069:7062
6069:7063
6069:7064
6069:7065
6069:7066


6070:7060
6070:7061
6070:7062
6070:7063
6070:7064
6070:7065
6070:7066


6071:7060
6071:7061
6071:7062
6071:7063
6071:7064
6071:7065
6071:7066


6072:7060
6072:7061
6072:7062
6072:7063
6072:7064
6072:7065
6072:7066


6073:7060
6073:7061
6073:7062
6073:7063
6073:7064
6073:7065
6073:7066


6074:7060
6074:7061
6074:7062
6074:7063
6074:7064
6074:7065
6074:7066


6075:7060
6075:7061
6075:7062
6075:7063
6075:7064
6075:7065
6075:7066


6076:7060
6076:7061
6076:7062
6076:7063
6076:7064
6076:7065
6076:7066


6077:7060
6077:7061
6077:7062
6077:7063
6077:7064
6077:7065
6077:7066


6078:7060
6078:7061
6078:7062
6078:7063
6078:7064
6078:7065
6078:7066


6061:7067
6061:7068
6061:7069
6061:7070
6061:7071
6061:7072
6061:7073


6062:7067
6062:7068
6062:7069
6062:7070
6062:7071
6062:7072
6062:7073


6063:7067
6063:7068
6063:7069
6063:7070
6063:7071
6063:7072
6063:7073


6064:7067
6064:7068
6064:7069
6064:7070
6064:7071
6064:7072
6064:7073


6065:7067
6065:7068
6065:7069
6065:7070
6065:7071
6065:7072
6065:7073


6066:7067
6066:7068
6066:7069
6066:7070
6066:7071
6066:7072
6066:7073


6067:7067
6067:7068
6067:7069
6067:7070
6067:7071
6067:7072
6067:7073


6068:7067
6068:7068
6068:7069
6068:7070
6068:7071
6068:7072
6068:7073


6069:7067
6069:7068
6069:7069
6069:7070
6069:7071
6069:7072
6069:7073


6070:7067
6070:7068
6070:7069
6070:7070
6070:7071
6070:7072
6070:7073


6071:7067
6071:7068
6071:7069
6071:7070
6071:7071
6071:7072
6071:7073


6072:7067
6072:7068
6072:7069
6072:7070
6072:7071
6072:7072
6072:7073


6073:7067
6073:7068
6073:7069
6073:7070
6073:7071
6073:7072
6073:7073


6074:7067
6074:7068
6074:7069
6074:7070
6074:7071
6074:7072
6074:7073


6075:7067
6075:7068
6075:7069
6075:7070
6075:7071
6075:7072
6075:7073


6076:7067
6076:7068
6076:7069
6076:7070
6076:7071
6076:7072
6076:7073


6077:7067
6077:7068
6077:7069
6077:7070
6077:7071
6077:7072
6077:7073


6078:7067
6078:7068
6078:7069
6078:7070
6078:7071
6078:7072
6078:7073


6061:7074
6061:7075
6061:7076
6061:7077





6062:7074
6062:7075
6062:7076
6062:7077


6063:7074
6063:7075
6063:7076
6063:7077


6064:7074
6064:7075
6064:7076
6064:7077


6065:7074
6065:7075
6065:7076
6065:7077


6066:7074
6066:7075
6066:7076
6066:7077


6067:7074
6067:7075
6067:7076
6067:7077


6068:7074
6068:7075
6068:7076
6068:7077


6069:7074
6069:7075
6069:7076
6069:7077


6070:7074
6070:7075
6070:7076
6070:7077


6071:7074
6071:7075
6071:7076
6071:7077


6072:7074
6072:7075
6072:7076
6072:7077


6073:7074
6073:7075
6073:7076
6073:7077


6074:7074
6074:7075
6074:7076
6074:7077


6075:7074
6075:7075
6075:7076
6075:7077


6076:7074
6076:7075
6076:7076
6076:7077


6077:7074
6077:7075
6077:7076
6077:7077


6078:7074
6078:7075
6078:7076
6078:7077
















TABLE C







Example combinations of a compound X with a compound Y.












