WO2006091905A1 - Bicyclo (3.1.0) hexane derivatives as antiviral compounds - Google Patents

Abstract

The invention provides a compound of formula (I) and (II), or a salt or prodrug thereof, as described herein, as well as pharmaceutical compositions comprising the compounds, and therapeutic methods comprising administering the compounds. The compounds have anti-viral properties and are useful for treating viral infections (e.g. HCV) in animals (e.g. humans).

Description

BI CYCLO ( 3 . 1 . 0 ) HEXANE DERIVATIVES AS ANTIVIRAL COMPOUNDS

BACKGROUND OF THE INVENTION

Hepatitis C (HCV) is the most comon blood-born infection in the United States, where about 35,000 new cases are estimeted to occur each year. There is currently a need for compounds, compositions, and methods that are useful for treating viral infections such as HCV.

SUMMARY OF THE INVENTION

The present invention provides compounds that inhibit one or more viral proteases. Accordingly, the compounds may be useful for treating viruses, such as HCV.

In one embodiment the invention provides a compound of the invention, which is a compound of formula I or II:

wherein:

Ri is H, halo, OR_a, SR_a, or NR_bR_c;

R₂ is H, halo, (C₁-C₆)alkyl , (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl;

R₃ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₄ is H, halo, azido, cyano, nitro, OR_a, SR_a, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₃ and R₄ taken together are =O, =NR_d, =CR_fR_g; or R₃ and R₄ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -O-, -S-, or -NR_a-;

R₅ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₆ is

H, halo, azido, cyano, nitro, OR_a, SR_a, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₅ and R₆ taken together are =O, =NR_d, =CR_fR_g; or R₅ and R₆ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -O-, -S-, or -NR_a-; R₇ and R₈ are each independently H or halo;

R₉ is a nucleoside base;

R₁₀ is OH, -OP(=O)(OH)₂, -OP(=O)(OH)-P(=O)(OH)₂, -OP(=OXOH)-P(=O)(OH)-P(=O)(OH)₂, or a phosphonate; each R₃ is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_b and R_c is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_d is independently H, (C₁-C₆)alkyl, or OH; each R_e is independently H or (C₁-C₆)alkyl; and each R_f and R_g is independently H, (C₁-C₆)alkyl, or halo; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl OfR₂-R₆ and R_a-R_g is optionally substituted with one or more halo, hydroxy, or (C₁- C₆)alkoxy; or a pharmaceutically acceptable salt or prodrug thereof. The invention also provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient. The invention also provides metabolites of compounds of the invention, as well as salts thereof.

The invention also