X:Y
X:Y
X:Y
X:Y
X:Y
X:Y





6000:8000
6000:8001
6000:8002
6000:8003
6000:8004
6000:8005


6001:8000
6001:8001
6001:8002
6001:8003
6001:8004
6001:8005


6002:8000
6002:8001
6002:8002
6002:8003
6002:8004
6002:8005


6003:8000
6003:8001
6003:8002
6003:8003
6003:8004
6003:8005


6004:8000
6004:8001
6004:8002
6004:8003
6004:8004
6004:8005


6005:8000
6005:8001
6005:8002
6005:8003
6005:8004
6005:8005


6006:8000
6006:8001
6006:8002
6006:8003
6006:8004
6006:8005


6007:8000
6007:8001
6007:8002
6007:8003
6007:8004
6007:8005


6008:8000
6008:8001
6008:8002
6008:8003
6008:8004
6008:8005


6009:8000
6009:8001
6009:8002
6009:8003
6009:8004
6009:8005


6010:8000
6010:8001
6010:8002
6010:8003
6010:8004
6010:8005


6011:8000
6011:8001
6011:8002
6011:8003
6011:8004
6011:8005


6012:8000
6012:8001
6012:8002
6012:8003
6012:8004
6012:8005


6013:8000
6013:8001
6013:8002
6013:8003
6013:8004
6013:8005


6014:8000
6014:8001
6014:8002
6014:8003
6014:8004
6014:8005


6015:8000
6015:8001
6015:8002
6015:8003
6015:8004
6015:8005


6016:8000
6016:8001
6016:8002
6016:8003
6016:8004
6016:8005


6017:8000
6017:8001
6017:8002
6017:8003
6017:8004
6017:8005


6018:8000
6018:8001
6018:8002
6018:8003
6018:8004
6018:8005


6019:8000
6019:8001
6019:8002
6019:8003
6019:8004
6019:8005


6020:8000
6020:8001
6020:8002
6020:8003
6020:8004
6020:8005


6000:8006
6000:8007
6000:8008
6000:8009
6000:8010
6000:8011


6001:8006
6001:8007
6001:8008
6001:8009
6001:8010
6001:8011


6002:8006
6002:8007
6002:8008
6002:8009
6002:8010
6002:8011


6003:8006
6003:8007
6003:8008
6003:8009
6003:8010
6003:8011


6004:8006
6004:8007
6004:8008
6004:8009
6004:8010
6004:8011


6005:8006
6005:8007
6005:8008
6005:8009
6005:8010
6005:8011


6006:8006
6006:8007
6006:8008
6006:8009
6006:8010
6006:8011


6007:8006
6007:8007
6007:8008
6007:8009
6007:8010
6007:8011


6008:8006
6008:8007
6008:8008
6008:8009
6008:8010
6008:8011


6009:8006
6009:8007
6009:8008
6009:8009
6009:8010
6009:8011


6010:8006
6010:8007
6010:8008
6010:8009
6010:8010
6010:8011


6011:8006
6011:8007
6011:8008
6011:8009
6011:8010
6011:8011


6012:8006
6012:8007
6012:8008
6012:8009
6012:8010
6012:8011


6013:8006
6013:8007
6013:8008
6013:8009
6013:8010
6013:8011


6014:8006
6014:8007
6014:8008
6014:8009
6014:8010
6014:8011


6015:8006
6015:8007
6015:8008
6015:8009
6015:8010
6015:8011


6016:8006
6016:8007
6016:8008
6016:8009
6016:8010
6016:8011


6017:8006
6017:8007
6017:8008
6017:8009
6017:8010
6017:8011


6018:8006
6018:8007
6018:8008
6018:8009
6018:8010
6018:8011


6019:8006
6019:8007
6019:8008
6019:8009
6019:8010
6019:8011


6020:8006
6020:8007
6020:8008
6020:8009
6020:8010
6020:8011


6000:8012
6021:8000
6021:8001
6021:8002
6021:8003
6021:8004


6001:8012
6022:8000
6022:8001
6022:8002
6022:8003
6022:8004


6002:8012
6023:8000
6023:8001
6023:8002
6023:8003
6023:8004


6003:8012
6024:8000
6024:8001
6024:8002
6024:8003
6024:8004


6004:8012
6025:8000
6025:8001
6025:8002
6025:8003
6025:8004


6005:8012
6026:8000
6026:8001
6026:8002
6026:8003
6026:8004


6006:8012
6027:8000
6027:8001
6027:8002
6027:8003
6027:8004


6007:8012
6028:8000
6028:8001
6028:8002
6028:8003
6028:8004


6008:8012
6029:8000
6029:8001
6029:8002
6029:8003
6029:8004


6009:8012
6030:8000
6030:8001
6030:8002
6030:8003
6030:8004


6010:8012
6031:8000
6031:8001
6031:8002
6031:8003
6031:8004


6011:8012
6032:8000
6032:8001
6032:8002
6032:8003
6032:8004


6012:8012
6033:8000
6033:8001
6033:8002
6033:8003
6033:8004


6013:8012
6034:8000
6034:8001
6034:8002
6034:8003
6034:8004


6014:8012
6035:8000
6035:8001
6035:8002
6035:8003
6035:8004


6015:8012
6036:8000
6036:8001
6036:8002
6036:8003
6036:8004


6016:8012
6037:8000
6037:8001
6037:8002
6037:8003
6037:8004


6017:8012
6038:8000
6038:8001
6038:8002
6038:8003
6038:8004


6018:8012
6039:8000
6039:8001
6039:8002
6039:8003
6039:8004


6019:8012
6040:8000
6040:8001
6040:8002
6040:8003
6040:8004


6020:8012







6021:8005
6021:8006
6021:8007
6021:8008
6021:8009
6021:8010


6022:8005
6022:8006
6022:8007
6022:8008
6022:8009
6022:8010


6023:8005
6023:8006
6023:8007
6023:8008
6023:8009
6023:8010


6024:8005
6024:8006
6024:8007
6024:8008
6024:8009
6024:8010


6025:8005
6025:8006
6025:8007
6025:8008
6025:8009
6025:8010


6026:8005
6026:8006
6026:8007
6026:8008
6026:8009
6026:8010


6027:8005
6027:8006
6027:8007
6027:8008
6027:8009
6027:8010


6028:8005
6028:8006
6028:8007
6028:8008
6028:8009
6028:8010


6029:8005
6029:8006
6029:8007
6029:8008
6029:8009
6029:8010


6030:8005
6030:8006
6030:8007
6030:8008
6030:8009
6030:8010


6031:8005
6031:8006
6031:8007
6031:8008
6031:8009
6031:8010


6032:8005
6032:8006
6032:8007
6032:8008
6032:8009
6032:8010


6033:8005
6033:8006
6033:8007
6033:8008
6033:8009
6033:8010


6034:8005
6034:8006
6034:8007
6034:8008
6034:8009
6034:8010


6035:8005
6035:8006
6035:8007
6035:8008
6035:8009
6035:8010


6036:8005
6036:8006
6036:8007
6036:8008
6036:8009
6036:8010


6037:8005
6037:8006
6037:8007
6037:8008
6037:8009
6037:8010


6038:8005
6038:8006
6038:8007
6038:8008
6038:8009
6038:8010


6039:8005
6039:8006
6039:8007
6039:8008
6039:8009
6039:8010


6040:8005
6040:8006
6040:8007
6040:8008
6040:8009
6040:8010


6021:8011
6021:8012
6041:8000
6041:8001
6041:8002
6041:8003


6022:8011
6022:8012
6042:8000
6042:8001
6042:8002
6042:8003


6023:8011
6023:8012
6043:8000
6043:8001
6043:8002
6043:8003


6024:8011
6024:8012
6044:8000
6044:8001
6044:8002
6044:8003


6025:8011
6025:8012
6045:8000
6045:8001
6045:8002
6045:8003


6026:8011
6026:8012
6046:8000
6046:8001
6046:8002
6046:8003


6027:8011
6027:8012
6047:8000
6047:8001
6047:8002
6047:8003


6028:8011
6028:8012
6048:8000
6048:8001
6048:8002
6048:8003


6029:8011
6029:8012
6049:8000
6049:8001
6049:8002
6049:8003


6030:8011
6030:8012
6050:8000
6050:8001
6050:8002
6050:8003


6031:8011
6031:8012
6051:8000
6051:8001
6051:8002
6051:8003


6032:8011
6032:8012
6052:8000
6052:8001
6052:8002
6052:8003


6033:8011
6033:8012
6053:8000
6053:8001
6053:8002
6053:8003


6034:8011
6034:8012
6054:8000
6054:8001
6054:8002
6054:8003


6035:8011
6035:8012
6055:8000
6055:8001
6055:8002
6055:8003


6036:8011
6036:8012
6056:8000
6056:8001
6056:8002
6056:8003


6037:8011
6037:8012
6057:8000
6057:8001
6057:8002
6057:8003


6038:8011
6038:8012
6058:8000
6058:8001
6058:8002
6058:8003


6039:8011
6039:8012
6059:8000
6059:8001
6059:8002
6059:8003


6040:8011
6040:8012
6060:8000
6060:8001
6060:8002
6060:8003


6041:8004
6041:8005
6041:8006
6041:8007
6041:8008
6041:8009


6042:8004
6042:8005
6042:8006
6042:8007
6042:8008
6042:8009


6043:8004
6043:8005
6043:8006
6043:8007
6043:8008
6043:8009


6044:8004
6044:8005
6044:8006
6044:8007
6044:8008
6044:8009


6045:8004
6045:8005
6045:8006
6045:8007
6045:8008
6045:8009


6046:8004
6046:8005
6046:8006
6046:8007
6046:8008
6046:8009


6047:8004
6047:8005
6047:8006
6047:8007
6047:8008
6047:8009


6048:8004
6048:8005
6048:8006
6048:8007
6048:8008
6048:8009


6049:8004
6049:8005
6049:8006
6049:8007
6049:8008
6049:8009


6050:8004
6050:8005
6050:8006
6050:8007
6050:8008
6050:8009


6051:8004
6051:8005
6051:8006
6051:8007
6051:8008
6051:8009


6052:8004
6052:8005
6052:8006
6052:8007
6052:8008
6052:8009


6053:8004
6053:8005
6053:8006
6053:8007
6053:8008
6053:8009


6054:8004
6054:8005
6054:8006
6054:8007
6054:8008
6054:8009


6055:8004
6055:8005
6055:8006
6055:8007
6055:8008
6055:8009


6056:8004
6056:8005
6056:8006
6056:8007
6056:8008
6056:8009


6057:8004
6057:8005
6057:8006
6057:8007
6057:8008
6057:8009


6058:8004
6058:8005
6058:8006
6058:8007
6058:8008
6058:8009


6059:8004
6059:8005
6059:8006
6059:8007
6059:8008
6059:8009


6060:8004
6060:8005
6060:8006
6060:8007
6060:8008
6060:8009


6041:8010
6041:8011
6041:8012
6061:8000
6061:8001
6061:8002


6042:8010
6042:8011
6042:8012
6062:8000
6062:8001
6062:8002


6043:8010
6043:8011
6043:8012
6063:8000
6063:8001
6063:8002


6044:8010
6044:8011
6044:8012
6064:8000
6064:8001
6064:8002


6045:8010
6045:8011
6045:8012
6065:8000
6065:8001
6065:8002


6046:8010
6046:8011
6046:8012
6066:8000
6066:8001
6066:8002


6047:8010
6047:8011
6047:8012
6067:8000
6067:8001
6067:8002


6048:8010
6048:8011
6048:8012
6068:8000
6068:8001
6068:8002


6049:8010
6049:8011
6049:8012
6069:8000
6069:8001
6069:8002


6050:8010
6050:8011
6050:8012
6070:8000
6070:8001
6070:8002


6051:8010
6051:8011
6051:8012
6071:8000
6071:8001
6071:8002


6052:8010
6052:8011
6052:8012
6072:8000
6072:8001
6072:8002


6053:8010
6053:8011
6053:8012
6073:8000
6073:8001
6073:8002


6054:8010
6054:8011
6054:8012
6074:8000
6074:8001
6074:8002


6055:8010
6055:8011
6055:8012
6075:8000
6075:8001
6075:8002


6056:8010
6056:8011
6056:8012
6076:8000
6076:8001
6076:8002


6057:8010
6057:8011
6057:8012
6077:8000
6077:8001
6077:8002


6058:8010
6058:8011
6058:8012
6078:8000
6078:8001
6078:8002


6059:8010
6059:8011
6059:8012





6060:8010
6060:8011
6060:8012





6061:8003
6061:8004
6061:8005
6061:8006
6061:8007
6061:8008


6062:8003
6062:8004
6062:8005
6062:8006
6062:8007
6062:8008


6063:8003
6063:8004
6063:8005
6063:8006
6063:8007
6063:8008


6064:8003
6064:8004
6064:8005
6064:8006
6064:8007
6064:8008


6065:8003
6065:8004
6065:8005
6065:8006
6065:8007
6065:8008


6066:8003
6066:8004
6066:8005
6066:8006
6066:8007
6066:8008


6067:8003
6067:8004
6067:8005
6067:8006
6067:8007
6067:8008


6068:8003
6068:8004
6068:8005
6068:8006
6068:8007
6068:8008


6069:8003
6069:8004
6069:8005
6069:8006
6069:8007
6069:8008


6070:8003
6070:8004
6070:8005
6070:8006
6070:8007
6070:8008


6071:8003
6071:8004
6071:8005
6071:8006
6071:8007
6071:8008


6072:8003
6072:8004
6072:8005
6072:8006
6072:8007
6072:8008


6073:8003
6073:8004
6073:8005
6073:8006
6073:8007
6073:8008


6074:8003
6074:8004
6074:8005
6074:8006
6074:8007
6074:8008


6075:8003
6075:8004
6075:8005
6075:8006
6075:8007
6075:8008


6076:8003
6076:8004
6076:8005
6076:8006
6076:8007
6076:8008


6077:8003
6077:8004
6077:8005
6077:8006
6077:8007
6077:8008


6078:8003
6078:8004
6078:8005
6078:8006
6078:8007
6078:8008


6061:8009
6061:8010
6061:8011
6061:8012




6062:8009
6062:8010
6062:8011
6062:8012




6063:8009
6063:8010
6063:8011
6063:8012




6064:8009
6064:8010
6064:8011
6064:8012




6065:8009
6065:8010
6065:8011
6065:8012




6066:8009
6066:8010
6066:8011
6066:8012




6067:8009
6067:8010
6067:8011
6067:8012




6068:8009
6068:8010
6068:8011
6068:8012




6069:8009
6069:8010
6069:8011
6069:8012




6070:8009
6070:8010
6070:8011
6070:8012




6071:8009
6071:8010
6071:8011
6071:8012




6072:8009
6072:8010
6072:8011
6072:8012




6073:8009
6073:8010
6073:8011
6073:8012




6074:8009
6074:8010
6074:8011
6074:8012




6075:8009
6075:8010
6075:8011
6075:8012




6076:8009
6076:8010
6076:8011
6076:8012




6077:8009
6077:8010
6077:8011
6077:8012




6078:8009
6078:8010
6078:8011
6078:8012
















TABLE D







Example combinations of a compound X with a compound Y.










X:Y
X:Y
X:Y
X:Y





6000:9000
6020:9000
6040:9000
6060:9000


6001:9000
6021:9000
6041:9000
6061:9000


6002:9000
6022:9000
6042:9000
6062:9000


6003:9000
6023:9000
6043:9000
6063:9000


6004:9000
6024:9000
6044:9000
6064:9000


6005:9000
6025:9000
6045:9000
6065:9000


6006:9000
6026:9000
6046:9000
6066:9000


6007:9000
6027:9000
6047:9000
6067:9000


6008:9000
6028:9000
6048:9000
6068:9000


6009:9000
6029:9000
6049:9000
6069:9000


6010:9000
6030:9000
6050:9000
6070:9000


6011:9000
6031:9000
6051:9000
6071:9000


6012:9000
6032:9000
6052:9000
6072:9000


6013:9000
6033:9000
6053:9000
6073:9000


6014:9000
6034:9000
6054:9000
6074:9000


6015:9000
6035:9000
6055:9000
6075:9000


6016:9000
6036:9000
6056:9000
6076:9000


6017:9000
6037:9000
6057:9000
6077:9000


6018:9000
6038:9000
6058:9000
6078:9000


6019:9000
6039:9000
6059:9000









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
General Synthesis of Reagents 1 and 2



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Step 1: Synthesis of 1-naphthyloxydichlorophosphothioate reagent (1a)



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A 500 mL round bottom flask containing a magnetic stir bar was charged with phosphorus thiotrichloride (5.7 g, 33.65 mmol) and 1-naphthol (4.85 g, 33.64 mmol), and 40 mL of diethyl ether was added. Under an argon atmosphere, the solution was cooled in a dry ice/acetone bath. After 10 minutes of cooling, triethylamine (4.7 mL, 33.7 mmol) was added, and a precipitate formed. The mixture was allowed to warm to ambient temperature, and was then stirred for 2 days. The precipitated triethylammonium hydrochloride was filtered off, and was washed twice with ether. The solvents were removed under reduced pressure to leave 9.8 g of compound 1a as a cloudy, light yellow oil. 1a was used in the next step without further purification.


Step 2: Synthesis of the L-alanine methyl ester derived 1-naphthyloxy-chlorophosphothioate reagent (2a)



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Into a 250 mL round bottom flask containing 1-naphthol-dichlorophosphothioate reagent 1a (1.97 g, 7.1 mmol) and L-alanine methyl ester hydrochloride (0.99 g, 7.1 mmol) was added in 50 mL of dichloromethane. At water/ice temperature under an argon atmosphere, triethylamine (1 mL, 7.2 mmol) was added. The reaction was allowed to warm to ambient temperature and was then stirred overnight. The solvents were removed using a rotary evaporator. The residue was purified using chromatography on silica gel, and eluting with 20% ethyl acetate in hexanes. The product 2a (1.0 g) was obtained as a viscous oil. 31P NMR (CDCl3, 64.78, 65.0) (approximately a 1:1 mixture of diastereomers).


The reagents shown in Tables 6 and 7 were prepared using the procedures described for compounds 1a and 2a, with the ArOH compounds listed in Table 6 in place of 1-naphthol, and with hydrochloride salts of the amino acids listed in Table 7 in place of L-alanine methyl ester hydrochloride.











TABLE 6





ArOH
Dichloridates
Reagent No.







Phenol


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1b





p-fluoro-phenol


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1c





p-chloro-phenol


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1d





o-chloro-phenol


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1e





p-chloro-m- chloro-phenol


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1f





p-methyl-phenol


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1g





o-methyl-phenol


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1h





p-methoxy-phenol


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1i





quinolin-5-ol


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1j





pyridine-3-ol


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1k



















TABLE 7





Amino
Aryloxy amino acid
Reagent

31P NMR



Acid
thiophosphochloridate
No.
(CDCl3)







L-alanine isopropyl ester


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2b
64.75 (s) 64.65 (s)





L-alanine cyclohexyl ester


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2c
64.80 (s) 64.69 (s)





L-alanine neopentyl ester


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2d
64.59 (s) 64.31 (s)





L-alanine isopropyl ester


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2e
64.51 (s) 64.23 (s)





L-alanine cyclohexyl ester


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2f
64.55 (s) 64.25 (s)





L-alanine neopentyl ester


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2g
64.51 (s) 64.27 (s)





L-valine isopropyl ester


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2h
67.72 65.87









Example 2
Preparation of 2′-C-Methyluridine 5′-(O-(1-naphthyl)-N—(S)-1-(methoxycarbonyl)ethyl)thiophosphoramidate (3a)



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A solution of cyclopentylidine protected 2′-C-methyluridine (262 mg, 0.81 mmol) in 2 mL tetrahydrofuran was cooled in an ice/water bath under argon, and treated with 2.1 mL tBuMgCl (1 M, 2.1 mmol). After 10 minutes, reagent 2a (0.83 g, 2.4 mmol) was added as a solution in 2 mL of tetrahydrofuran (THF). The reaction was stirred at ambient temperature for 2 days. An additional 1 mL tBuMgCl was then added (1 mmol). After an additional 2 days, the reaction was diluted with ethyl acetate and water. The organic layer was washed two times with brine, and dried over sodium sulfate. Chromatography on silica gel using a gradient of 1% methanol in dichloromethane to 10% methanol in dichloromethane afforded 0.2 g of a residue which was used without further purification. To the residue was added 4 mL of 80% aqueous formic acid. The mixture was heated to 50° C. using a water bath. After 2 hours, the reaction was cooled, and the solvents were removed under reduced pressure. A solution of 1:1 methanol:toluene was added to the residue. The solvents were then removed under reduced pressure. The addition of a solution of 1:1 methanol:toluene and removal of solvents were repeated 2 more times. The product was isolated following chromatography using silica gel with a gradient from 4% to 8% methanol in dichloromethane. The solvent was removed, and the residue was taken up in chloroform and treated with excess hexanes. The supernatant was decanted off, and the remaining solid was subjected to high vacuum overnight. Product 3a was isolated as a colorless solid (22.2 mg). 31P NMR (CDCl3, 67.12, 67.86) and mass spectral data (M−H, 564.5) were consistent with the desired product 3a as a near 1:1 mixture of diastereomers at the phosphorus chiral center.


Example 3
Preparation of 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3b)



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Step 1: Compound 3b-1—


To a suspension of 2′-methyluridine (20 g, 77.52 mmol) in dry CH3CN (200 mL) were added cyclopentanone (20 mL) and trimethylorthoformate (20 mL) followed by p-toluenesulfonic acid monohydrate (7.4 g, 38.76 mmol). The reaction mixture was stirred at 40° C. overnight. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried and evaporated to give pure 3b-1 as a white solid (14.5 g, 57.7%). 1H NMR (CDCl3, 400 MHz) δ8.86 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, J=8.0 Hz, 1H), 4.50 (d, J=4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m, 1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H).


Step 2: Compound 3b-2—


To a suspension of 3b-1 (20 g, 61.7 mmol) in dry CH3CN (100 mL) was added N-methylimidazole (50 mL) and 2b (80 g, 249.2 mmol). The reaction mixture was stirred at 70° C. for 2 h. Solvent was removed and the residue was dissolved in ethyl acetate (500 mL). The solution was washed with brine, dried and evaporated. The residue was purified on a silica gel column (20˜50% ethylacetate (EA) in petroleum ether (PE)) to give 3b-2 as a white foam (two isomers, 12.5 g, 33%). 1H NMR (CDCl3, 400 MHz) δ8.79-8.92 (m, 1H), 7.55 (m, 1H), 7.34 (m, 2H), 7.20 (m, 3H), 6.09 (d, J=13.6 Hz, 1H), 5.70-5.61 (m, 1H), 5.06-5.01 (m, 1H), 4.38-4.09 (m, 6H), 2.08 (m, 1H), 1.96 (m, 1H), 1.73 (m, 2H), 1.66 (m, 5H), 1.39 (m, 3H), 1.23 (m, 9H); 31P NMR (CDCl3, 162 MHz) δ67.62, 67.31.


Step 3: Compound 3b—


Compound 3b-2 (10 g, 16.4 mmol) was suspended in 100 mL of 80% formic acid and the reaction mixture was stirred at 50° C. for 1.5 hours. Solvent was evaporated and the residue was co-evaporated with toluene to remove traces of acid and water. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water as mobile phase) to give 3b (a mixture of two P-diastereomers, 5.6 g, 63%). 1H NMR (CD3OD, 400 MHz) δ 7.79, 7.87 (2d, J=8.0 Hz, 1H), 7.18-7.38 (m, 5H), 5.98, 6.01 (2s, 1H), 5.59, 5.63 (2d, J=8.0 Hz, 1H), 4.95-5.05 (m, 1H), 4.51-4.56 (m, 1H), 4.30-4.44 (m, 1H), 4.05-4.17 (m, 2H), 3.82-3.87 (m, 1H), 1.34, 1.38 (2d, J=7.2 Hz, 3H), 1.17, 1.25 (2d, J=6.0 Hz, 6H), 1.24, 125 (2s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.17, 68.40; ESI-LCMS: m/z 544.0 [M+H]+.


Step 4: Separation of 3b(i)-Rp and 3b(ii)-Sp—


Compound 3b was separated into its Rp and Sp diastereomers by two methods: (a) supercritical fluid chromatography (SFC) and (b) crystallization.


(a) Via SFC:


Compound 3b (440 mg, consisting of both 3b(i)-Rp and 3b(ii)-Sp in ˜1:1 ratio) was subjected to separation by SFC (chiral PAK AD, 5 um. 250*30 mm using 25% MeOH and 75% CO2 as mobile phase) to give 3b(i)-Rp (123.8 mg) and 3b(ii)-Sp (162.5 mg) as a white solid; 3b(i)-Rp: 1H NMR (CD3OD, 400 MHz) δ7.87 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.01 (s, 1H), 5.62 (d, J=8.0 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.92 (m, 1H), 4.44-4.39 (m, 1H), 4.16-4.13 (m, 1H), 4.10-4.05 (m, 1H), 3.86 (d, J=9.2 Hz, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.4 Hz, 6H), 1.16 (s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.18; ESI-LCMS: m/z=544 [M+H]+. 3b(ii)-Sp: 1H NMR (CD3OD, 400 MHz) δ7.89 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 5.99 (s, 1H), 5.60 (d, J=8.4 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.51 (m, 1H), 4.35-4.30 (m, 1H), 4.14-4.10 (m, 2H), 3.83 (d, J=9.2 Hz, 1H), 1.39 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.4 Hz, 6H), 1.17 (s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.42; ESI-LCMS: m/z=566 [M+Na]+.


(b) Via Crystallization:


Compound 3b as a mixture of diastereomers (1:1, 10 g) was dissolved in 100 mL of dichloromethane (DCM)/ether (1:3). Hexane was added dropwise until the solution became cloudy. The solution was left at (room temperature) RT for 5 h and overnight at −20° C. Precipitated crystals were recrystallized from DCM/ether 1:3 v/v, and one more time from DCM/ether 1:2. Compound 3b(i)-Rp (3 g) was obtained as a pure single diastereomer. The mother liquor after first crystallization was concentrated, and then dissolved in isopropanol. Hexane was added (30% by volume). The clear solution was left overnight at RT to produce a small amount of crystals, which were used as seeds. The mother liquor was evaporated and crystallized 2 times from hexane/isopropanol (4:1) to give 2.3 g of 3b(ii)-Sp.


Example 4
Preparation of 2′,3′-O-dipropionyl-2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (4a)



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Compound 3b (85 mg, 0.156 mmol) was dissolved in 3 mL of dry pyridine. Propionic anhydride (0.1 mL, 0.624 mmol) was added, and the mixture left for 18 hours at ambient temperature. Water (7 mL) and ethyl acetate (7 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, and evaporated. The resulting oil was purified by flash chromatography using a gradient of methanol in dichloromethane from 0 to 4%. The fractions containing phosphorothioate were combined and concentrated in vacuum. Repurification by RP HPLC using a gradient of methanol in water from 50% to 100% yielded 44 mg of product 4a. 31P NMR (CDCl3, 67.71, 67.74) and mass spectral analysis (M−H, 654.5) were consistent with the desired product 4a as near 1:1 mixture of diastereomers at the phosphorus chiral center.


Example 5
Preparation of 2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3c)



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2′-Deoxy-2′-fluoro-2′-methyluridine (200 mg, 0.62 mmol) was suspended in dry THF (20 mL) under N2. A solution of 2b in dry THF (3 mL, 3 mmol), DMAP (4-dimethylaminopyridine) (100 mg, 0.9 mmol) and triethylamine (1 mL, 7 mmol) were added at RT. The reaction was stirred at 80° C. for 18 hrs. The solvents were removed, and the residue was purified by column and RP HPLC (HCOOH system) to give 3c as a white solid (3.5 mg). 1H NMR (CDCl3) δ8.49, 8.31 (m, 1H), 7.49, 7.43 (2d, J=8.0 Hz, 1H), 7.31, 7.26 (m, 2H), 7.19, 7.11 (m, 3H), 6.17, 6.11 (2d, J=7.2 Hz, 1H), 5.62, 5.53 (2d, 1H), 4.99, 4.93 (m, 1H), 4.54, 4.27 (m, 2H), 4.08, 4.02 (m, 3H), 3.89, 3.83 (m, 1H), 1.36, 1.22 (m, 6H), 1.20, 1.12 (m, 6H). 31P NMR (CDCl3) δ68.08, 67.05. LCMS m/z 545.8 (MH+).


Example 6
Preparation of 2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine 5′-(O-phenyl-N—(S)-1-(cyclohexoxycarbonyl)ethyl)thiophosphoramidate (3d)



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Compound 3d was prepared using the procedure for preparing compound 3c, with 2c in place of 2b. 1H NMR (DMSO-d6) δ11.55 (s, 1H), 7.61 (d, J=8.4 Hz, 0.43H), 7.57 (d, J=7.6 Hz, 0.56H), 7.40 (m, 2H), 7.21 (overlap, 3H), 6.68 (m, 1H), 6.04 (m, 1H), 5.95 (d, J=7.6 Hz, 0.40H), 5.88 (d, J=6.8 Hz, 0.60H), 5.57 (s, 0.50H), 5.55 (s, 0.50H), 4.64 (s, 1H), 4.39 (m, 1H), 4.23 (m, 1H), 4.09-3.86 (m, 2H), 3.84 (m, 1H), 1.63 (s, 2H), 1.45 (s, 2H), 1.36 (brs, 1H), 1.34-1.29 (m, 11H). 31P NMR (DMSO-d6) δ67.96, 67.89; MS m/z 586.2 (MH+).


Example 7
Preparation of 2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine 5′-(O-phenyl-N—(S)-1-(neopentoxycarbonyl)ethyl)thiophosphoramidate (3e)



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Compound 3e was prepared using the procedure for preparing compound 3c, with 2d in place of 2b. 1H NMR (CD3OD) δ7.77-7.66 (q, J=8.0, 8.4 Hz, 1H), 7.36-7.16 (m, 5H), 6.13 (m, 1H), 6.04 (m, 1H), 5.65-5.56 (q, J=8.4, 8.0 Hz, 1H), 4.19-4.09 (m, 2H), 3.93-3.75 (m, 2H), 1.41-1.28 (m, 6H), 0.93 (s, 9H). 31P NMR (CD3OD) δ66.9, 66.9. MS m/z 574.2 (MH+).


Example 8
Preparation of 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(neopentoxycarbonyl)ethyl)thiophosphoramidate (3f)



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2′-C-methyluridine (77 mg, 0.3 mmol) was dissolved in 10 mL of anhydrous acetonitrile and 2 mL of N-methylimidazole. Compound 2d was added (0.3 g, 0.9 mmol) and the mixture was heated at 70° C. for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 30 mL of ethyl acetate, washed with 10% citric acid (2×10 mL), water, brine, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography on silica gel with methanol in dichloromethane (0 to 10%) to give 3f (224 mg) as light-tan solid. An analytical sample was obtained as a colorless solid by RP HPLC purification in gradient of methanol in water from 10% to 95% on a Synergy 4u Hydro-RP column (Phenominex). 1H NMR (CDCl3): δ 9.90 (bs, 1H), 7.62-7.58 (m, 1H), 7.32-7.28 (m, 2H), 7.20-7.16 (m, 2H), 5.97 & 5.94 (2s, 1H), 5.65 & 5.52 (2d, 1H), 4.54-4.46 (m, 1H), 4.39-4.24 (m, 1H), 4.20-4.04 (m, 3H), 3.85-3.79 (m, 1H), 3.73-3.65 (m, 2H), 1.39-1.32 (dd, 3H), 1.16-1.14 (d, 1H), 0.87-0.86 (m, 9H); 31P NMR: δ67.85, 67.16 (1:1 mixture of diastereomers); ESI-LCMS: m/z 570.4 [M+H]+.


Example 9
Preparation of 2′-C-Methyluridine 5′-(O-phenyl-N—(S)-1-(cyclohexoxycarbonyl)ethyl)thiophosphoramidate (3g)



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Compound 3g was prepared using the procedure for preparing compound 3f, with 2c in place of 2d. 1H NMR (CDCl3): δ 9.40 (bs, 1H), 7.60-7.55 (m, 1H), 7.29-7.11 (m, 5H), 5.95 & 5.92 (2s, 1H), 5.63 & 5.53 (2d, 1H), 4.75-4.68 (m, 1H), 4.50-4.23 (m, 2H), 4.10-4.00 (m, 3H), 3.74-3.72 (m, 1H), 1.80-1.05 (m, 17H); 31P NMR: δ67.80, 67.16 (3:4 mixture of diastereomers); ESI-LCMS: m/z 582.5 [M+H]+.


Example 10
Preparation of 2′-C-Methyluridine 5′-(O-(1-naphthyl)-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3h)



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Compound 3h was prepared using the procedure for preparing compound 3f, with 2e in place of 2d. 1H NMR (CDCl3): δ 9.10 (bs, 1H), 8.05-7.20 (m, 9H), 5.95&5.92 (2s, 1H), 5.38 & 5.33 (2d, 1H), 4.99-4.91 (m, 1H), 4.59-4.28 (m, 2H), 4.20-4.03 (m, 3H), 3.72-3.69 (m, 1H), 1.36-1.27 (2d, 3H), 1.20-1.11 (m, 6H), 1.06-1.04 (2s, 3H); 31P NMR: δ 67.92, 67.28 (2:3 mixture of diastereomers); ESI-LCMS: m/z 592.2 [M+H]+.


Example 11
Preparation of 2′-C-Methyluridine 5′-(O-(1-naphthyl)-N—(S)-1-(cyclohexoxycarbonyl)ethyl)thiophosphoramidate (3i)



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Compound 3i was prepared using the procedure for preparing compound 3f, with 2f in place of 2d. 1H NMR (CDCl3): δ 9.80 (bs, 1H), 8.05-7.30 (m, 9H), 5.92 & 5.91 (2s, 1H), 5.38-5.29 (2d, 1H), 4.79-4.69 (m, 1H), 4.59-4.32 (m, 1H), 4.50-4.46 (m, 1H), 4.38-4.03 (m, 4H), 3.70-3.66 (m, 1H), 1.80-1.00 (m, 17H); 31P NMR: δ67.74, 67.43 (1:1 mixture of diastereomers); ESI-LCMS: m/z 632.5 [M+H]+.


Example 12
Preparation of 2′-C-Methyluridine 5′-(O-(1-naphtyl)-N—(S)-1-(neopentoxycarbonyl)ethyl)thiophosphoramidate (3i)



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Compound 3j was prepared using the procedure for preparing compound 3f, with 2g in place of 2d. 1H NMR (CDCl3): δ 9.80 (bs, 1H), 8.05-7.30 (m, 9H), 5.90 & 5.87 (2s, 1H), 5.38 &5.30 (2d, 1H), 4.60-3.60 (m, 9H), 3.72-3.69 (m, 1H), 1.41 & 1.39 (2d, 3H), 1.08 & 1.06 (2s, 3H), 0.87 & 0.86 (2s, 9H); 31P NMR: δ68.01, 67.35 (1:1 mixture of diastereomers); ESI-LCMS: m/z 620.8 [M+H]+.


Example 13
Preparation of 5′-dideuterated 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3l)



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Step 1. Compound 3l-1—


To a suspension of 2′-C-methyluridine (2.50 g, 7.6 mmol) in acetone (100 mL) were added p-Toluenesulfonic acid monohydrate (1.76 g, 9.2 mmol) and 2,2-dimethoxypropane (20 mL). The mixture was stirred at RT for 16 h. Then saturated NaHCO3 was added to adjust the pH to between approximately 6-7. The suspension was concentrated and the residue was purified on a silica gel column (5-7% MeOH in DCM) to give 3l-1 as a white solid (2.30 g, 82%).


Step 2. Compound 3l-2—


To a solution of 3l-1 (2.30 g, 7.7 mmol) in anhydrous DCM (50 mL) was added pyridinium dichromate (PDC) (5.80 g, 15.4 mmol), followed by acetic anhydride (7.87 g, 77.18 mmol) and tert-butyl alcohol (11.40 g, 154.0 mmol). The resulting solution was stirred at RT for 3 h. The mixture was loaded on a very short silica gel column and eluted with EA. The fractions containing 3l-2 were combined and concentrated. Chromatography on silica gel with EA/hexanes (1:1 to 3:2) gave 3l-2 as a white foam (2.07 g, 73%).


Step 3. Compound 3l-3—


NaBD4 (1.10 g, 26.22 mmol) was added to a solution of 3l-2 (2.07 g, 6.9 mmol) at RT and the resulting mixture stirred at 80° C. overnight. The reaction was quenched with acetic acid (AcOH) at 0° C. The mixture was diluted with EA and washed with brine. The organic phase was dried and concentrated. The residue was purified by chromatography on silica gel (2-5% MeOH in DCM) to give 3l-3 as a white foam (854 mg, 50.83%).


Step 4. Compound 3l-4—


Compound 3l-3 (850 mg, 2.8 mmol) was dissolved in 95% trifluoroacetic acid (TFA)/5% water at 0° C. and then stirred at RT for 30 minutes. The solvent was evaporated and the residue was purified by chromatography on silica gel (5-10% MeOH in DCM) to give 3l-4 (663 mg, 90%). 1H NMR (CD3OD, 400 MHz) δ 8.16 (d, 1H), 5.98 (s, 1H), 5.69 (d, 1H), 3.86-3.92 (m, 2H), 1.13 (s, 3H); ESI-MS: m/z 261.1 [M+H]+.


Step 5. Compound 3l—


To a suspension of 3l-4 (150 mg, 0.57 mmol) in anhydrous acetonitrile (1.0 mL) was added N-methylimidazole (0.5 mL), followed by 2b (1.7 mmol, 1 M in CH3CN) at RT. The resulting solution was stirred at RT for 24 h. The mixture was diluted with EA and concentrated. The residue was purified by RP HPLC (0.5 HCOOH in MeCN and water) to give 3l as a white solid (two isomers, 122 mg, 39%). 1H NMR (CD3OD, 400 MHz) δ7.79, 7.87 (2d, J=8.0 Hz, 1H), 7.20-7.38 (m, 5H), 5.98, 6.01 (2s, 1H), 5.59, 5.62 (2d, J=8.0 Hz, 1H), 4.99-5.01 (m, 1H), 4.10-4.12 (m, 2H), 3.82-3.84 (m, 1H), 1.34, 1.38 (2d, J=7.2 Hz, 3H), 1.24, 1.25 (2s, 3H), 1.17, 1.26 (2d, J=6.0 Hz, 6H); 31P NMR (CD3OD, 162 MHz) δ68.42, 68.21; ESI-LCMS: m/z 546.1 [M+H]+.


Example 14
Preparation of 3′-O-acetyl-5′-dideuterated 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (4d)



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To a suspension of 3l (750 mg, 1.38 mmol) in dry pyridine (50 mL) was added acetic anhydride (704 mg, 6.9 mmol). The reaction mixture was heated at 35° C. for 16 h. The reaction was quenched with water and the solvent was removed. The residue was purified on a silica gel column (1˜3% MeOH in DCM) to give 4d as a white solid (710 mg, 88%). 1H NMR (CD3OD, 400 MHz) δ7.78, 7.84 (2d, J=8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.17-7.38 (m, 5H), 5.99, 6.02 (2s, 1H), 5.59, 5.61 (2d, J=8.0 Hz, 1H), 5.13, 5.17 (2d, J=9.2 Hz, 1H), 5.04-4.97 (m, 1H), 4.52-4.25 (m, 3H), 4.14-4.06 (m, 1H), 2.16 (s, 3H), 1.35, 1.38 (2d, J=7.2 Hz, 1H), 1.18-1.24 (m, 9H); 31P NMR (CD3OD, 162 MHz) δ68.90, 68.23; ESI-LCMS: m/z=585.9 [M+H]+.


Example 15
Preparation of 2′-C-methylthymidine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3m)



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Step 1. Compound 3m-2—


To a suspension of thymine (0.869 g, 5.63 mmol) in acetonitrile (27 mL) was added N, O-bis(trimethylsilyl)acetamide (5 mL) and the mixture was refluxed for 2 hours. The resulting solution was cooled to ambient temperature and a solution of 3m-1 (2.0 g, 3.45 mmol) in acetonitrile (10 mL) was added. Then SnCl4 (1.6 mL, 13.6 mmol) was slowly added and the reaction mixture was heated to 100° C. for 5 h. The reaction mixture was cooled to 0° C. and solid NaHCO3 was added, and a minimal amount of ice was added into the mixture. The reaction mixture was partially concentrated, diluted with EA and treated with a cold saturated aqueous solution of NaHCO3. The salts were filtered through celite and extracted with EA. The organic phase was washed successively with a saturated aqueous solution of NaHCO3 and brine, dried by anhydrous Na2SO4, and concentrated to dryness. The residue was purified by silica gel column (0-20% EA in CH2Cl2) to give 3m-2 (1.6 g, 85%) as a white solid.


Step 2. Compound 3m-3—


Compound 3m-2 (1.6 g, 2.74 mmol) was dissolved in methanolic ammonia (120 mL, saturated at 0° C.). The mixture was stirred at RT for 20 hours. The solution was evaporated to dryness and the residue was purified on a silica gel column (DCM:MeOH=100:1 to 50:1) to give 3m-3 as a light yellow foam (620 mg, 83.1%). 1H NMR (MeOD, 400 MHz) δ8.05 (s, 1H), 5.93 (s, 1H), 4.01-3.97 (m, 1H), 3.91-3.86 (m, 2H), 3.80-3.76 (m, 1H), 1.85 (s, 3H), 1.13 (s, 3H).


Step 3. Compound 3m—


To a suspension of 3m-3 (150 mg, 0.55 mmol) in anhydrous CH3CN (3 mL) was added N-methylimidazole (0.4 mL), followed by addition of 2b (530 mg, 1.65 mmol) in anhydrous CH3CN (1 mL). The resulting solution was stirred at RT for 12 h. The reaction was quenched with water and the solvent was removed. The residue was purified by RP HPLC (0.5 HCOOH in MeCN and water) to give compound 3m as a white solid (two isomers, 43 mg, 14.0%). 1H NMR (MeOD, 400 MHz) δ7.54, 7.64 (2s, 1H), 7.16˜7.36 (m, 5H), 5.98, 6.01 (2s, 1H). 5.02˜4.94 (m, 1H), 4.56˜4.52 (m, 1H), 4.43˜4.29 (m, 1H), 4.17˜4.02 (m, 2H), 3.94˜3.84 (m, 1H), 1.81, 1.84 (2s, 3H), 1.31, 1.36 (2d, J=7.2 Hz, 3H), 1.25˜1.23 (m, 6H), 1.15 (s, 3H); 31P NMR (MeOD, 162 MHz) δ69.17, 68.68; ESI-LCMS: m/z=558.1 [M+H]+.


Example 16
Preparation of 1-(2-amino-6-cyclopropylaminopurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3z)



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Step 1. Compound 3z-1—


To a solution of compound 3m-1 (20.0 g, 34.47 mmol) and 6-chloro-2-aminopurine (5.90 g, 34.91 mmol) in anhydrous MeCN (300 mL) was added 1,8-diazabicycloundec-7-ene (DBU) (15.8 g, 103.9 mmol) at 0° C. The mixture was stirred at 0° C. for 5 minutes and then trimethylsilyltrifluoromethane sulfonate (TMSOTf) (27.0 mL, 137.8 mmol) was added dropwise. Stirring was continued for another 30 minutes and then the mixture was heated to 70° C. and stirred for 18 hour. The reaction was then cooled to RT and diluted with EA. The solution was washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by a silica gel column (20˜40% EA in PE) and then RP HPLC (0.5% HCOOH in MeCN and water) to give compound 23-2 as a white solid (5.4 g, 25.6%). 1H NMR (DMSO-d6, 400 MHz) δ8.38 (s, 1H), 7.97-8.05 (m, 4H), 7.82-7.85 (m, 2H), 7.58-7.66 (m, 3H), 7.39-7.53 (m, 4H), 7.18-7.37 (m, 2H), 7.19 (brs, 2H), 6.61 (s, 1H), 5.94 (d, J=4.8 Hz, 1H), 4.70-4.89 (m, 3H), 1.58 (s, 3H).


Step 2. Preparation of compound 3z-2—


Compound 3z-1 (100 mg, 0.16 mmol) and THF (10 mL) were placed into a dry flask and then cyclopropyl amine (1.61 g, 28.21 mmol) was added. After the addition, the mixture was heated to reflux overnight. Then the solvent was removed and the residue was purified on a silica gel column (2˜10% MeOH in DCM) to give 3z-2 as a white solid (82 mg, 77.6%).


Step 3. Compound 3z-3—


Compound 3z-2 (402 mg, 0.62 mmol) was dissolved in methanolic ammonia (20 mL, saturated at 0° C.) and the mixture was stirred at RT for 12 hours. The solvent was removed and the residue was purified on a silica gel column (2˜10% MeOH in DCM) to give 3z-3 as a white solid (149 mg, 72.4%). 1H NMR (CD3OD, 400 MHz) δ8.14 (d, J=11.2 Hz, 1H), 5.93 (s, 1H), 4.22 (d, J=8.4 Hz, 1H), 4.03 (d, J=10.8 Hz, 2H), 3.86 (d, J1=12.8 Hz, J2=3.2 Hz, 1H), 2.91 (s, 1H), 0.79-0.98 (m, 2H), 0.61-0.70 (m, 2H); ESI-LCMS: m/z 337.1 [M+H]+, 360.1 [M+Na]+.


Step 4. Compound 3z—


To a stirred suspension of 3z-3 (110 mg, 0.33 mmol) in anhydrous acetonitrile (1.0 mL) was added N-methylimidazole (0.5 mL) followed by slow addition of 2b (1.05 g, 3.273 mmol, 1M in MeCN) at RT. The resulting solution was stirred at 50° C. for 4 hours and then diluted with EA. The solution was washed with 10% AcOH/H2O, brine, 5% NaHCO3 aqueous solution, and dried over Na2SO4. The solvent was removed and the residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3z as a white solid (two isomers, 131 mg, 64%). 1H NMR (CD3OD, 400 MHz) δ7.96, 8.00 (2s, 1H), 7.28-7.36 (m, 5H), 7.14-7.20 (m, 1H), 5.96, 5.99 (2s, 1H), 4.92-4.98 (m, 1H), 4.37-4.57 (m, 2H), 4.04-4.23 (m, 3H), 2.91 (br, 1H), 1.36, 1.32 (2d, J=7.2 Hz, 3H), 1.17-1.23 (m, 7H), 0.96, 0.99 (2s, 3H), 0.87-0.90 (m, 2H), 0.63-0.69 (m, 2H); 31P NMR (CD3OD, 162 MHz) δ 68.53, 68.38; ESI-LCMS: m/z 622.2 [M+H]+, 644.2 [M+Na]+.


Example 17
Preparation of 1-(2,6-diaminopurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3aa)



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Step 1. Compound 3aa-1—


Compound 3z-1 (1.01 g, 1.56 mmol) was suspended in aqueous ammonia (28%, 40 mL) and dioxane (4 mL) in a sealed vessel. The mixture was heated at 100° C. overnight. Then the solvent was removed and the residue was purification on a silica gel column (2˜10% MeOH in DCM) to give 3aa-1 as a white solid (418 mg, 88.9%). 1H NMR (CD3OD, 400 MHz) δ88.17 (s, 1H), 5.93 (s, 1H), 4.24 (d, J=8.8 Hz, 1H), 4.01-4.04 (m, 2H), 3.86 (dd, J1=12.8 Hz, J2=3.2 Hz, 1H), 0.96 (s, 3H); ESI-LCMS: m/z 297.1 [M+H]+.


Step 2. Compound 3aa—


To a stirred suspension of 3aa-1 (62 mg, 0.20 mmol) in anhydrous acetonitrile (1.0 mL) was added N-methylimidazole (0.5 mL) followed by slow addition of 2b (652 mg, 2.02 mmol, 1M in MeCN) at RT. The resulting solution was stirred at RT for 24 hours. The solution was diluted with EA and washed with 10% AcOH in H2O, brine, 5% NaHCO3 aqueous solution, and dried over Na2SO4. The solvent was removed and the residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3aa as a white solid (31 mg, 25.6%). 1H NMR (DMSO-d6, 400 MHz) δ77.81, 7.83 (2s, 1H), 7.33-7.38 (m, 2H), 7.17-7.25 (m, 3H), 6.58-6.78 (m, 3H), 5.81-5.83 (m, 3H), 5.32-5.43 (m, 1H), 5.19, 5.20 (2s, 1H), 4.78-4.85 (m, 1H), 4.21-4.42 (m, 2H), 3.87-4.15 (m, 3H), 1.24-1.26 (m, 3H), 1.08-1.15 (m, 6H), 0.83, 0.84 (2s, 3H); 31P NMR (DMSO-d6, 162 MHz) δ 68.19, 67.90; ESI-LCMS: m/z 589.1[M+H]+, 604.1 [M+Na]+.


Example 18
Preparation of 1-(2-amino-6-allylaminopurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3bb)



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Step 1. Compound 3bb-1—


A mixture of 3z-1 (802 mg, 1.27 mmol) and ally amine (7.26 g, 127.3 mmol) in THF (30 mL) was refluxed overnight. The solvent was removed and the residue was purified on a silica gel column (2˜10% MeOH in DCM) to give crude 3bb-1 (405 mg), which was dissolved in 20 mL methanolic ammonia (saturated at 0° C.). The mixture was stirred at RT for 12 hours. The solvent was removed and the residue was purified on a silica gel column (2˜10% MeOH in DCM) to give 3bb-1 as a white solid (153 mg, 35.9%). 1H NMR (CD3OD, 400 MHz) δ8.10 (s, 1H), 5.92-6.03 (m, 2H), 5.27 (d, J=17.6 Hz, 1H), 5.14 (d, J=10.4 Hz, 1H), 4.18-4.24 (m, 3H), 4.03 (d, J=10.0 Hz, 2H), 3.86 (d, J=10.4 Hz, 1H), 0.95 (s, 3H); ESI-LCMS: m/z 337.1 [M+H]+.


Step 2. Compound 3bb—


To a stirred suspension of 3bb-1 (200 mg, 0.59 mmol) in anhydrous acetonitrile (1.0 mL) was added N-methylimidazole (0.5 mL) followed by 2b (573 mg, 1.79 mmol, 1M in MeCN) at RT. The resulting solution was stirred at RT for 24 hrs and then was diluted with EA. The solution was washed with 10% AcOH in H2O, brine and 5% NaHCO3 aqueous solution. The organic solution was dried and concentrated. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3bb as a white solid (two isomers, 155 mg, 40.8%). 1H NMR (CD3OD, 400 MHz) δ 7.94, 7.98 (2s, 1H), 7.29-7.34 (m, 4H), 7.18-7.28 (m, 1H), 5.96-6.09 (m, 2H), 5.27, 5.31 (2s, 1H), 5.15, 5.17 (2d, J=1.2 Hz, 1H), 4.92-4.96 (m, 1H), 4.35-4.57 (m, 2H), 4.01-4.28 (m, 5H), 1.32, 1.36 (2d, J=7.2 Hz, 3H), 1.16-1.25 (m, 6H), 0.97 (2s, 3H); 31P NMR (CD3OD, 160 MHz) δ 68.51, 68.40; ESI-LCMS: m/z 622.1 [M+H]+, 644.1 [M+Na]+.


Example 19
Preparation of 1-(2-amino-6-chloropurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3cc)



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Step 1. Compound 3cc-1—


Compound 3z-1 (506 mg, 0.79 mmol) was dissolved in 100 mL of methanolic ammonia and the mixture was stirred at RT for 12 h. The solvent was removed and the residue was purified on a silica gel column (2˜10% MeOH in DCM) to give 3cc-1 as a white solid (204 mg, yield: 79.9%).


Step 2. Compound 3cc—


To a stirred suspension of 3cc-1 (198 mg, 0.63 mmol) in anhydrous acetonitrile (1.0 mL) was added N-methylimidazole (0.5 mL) followed by 2b (611 mg, 1.904 mmol, 1M in MeCN) at RT. The resulting solution was stirred at 30-40° C. for 12 hours and then diluted with EA. The solution was washed with 10% AcOH in H2O, brine, and 5% NaHCO3. The organic phase was dried and concentrated. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3cc as a white solid (118 mg, 31.6%). 1H NMR (CD3OD, 400 MHz) δ 8.25, 8.28 (2s, 1H), 7.27-7.35 (m, 4H), 7.15-7.18 (m, 1H), 6.02, 6.05 (2s, 1H), 4.93-4.98 (m, 1H), 4.40-4.54 (m, 2H), 4.20-4.27 (m, 2H), 4.05-4.13 (m, 1H), 1.15-1.35 (m, 9H), 0.99, 1.01 (2s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.66, 68.53; ESI-LCMS: m/z 601.1 [M+H]+.


Example 20
Preparation of 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)isobutyl)thiophosphoramidate (3n)



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To a solution of 2′-C-methyluridine (150 mg, 0.581 mmol) in MeCN (1 mL) and N-methylimidazole (0.7 mL) was added 2h (651 mg, 1.86 mmol). The mixture was stirred at RT for 3 days. The solvent was removed and the residue was purified by RP HPLC (0.1% HCOOH in MeCN and water) to give 3n as a white solid (two isomers, 22 mg, 6.6%). 1H NMR (CD3OD, 400 MHz) δ7.76, 7.78 (2d, J=9.2 Hz, 1H), 7.14-7.35 (m, 5H), 5.95, 5.97 (2s, 1H), 5.56, 5.63 (2d, J=8.4 Hz, 1H), 4.95-5.03 (m, 1H), 4.44-4.56 (m, 1H), 4.30-4.41 (M, 1H), 4.08-4.11 (m, 1H), 3.75-3.90 (m, 2H), 2.00-2.07 (m, 1H), 1.12-1.25 (m, 6H), 1.11, 1.15 (2s, 3H), 0.87-0.97 (m, 6H); 31P NMR (CD3OD, 162 MHz) δ70.38, 69.13; ESI-LCMS: m/z 572 [M+H]+.


Example 21
Preparation of 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)isopentyl)thiophosphoramidate (3o)



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Compound 3o was prepared using the procedure for preparing compound 3n, with 2i in place of 2h. 1H NMR (CD3OD, 400 M Hz) δ 7.77, 7.84 (2d, J=8.0 Hz, 1H), 7.14-7.35 (m, 5H), 5.96 (2s, 1H), 5.57, 5.62 (2d, J=8.0 Hz, 1H), 4.84-4.98 (m, 1H), 4.46-4.53 (m, 1H), 4.28-4.42 (m, 1H), 3.97-4.12 (m, 2H), 3.80 (2s, 1H), 1.58-1.81 (m, 1H), 1.48-1.56 (m, 2H), 1.20-1.23 (m, 6H), 1.13 (2s, 3H), 0.81-0.92 (m, 6H); 31P NMR (CD3OD, 400 MHz) δ 68.56, 69.15; ESI-MS: m/z 586 [M+H]+, m/z 608 [M+Na]+.


Example 22
Preparation of 2′-C-methylguanosine 5′-(O-phenyl-N—(S)-1-(cyclohexoxycarbonyl)ethyl)thiophosphoramidate (3s)



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To a stirred suspension of commercial 2′-C-methylguanosine (100 mg, 0.34 mmol) in anhydrous acetonitrile (1.5 mL) was added N-methylimidazole (0.56 mL, 6.8 mmol, 20 equivalent) followed by 2c (303 mg, 0.84 mmol, 1M in MeCN) at RT. The resulting solution was stirred at 40° C. for 3 hours and then diluted with EA. The solution was washed with 10% AcOH in 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 was purified on a silica gel column (3˜7% MeOH in DCM). The collected fractions were concentrated and re-purified on a silica gel column (2˜5% MeOH in DCM) to give (127.8 mg, 61.2%) of 3s as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.6 (s, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.22-7.01 (m, 4H), 6.56-6.48 (m, 3H), 5.74 (d, J=8.4 Hz, 1H), 5.42 & 5.35 (2d, each J=6.4 Hz, 1H), 5.16 (d, J=2.8 Hz, 1H), 4.62-3.93 (m, 6H), 1.67-1.58 (m, 5H), 1.33-1.16 (m, 12H), 0.79 (s, 3H); 31P NMR (DMSO-d6) δ 68.07, 67.71; ESI-LCMS: m/z=623.1 [M+H]+.


Example 23
Preparation of 2′-C-Methylguanosine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3r)



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Compound 3r was prepared using the procedure for preparing compound 3s, with 2b in place of 2c. 1H NMR (DMSO-d6, 400 MHz) δ10.6 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.34-7.31 (m, 2H), 7.22-7.14 (m, 4H), 6.62-6.48 (m, 3H), 5.74 (d, J=7.2 Hz, 1H), 5.42 & 5.33 (2d, each J=6.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.84-3.77 (m, 1H), 4.42-3.85 (m, 5H), 1.25-1.1 (m, 12H), 0.81 & 0.8 (2s, 3H); 31P NMR (DMSO-d6) δ 68.23, 67.64; ESI-LCMS: m/z=583.4 [M+H]+.


Example 24
Preparation of 2′-Deoxy-2′-fluoro-2′-C-methyl-6-methoxyguanosine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)-thiophosphoramidate (3t)



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Compound 3t was prepared using the procedure for preparing compound 3s, with 2b in place of 2c, and with 2′-deoxy-2′-fluoro-2′-C-methyl-6-methoxyguanosine in place of 2′-C-methylguanosine. 1H NMR (DMSO-d6, 400 MHz) δ 7.96 & 9.95 (2s, 1H), 7.36-7.29 (m, 2H), 7.21-7.14 (m, 3H), 6.57 (br s, 2H), 6.1 & 6.05 (2d, each J=8.8 Hz, 1H), 5.75 (br s, 2H), 4.82-4.76 (m, 1H), 4.45-4.04 (m, 3H), 3.93 (s, 3H), 1.24-1.13 (m, 3H), 1.12-1.03 (m, 9H); 31P NMR (DMSO-d6) δ68.21, 67.82; ESI-LCMS: m/z=599.4 [M+H]+.


Example 25
Preparation of 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)-thiophosphoramidate (3u)



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Compound 3u was prepared using the procedure for preparing compound 3s, with 2b in place of 2c, and with 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose in place of 2′-C-methylguanosine. 1H NMR (DMSO-d6, 400 MHz) δ7.93 (s, 1H), 7.35-7.30 (m, 2H), 7.22-7.14 (m, 3H), 6.61-6.52 (m, 1H), 6.48 (br s, 2H), 5.86 (d, each J=5.2 Hz, 1H), 5.43, 5.32 (br s, 1H), 5.20 (br s, 1H), 4.84-4.76 (m, 1H), 4.36-4.04 (m, 4H), 3.93 (s, 3H), 1.24-1.15 (m, 3H), 1.19-1.06 (m, 6H), 0.8-0.78 (m, 3H); 31P NMR (DMSO-d6) δ 68.21, 67.65; ESI-LCMS: m/z=597.5 [M+H]+.


Example 26
Preparation of 2′-Deoxy-2′-α-fluoro-2′-β-C-methylguanosine 5′-(O-phenyl-N—(S)-1-(neopentoxycarbonylethyl)thiophosphoramidate (3q)



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Compound 3q was prepared using the procedure for preparing compound 3s, with 2d in place of 2c, and with 2′-deoxy-2′-α-fluoro-2′-β-C-methylguanosine in place of 2′-C-methylguanosine. 1H NMR (DMSO-d6, 400 MHz) δ 10.66 (br s, 1H), 7.79 (s, 1H), 7.36-7.30 (m, 2H), 7.22-7.15 (m, 3H), 6.61-6.52 (m, 1H), 6.48 (br s, 2H), 6.72-6.56 (m, 3H), 6.00, 5.95 (2d, J=8.0, 8.4 Hz, 1H), 5.75-5.82 (m, 1H), 4.43-3.92 (m, 5H), 3.76-3.53 (m, 2H), 1.29-1.24 (m, 3H), 1.09-1.00 (m, 4H), 0.84, 0.81 (2s, 8H); 31P NMR (DMSO-d6) δ 68.09, 68.03; ESI-LCMS: m/z=613.7 [M+H]+.


Example 27
Preparation of 2′-C-Methyladenosine 5′-(O-phenyl-N—(S)-1-(neopentoxycarbonyl)ethyl)thiophosphoramidate (3dd)



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Compound 3dd was prepared using the procedure for preparing compound 3s, with 2d in place of 2c, and with 2′-C-methyladenosine in place of 2′-C-methylguanosine. 1H NMR (DMSO-d6, 400 MHz) δ 8.22, 8.2 (2s, 1H), 8.12 (s, 1H), 7.36-7.13 (m, 6H), 6.61-6.55 (m, 1H), 5.97, 5.94 (2s, 1H), 5.40, 5.34, 5.31 (3d, J=6.8, 6.8, 6.0 Hz, 2H), 4.39-3.99 (m, 5H), 3.76-3.61 (m, 2H), 3.42 (d, J=10.4 Hz, 1H), 1.27-1.23 (m, 3H), 0.83, 0.77 (2s, 4H), 0.77, 0.76 (2s, 8H); 31P NMR (DMSO-d6) δ68.15, 67.74; ESI-LCMS: m/z=595.0 [M+H]+.


Example 28
Preparation of 2′-C-Methyladenosine 5′-(O-(1-naphthyl)-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (3ee)



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Compound 3dd was prepared using the procedure for preparing compound 3s, with 2e in place of 2c, and with 2′-C-methyladenosine in place of 2′-C-methylguanosine. 1H NMR (DMSO-d6, 400 MHz) δ 8.28, 8.24 (2s, 1H), 8.12-8.06 (m, 2H), 7.93-7.91 (m, 1H), 7.29-7.68 (m, 1H), 7.54-7.37 (m, 4H), 7.26 (br s, 2H), 6.82-6.72 (m, 1H), 6.00, 5.98 (2s, 1H), 5.47, 5.39, 5.31 (3d, J=6.4, 6.8, 10.0 Hz, 2H), 4.82-4.74 (m, 1H), 4.48-4.35 (m, 2H), 4.28-4.15 (m, 2H), 4.03-3.96 (m, 1H), 1.27-1.24 (m, 3H), 1.1-1.00 (m, 6H), 0.8 (s, 3H); ESI-LCMS: m/z=617.1 [M+H]+.


Example 29
Preparation of 2′-C-methylguanosine 5′-(O-phenyl-N—(S)-1-(neopentoxycarbonyl)ethyl)thiophosphoramidate (3p)



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Step 1. Compound 3p-1—


A mixture of 2′-C-methylguanosine (1.0 g, 3.36 mmol), trimethyl orthoformate (20 mL) and p-toluenesulfonic acid monohydrate (961 mg, 5.05 mmol) in 1,4-dioxane (30 mL) was stirred at RT for 24 h. Dowex MWA-1 basic resin we added and stirred until the solution was neutralized. The resin was filtered and washed thoroughly with MeOH and then with MeOH/DCM (1:1). The filtrate was concentrated and the residue was subjected to flash chromatography on a silica gel column eluting with 5-10% MeOH in DCM to give (0.94 g) of 3p-1 as a white solid.


Step 2. Compound 3p-2—


A solution of 3p-1 (0.94 g, 2.77 mmol), dimethylaminopyridine (DMAP) (338 mg, 2.77 mmol) and t-butyldimethylsilyl chloride (TBSCl) (543 mg, 3.60 mmol) in pyridine (10 mL) was stirred at 25° C. overnight. 4-Methoxytrityl chloride (1.56 g, 5.0 mmol) was added and the resulting mixture stirred at RT 50° C. for 3 h. The mixture was diluted with ethyl acetate, and washed with brine three times. The solvent was evaporated and the residue was chromatographed on silica gel with 3-5% MeOH in DCM to give 1.66 g of a protected intermediate as foam solid. A solution of the intermediate (1.66 g, 2.66 mmol) and 1.0 M tetrabutylammonium fluoride (TBAF)/THF (4 mL) in 10 mL of THF stood at RT for 20 h. The solution was concentrated. The residue was subjected to flash chromatography on silica gel with 5-6% MeOH in DCM to give 1.33 g of 3p-2 as a white foam. MS m/z 611.9 (MH+).


Step 3. Compound 3p—


Compound 2d (1.0 M in MeCN, 0.5 mL) was added dropwise to a solution of 3p-2 (61 mg, 0.1 mmol) and diisopropylethylamine (0.3 mL) in anhydrous acetonitrile (0.4 mL). The resulting solution was heated at 82° C. for 20 h, diluted with ethyl acetate, washed with brine three times, dried over sodium sulfate, and concentrated. Chromatography on silica gel with 20-30% ethyl acetate in hexanes gave 82 mg of a protected intermediate as a white foam, which was dissolved in a mixture of 80% formic acid and 20% water (3 mL). The solution stood at RT overnight, was concentrated, and then co-evaporated with MeOH/toluene three times. Chromatography on silica gel with 6-10% MeOH in DCM gave 27 mg of 3p as a white solid; 1H NMR (acetone-d6) δ 7.83, 7.92 (2s, 1H), 7.10-7.34 (m, 5H), 5.88, 5.90 (2s, 1H), 4.33-3.53 (m, 2H), 4.11-4.24 (m, 3H), 3.61-3.79 (m, 2H), 1.39, 1.36 (2d, J=7.2 Hz, 3H), 0.94, 0.95 (2s, 3H), 0.84, 0.87 (2s, 9H); 31P NMR (acetone-d6) δ68.27, 67.85; ESI-LCMS: m/z 611.3 [M+H]+.


Example 30
Preparation of 2′,5′(S)—C,C-Dimethyladenosine 5′-(O-phenyl-N—(S)-1-(neopentoxycarbonyl)ethyl)thiophosphoramidate (3hh)



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Compound 3hh was prepared using the procedure for preparing compound 3p, with 2′,5′-C,C-dimethyladenosine in place of 2′-C-methylguanosine. 1H NMR (CD3OD) δ 8.40, 8.36 (2s, 1H), 8.22, 8.20 (2s, 1H), 7.07-7.36 (m, 5H), 6.06, 6.05 (2d, J=5.2 Hz, 1H), 5.88, 5.90 (2s, 1H), 4.59 (t, J=5.2 Hz, 0.5H), 4.50 (q, J=5.2 Hz, 1H), 4.40 (q, J=3.6, 5.2 Hz, 0.5H), 4.04-4.19 (m, 2H), 3.81 (d, J=0.8 Hz, 1H), 3.75 (d, J=10.4 Hz, 1H), 3.65 (d, J=10.4 Hz, 1H), 1.52, 1.40 (2d, J=6.4 Hz, 3H), 1.29, 1.30 (2s, 3H), 0.93, 0.87 (2s, 9H); 31P NMR (acetone-d6) δ68.40, 67.43; ESI-LCMS: m/z 595.1 [M+H]+.


Example 31
Preparation of 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(neopentoxycarbonyl)ethyl)-thiophosphoramidate (3v)



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Compound 3v was prepared using the procedure for preparing compound 3p, with 1-(2-amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose in place of 2′-C-methylguanosine. 1H NMR (CD3OD, 400 MHz) δ 7.97, 8.00 (2s, 1H), 7.10-7.33 (m, 5H), 5.99, 5.96 (2s, 1H), 4.33-4.55 (m, 2H), 4.031, 4.034 (2s, 3H), 3.56-3.72 (m, 2H), 1.31-1.36 (m, 3H), 0.94, 0.92 (2s, 3H), 0.89, 0.85 (2s, 9H); 31P NMR (DMSO-d6) δ68.52, 68.27. ESI-LCMS: m/z 625.3 [M+H]+.


Example 32
Preparation of 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-phenyl-N—(S)-1-(cyclohexoxycarbonyl)ethyl)-thiophosphoramidate (3w)



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Compound 3w was prepared using the procedure for preparing compound 3p, with 2c in place of 2d, and with 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose in place of 2′-C-methylguanosine. 1H NMR (CD3OD, 400 MHz) δ87.98, 8.01 (2s, 1H), 7.24-7.32 (m, 4H), 7.10-7.17 (m, 1H), 6.00, 5.96 (2s, 1H), 4.36-4.73 (m, 3H), 4.036, 4.034 (2s, 3H), 4.01-4.22 (m, 3H), 1.60-1.80 (m, 4H), 1.19-1.55 (m, 9H), 0.92, 0.94 (2s, 3H); 31P NMR (DMSO-d6) δ68.43, 68.32. ESI-LCMS: m/z 637.6 [M+H]+.


Example 33
Preparation of 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose 5-(O-(1-naphthyl)-N—(S)-1-(neopentoxycarbonyl)ethyl)-thiophosphoramidate (3x)



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Compound 3x was prepared using the procedure for preparing compound 3p, with 2g in place of 2d, and with 1-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-D-ribofuranose in place of 2′-C-methylguanosine. 1H NMR (CD3OD, 400 MHz) δ 8.15-8.19 (m, 1H), 8.03, 7.97 (2s, 1H), 7.80-7.85 (m, 1H), 7.31-7.67 (m, 5H), 6.00, 5.98 (2s, 1H), 4.43-4.62 (m, 2H), 4.18-4.27 (m, 3H), 4.01 (s, 3H), 3.57-3.79 (m, 2H), 1.33-1.37 (m, 3H), 0.941, 0.946 (2s, 3H), 0.855, 0.848 (2s, 9H); 31P NMR (DMSO-d6) δ68.55, 68.57. ESI-LCMS: m/z 675.3 [M+H]+.


Example 34
Preparation of additional 2′-C-methyluridine 5′-thiophosphoramidates

Compounds 3ii-3vv, as shown in Table 8, were prepared using a similar procedure for preparing compound 3n.










TABLE 8







31P NMR



Compound
ppm









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69.30 69.09







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68.92 68.58







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68.45 68.16







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69.69 69.28







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68.60 68.42







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68.25 67.79







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69.25 69.12







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69.52 68.53







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70.03 69.56







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68.87 68.76







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70.83 69.38







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69.12 68.45







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69.14 68.46







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68.74 66.82









Example 35
Preparation of 2′-C-Methyl-3′-O-propionyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)-thiophosphoramidate (4b)



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Compound 3b (1 g, 1.88 mmol) was dissolved in 10 mL of dry pyridine, propionic anhydride was added (385 mg, 2.81 mmol) and reaction mixture was left overnight at RT. TLC showed that reaction was not completed. More anhydride (385 mg, 2.81 mmol) was added and the mixture was heated at 40° C. for 2 hours. Solvents were evaporated. The residue was distributed between ethyl acetate and water. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel in a gradient of methanol in DCM from 2% to 7% resulted in 725 mg of 4b (64%). 1H NMR (CDCl3): δ 8.70 & 8.66 (2s, 1H), 7.59-7.48 (2d, 1H), 7.30-7.08 (m, 5H), 5.93 & 5.90 (2s, 1H), 5.60 & 5.49 (2d, 1H), 5.01-4.94 (m, 2H), 4.50-4.38 (m, 1H), 4.32-4.02 (m, 3H), 2.45-2.35 (m, 2H), 1.38-1.30 (m, 3H), 1.20-1.11 (m, 12H); 31P NMR: δ 67.72, 67.54 (1:1 mixture of diastereomers); ESI-LCMS: m/z 598.3 [M+H]+.


Example 36
Preparation of 2′,3′-O-diisobutyryl-2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (4c) and Preparation of 2′-C-methyl-3′-O-isobutyryluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (4f)



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Step 1. Compound 4c—


To a solution of 3b (0.1 g, 0.18 mmol) in anhydrous pyridine (2 mL), was added DMAP (22 mg, 0.18 mmol) followed by isobutyric anhydride (0.1 mL, 0.63 mmol) under N2 atmosphere. The reaction mixture was stirred at RT for 1 h. The reaction was quenched by adding isopropanol (0.5 mL). The solvent was removed under vacuum and the residue was taken up into EA (100 mL). The solution was washed with saturated NaHCO3 and brine. The organic layer was separated, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give a residue which was purified on a silica gel column (1˜5% MeOH in DCM) to give the faster eluting product 4c as a white solid (36.5 mg). 1H NMR (DMSO-d6, 400 MHz) δ11.46 (s, 1H), 7.59& 7.55 (2d, J=8.4, 8.4 Hz, 1H), 7.37-7.32 (m, 2H), 7.21-7.15 (m, 3H), 6.67-6.66 (m, 1H), 6.14 & 6.11 (each s, 1H), 5.58 (d, J=8.0 Hz, 1H), 5.2 (br s, 1H), 4.88-4.84 (m, 1H), 4.28-4.27 (m, 1H), 3.95-3.85 (m, 1H), 2.54-2.49 (m, 2H), 1.38 & 1.36 (2s, 3H), 1.26-1.21 (m, 2H), 1.56-1.12 (m, 6H), 1.09-1.05 (m, 12H); 31P NMR (DMSO-d6) δ68.44, 68.42; ESI-LCMS: m/z=682.4 [M−H].


Step 2. Compound 4f—


Further elution of the residue on the silica gel column using 5% MeOH in DCM gave the slower eluting product 4f (54.5 mg) as white foam after evaporation of solvent in-vacuo. 1H NMR (DMSO-d6, 400 MHz) δ11.42 (s, 1H), 7.65 & 7.63 (2d, J=8.0, 8.4 Hz, 1H), 7.37-7.32 (m, 2H), 7.21-7.15 (m, 3H), 6.68-6.61 (m, 1H), 5.84 & 5.81 (each s, 1H), 5.71 & 5.68 (each s, 1H), 5.56 & 5.47 (each d, each J=8.0 Hz, 1H), 4.98-4.94 (m, 1H), 4.87-4.82 (m, 1H), 4.31-4.16 (m, 3H), 3.85-3.95 (m, 1H), 2.62-2.58 (m, 1H), 1.26 & 1.2 (each d, J=7.2, 6.8 Hz, 3H), 1.16-1.08 (m, 12H), 1.01 (s, 3H); 31P NMR (DMSO-d6) δ68.93, 67.96; ESI-LCMS: m/z=612.4 [M+H]+.


Example 37
Preparation of 2′-C-2′-O-dimethyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (4e)



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Step 1. Compound 4e-1—


To an ice-cold solution of 2′-C-methyluridine (2.0 g, 7.6 mmol) in anhydrous pyridine (20 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) (2.40 g, 7.6 mmol) in small portions under N2. The reaction mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was taken up into EA (100 mL). The solution was washed with saturated NaHCO3 and brine. The organic layer was separated, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on a silica gel column (DCM/MeOH=100/1 to 50/1) to give 4e-1 (3.2 g, 85%) as a white foam.


Step 2. Compound 4e-2—


To a solution of 4e-1 (2.0 g, 4.0 mmol) in anhydrous THF (30 mL) was added NaH (384 mg, 16 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes before CH3I (1.2 g, 8 mmol) was added. Stirring was continued for 4 h at 0° C. The mixture was diluted with EA (100 mL), washed with saturated NaHCO3 and brine. The organic layer was dried with Na2SO4 and concentrated to a residue which was purified on a silica gel column (DCM/MeOH=100/1 to 50/1) to give 4e-2 (556 mg, 26.93%) as a white foam.


Step 3. Compound 4e-3—


To a stirred solution of 4e-2 (556 mg, 1.08 mmol) in MeOH (10 mL) was added NH4F (232 mg, 6.46 mmol). The mixture was stirred at 80° C. for 12 h. The solvent was removed and the residue was purified on a silica gel column (DCM/MeOH=100/1 to 20/1) to give 4e-3 (220 mg, 74%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ11.39 (brs, 1H), 8.07 (d, J=8.0 Hz, 1H), 5.91 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.21 (t, J=4.8 Hz, 1H), 5.05 (d, J=8.0 Hz, 1H), 3.78-3.82 (m, 2H), 3.59-3.71 (m, 2H), 3.36 (3, 3H), 1.08 (s, 3H); ESI-LCMS: m/z=273.1 [M+H]+.


Step 4. Compound 4e—


To a stirred suspension of 4e-3 (170 mg, 0.63 mmol) in anhydrous THF (2 mL) were added N-methylimidazole (0.5 mL) followed by 2b (598 mg, 1.875 mmol). The reaction mixture was stirred at 70° C. for 1 h. Solvents were evaporated and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give 4e (two isomers, 108 mg, 30.2%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ7.77, 7.85 (2d, J=8.0 Hz, 1H), 7.18-7.36 (m, 5H), 6.09, 6.12 (2s, 1H), 5.54, 5.63 (2d, J=8.0 Hz, 1H), 4.94-5.01 (m, 1H), 4.49-4.53 (m, 1H), 4.26-4.39 (m, 1H), 4.03-4.13 (m, 2H), 3.77-3.81 (m, 1H), 3.47 (s, 3H), 1.32, 1.36 (2d, J=7.2 Hz, 3H), 1.18-1.24 (m, 6H); 31P NMR (CD3OD, 162 MHz) δ68.2, 67.7; ESI-MS: m/z 558.2 [M+H]+.


Example 38

The structures of compounds 3a through 3vv and 4a through 4f are shown in Table 9.












TABLE 9








31P NMR




Compound
Product
(solvent)
MS









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3a
67.12 67.86 (CDCl3)
564.5 (M − H)







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3b
67.16 67.71 (CDCl3)
543.2 (M − H)







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3c
67.05 68.08 (CDCl3)
545.8 (MH+)







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3d
67.89 67.96 (DMSO)
586.2 (MH+)







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3e
66.9 66.9 (CD3OD)
574.2 (MH+)







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3f
67.85 67.16
570.4 (MH+)







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3g
67.80 67.16
582.5 (MH+)







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3h
67.92 67.28
592.2 (MH+)







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3i
67.74 67.43
632.5 (MH+)







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3j
68.01 67.35
620.8 (MH+)







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3l
68.42 68.21
546.1 (MH+)







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3m
69.17 68.68
558.1 (MH+)







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3n
70.38 69.13
572 (MH+)







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3o
69.15 68.56
586 (MH+)







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3p
68.27 67.85
611.3 (MH+)







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3q
68.09 68.03
613.7 (MH+)







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3r
68.23 67.64
583.4 (MH+)







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3s
68.07 67.71
623.1 (MH+)







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3t
68.21 67.82
599.4 (MH+)







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3u
68.21 67.65
597.5 (MH+)







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3v
68.52 68.27
625.3 (MH+)







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3w
68.43 68.32
637.6 (MH+)







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3x
68.55 68.57
675.3 (MH+)







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3y
68.66 68.36
687.4 (MH+)







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3z
68.53 68.38
622.2 (MH+)







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3aa
68.19 67.90
589.1 (MH+)







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3bb
68.51 68.40
622.1 (MH+)







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3cc
68.66 68.53
601.1 (MH+)







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3dd
68.15 67.74
595.0 (MH+)







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3ee
68.49 67.46
617.1 (MH+)







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3ff
67.78 66.86
569.4 (M − 1)







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3gg
68.11 67.06
597.5 (M − 1)







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3hh
68.40 67.43
595.1 (MH+)







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3ii
69.30 69.09
562.2 (MH+)







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3jj
68.92 68.58
578.0 (MH+)







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3kk
68.45 68.16
578.1 (MH+)







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3ll
69.69 69.28
618.0 (M + Na)+







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3mm
68.60 68.42
558.0 (MH+)







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3nn
68.25 67.79
558.2 (MH+)







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3oo
69.25 69.12
574.0 (MH+)







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3pp
69.52 68.53
595.0 (MH+)







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3qq
70.03 69.56
545.1 (MH+)







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3rr
68.87 68.76
626.2 (M + Na)+







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3ss
70.83 69.38
530.0 (MH+)







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3tt
69.12 68.45
558.0 (MH+)







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3uu
69.14 68.46
572.0 (MH+)







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3vv
68.74 66.82
620.0 (MH+)







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4a
67.71 67.74 (CDCl3)
654.5 (M − H)







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4b
67.72 67.54
598.3 (MH+)







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4c
68.44 68.42
682.4 (MH+)







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4d
68.90 68.23
585.9 (MH+)







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4e
68.2  67.7 
558.2 (MH+)







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4f
68.93 67.96
612.4 (MH+)









Example 39
General Synthesis of nucleoside 5′-O-(1-thiotriphosphates)



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1,2,4-Triazole (42 mg, 0.6 mmol) was suspended 1 mL of dry CH3CN. Triethylamine was added (0.088 mL, 0.63 mmol), and the mixture was vortexed to obtain a clear solution. After addition of PSCl3 (0.01 mL, 0.1 mmol), the mixture was vortexed and left for 20 minutes. The mixture was then centrifugated. The supernatant was added to the nucleoside (0.05 mmol), and the mixture was kept at ambient temperature for 1 hour. Tris(tetrabutylammonium) hydrogen pyrophosphate (180 mg, 0.2 mmol) was added. The mixture was then kept for 2 hours at RT. The reaction was cooled in an ice-water bath and quenched with water. The 5′-triphosphate, as mixture of diastereomers, was isolated by IE chromatography on an AKTA Explorer using column HiLoad 16/10 with Q Sepharose High Performance. The separation was done using a linear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractions containing the nucleotide α-thiotriphosphate were combined, concentrated and desalted by RP HPLC on the same column as in Example 3. A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium buffer was used for elution over 20 minutes, flow 10 mL/min. Two separate compounds corresponding to individual diastereomers at the phosphorus chiral center were collected. Analytical RP HPLS was done in 50 mM triethylammonium acetate buffer, pH 7.5, containing linear gradient of acetonitrile from 0% to 25% in 7 minutes on a Synergy 4 micron Hydro-RP column (Phenominex). Retention time (R.T.) for the individual diastereomers is provided in Table 10.









TABLE 10







α-Thiotriphosphates
















31P


31P


31P







NMR
NMR
NMR

R.T.


Structure




MS
min







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5b
43.17 d
−21.69 m
−5.32 d 
513.0
4.17







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5a
42.89 d
−21.75 q
−5.28 d 
513.0
4.50







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5c
43.14 d
−23.80 m
−10.20 bs
515.0
4.90







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5d
42.12 d
−23.48 q
−6.49 d 
515.0
5.52







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5e
43.42 d
−21.93 q
−5.47 d 
554.3
5.39







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5f
43.07 d
−21.90 q
−5.40 d 
554.2
5.79







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5g
43.41 d
−23.26 m
−10.10 bs
552.2
5.23







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5h
43.12 d
−24.20 m
−11.05 d
552.2
5.82





R.T. = retention time






In Table 10, 5a and 5b are diastereomers, and distinguishable by the chirality of the alpha-thiophosphate. Likewise, 5b and 5c; 5d and 5e; and 5f and 5h, respectively, are diastereomers and distinguishable by the chirality of the alpha-thiophosphate.


Example 40
HCV Replicon Assay
Cells

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


Determination of Anti-HCV Activity

Determination of 50% inhibitory concentration (EC50) of compounds in HCV replicon cells were performed by the following procedure. On the first day, 5,000 HCV replicon cells were plated per well in a 96-well plate. On the following day, test compounds were solubilized in 100% DMSO to 100× the desired final testing concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. Compounds in 100% DMSO are reduced to 10% DMSO by diluting 1:10 in cell culture media. The compounds were diluted to 10% DMSO with cell culture media, which were used to dose the HCV replicon cells in 96-well format. The final DMSO concentration was 1%. The HCV replicon cells were incubated at 37° C. for 72 hours. At 72 hours, cells were processed when the cells are still subconfluent. Compounds that reduce the LUC signal are determined by Bright-Glo Luciferase Assay (Promega, Madison, Wis.). Percent 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 11, where ‘A’ indicates an EC50<1 μM, ‘B’ indicates an EC50<10 μM, and ‘C’ indicates an EC50<100 μM.










TABLE 11





Compound
EC50









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A







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B







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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C







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B







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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A







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C







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C







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A







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A







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A







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A







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A







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A







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A







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A







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A







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B







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B







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A







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A







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B







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A







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A







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A







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C







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A







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A







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A







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A







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A









Example 41
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 μCi 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 hours 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 12. 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<10 μM, and a value of ‘C’ indicates an IC50 value of <100 μM.











TABLE 12







IC50



Structure
value







5a


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C





5b


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A





5c


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B





5d


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C





5e


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A





5f


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A





5g


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A





5h


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B









Example 42
Hepatocyte Activation Assay

Plated human hepatocytes were purchased from CellzDirect. 30 μL of test article (compound 3a) in DMSO at 5 mM was dosed to the incubation medium (3 mL) of each well containing ˜1.5 million human hepatocytes to reach a final concentration of 50 uM. After 6 hours of incubation at 37° C., the medium was removed and the cells were washed twice with 500 μL cold 0.9% NaCl in H2O. An aliquot of 500 μL cold methanol/H2O (70/30) was added to the well to lyse the hepatocytes. The cells were scraped off the well, and the entire content was removed to an Eppendorf tube. After more than 3 hours of storing at −20° C., the lysate was warmed to RT, vortexed, and centrifuged. The supernatant was evaporated in a Speed-Vac, and the sample was reconstituted with 500 μL 1 mM ammonium phosphate in H2O. 20 μL was injected into the LC/MS/MS system for the specific detection of the α-thiotriphosphate of the test article (see FIG. 1, panel D). A Thermo HyPurity C18 column (50×2.1 mm, 3u particle size) was used to achieve HPLC separation. Mobile phase A consisted of 3 mM ammonium formate and 10 mM dimethyl-hexylamine in H2O and mobile phase B consisted of 3 mM ammonium formate and 10 mM dimethyl-hexylamine in acetonitrile/H2O (50/50). The HPLC elution was via a linear gradient on increased mobile phase B at a flow rate of 0.22 mL/min. Compounds 5a and 5b were detected by a Sciex API 3200 via a negative ion MRM mode.


In FIG. 1, Panels A, B, C and D show the following. Panel A. HPLC chromatogram of a synthetic sample of the α-thiotriphosphate, 5a, at 300 nM in 1 mM ammonium phosphate in H2O. Panel B. HPLC chromatogram of a synthetic sample the α-thiotriphosphate, 5b, at 300 nM in 1 mM ammonium phosphate in H2O. Panel C. HPLC chromatogram of a purposely prepared 1:1 mixture of a synthetic sample of the α-thiotriphosphate diastereomers 5a and 5b, each at 150 nM in 1 mM ammonium phosphate in H2O. This shows that compounds 5a and 5b can be distinguished. Panel D. HPLC chromatogram of the α-thiotriphosphate diastereomer formed following incubation of compound 3a in human hepatocytes. As illustrated by Panel D, only compound 5b is formed.


Example 43
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 3b with one or more test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO. The cells were incubated with no compound as a control, with the test compounds, or the combination of compounds for 72 h. The direct effects of the combination of the test compounds were examined using a luciferase (LUC) based reporter as determined by the Bright-Glo Luciferase Assay (Promega, Madison, Wis.). Dose-response curves were determined for individual compounds and fixed ratio combinations of two or more test compounds.


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


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


The CI and synergy volume results for the combinations are provided in Table 13.











TABLE 13





Combination

Synergy Volume


Compound
CI at EC50
(μM2 %)

















INX-189
0.42
65


PSI-938
0.73
27


PSI-6130
0.78
15


PSI-7851
1.1
0


GS-9190
0.92
79


Filibuvir
0.85
23


ANA-598
0.02
161


7008
0.01
127


VX-222
0.67
38


VX-950
0.06
76


ITMN-191
0.28
126


TMC-435
0.5
126


BMS-790052
0.64
26


Ribavirin
1
22


Pegylated
0.33
117


Interferon




Consensus
1
31


Interferon




Cyclosporin A
0.07
60


BILN-2061
0.7
31


HCV-796
0.42
31


IFN-Lambda 1
0.35
116


IFN-Lambda 2
0.49
34


IFN-Lambda 3
0.63
35









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

Claims
  • 1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • 2. The compound of claim 1, wherein R2 is optionally substituted aryl.
  • 3. The compound of claim 2, wherein R2 is optionally substituted phenyl.
  • 4. The compound of claim 3, wherein R2 is unsubstituted phenyl.
  • 5. The compound of claim 4, wherein R1 is an optionally substituted N-linked α-amino acid.
  • 6. The compound of claim 5, wherein R1 is selected from the group consisting of N-alaninyl, N-asparaginyl, N-aspartatyl, N-cysteinyl, N-glutamatyl, N-glutaminyl, N-glycinyl, N-prolinyl, N-serinyl, N-tyrosinyl, N-argininyl, N-histidinyl, N-isoleucinyl, N-leucinyl, N-lysinyl, N-methioninyl, N-phenylalaninyl, N-threoninyl, N-tryptophanyl, and N-valinyl.
  • 7. The compound of claim 4, wherein R1 is an optionally substituted N-linked α-amino acid ester derivative.
  • 8. The compound of claim 7, wherein R1 is an N-linked α-amino acid ester selected from the group consisting of N-alaninyl ester, N-asparaginyl ester, N-aspartatyl ester, N-cysteinyl ester, N-glutamatyl ester, N-glutaminyl ester, N-glycinyl ester, N-prolinyl ester, N-serinyl ester, N-tyrosinyl ester, N-argininyl ester, N-histidinyl ester, N-isoleucinyl ester, N-leucinyl ester, N-lysinyl ester, N-methioninyl ester, N-phenylalaninyl ester, N-threoninyl ester, N-tryptophanyl ester, and N-valinyl ester.
  • 9. The compound of claim 8, wherein R1 is an N-linked α-amino acid ester, wherein the ester is selected from the group consisting of isopropyl ester, cyclopropyl ester, isobutyl ester, cyclobutyl ester, neopentyl ester, cyclopentyl ester, and cyclohexyl ester.
  • 10. The compound of claim 9, wherein R1 is selected from the group consisting of N-alaninyl isopropyl ester, N-alaninyl cyclohexyl ester, N-alaninyl neopentyl ester, N-valinyl isopropyl ester, and N-leucinyl isopropyl ester.
  • 11. The compound of claim 10, wherein R1 is N-alaninyl isopropyl ester.
  • 12. The compound of claim 1, wherein R6 and R7 are independently selected from the group consisting of —OH and —OC(═O)R13; or R6 and R7 are both oxygen atoms and linked together by a carbonyl group.
  • 13. The compound of claim 12, wherein R6 and R7 are both —OH.
  • 14. The compound of claim 13, wherein R8 is unsubstituted C1-C6 alkyl.
  • 15. The compound of claim 14, wherein R8 is methyl.
  • 16. The compound of claim 1, wherein B1 is an unsubstituted pyrimidine base.
  • 17. The compound of claim 16, wherein B1 is
  • 18. A compound of Formula (I), or a 5′-thio-monophosphate thereof, or a pharmaceutically acceptable salt of the foregoing:
  • 19. The compound of claim 18, wherein n is 1.
  • 20. The compound of claim 19, wherein R6 and R7 are independently selected from the group consisting of —OH and —OC(═O)R13; or R6 and R7 are both oxygen atoms and linked together by a carbonyl group.
  • 21. The compound of claim 20, wherein R6 and R7 are both —OH.
  • 22. The compound of claim 21, wherein R8 is unsubstituted C1-C6 alkyl.
  • 23. The compound of claim 22, wherein R8 is methyl.
  • 24. The compound of claim 18, wherein B1 is an unsubstituted pyrimidine base.
  • 25. The compound of claim 24, wherein B1 is
  • 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • 27. The pharmaceutical composition of claim 26, wherein the compound of Formula (I) is
  • 28. The pharmaceutical composition of claim 27, wherein the composition is formulated for oral administration or intravenous administration.
  • 29. A method for ameliorating or treating a HCV infection comprising contacting a cell infected with the HCV virus with an effective amount of a compound of Formula (I) of claim 1, or a pharmaceutically acceptable salt thereof.
  • 30. The method of claim 29, wherein the compound of Formula (I) is
  • 31. The method of claim 30, further comprising contacting the cell with a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of pegylated interferon-alpha-2a, pegylated interferon-alpha-2b, interferon lambda 1, interferon lambda 2, interferon lambda 3, consensus interferon, ribavirin, cyclosporine A,
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 13/236,435, filed Sep. 19, 2011, which claims the benefit of U.S. Provisional Application Nos. 61/385,363, filed Sep. 22, 2010; and 61/426,461, filed Dec. 22, 2010; all of which are incorporated herein by reference in their entirety, including any drawings.

Provisional Applications (2)
Number Date Country
61385363 Sep 2010 US
61426461 Dec 2010 US
Continuations (1)
Number Date Country
Parent 13236435 Sep 2011 US
Child 14519460 US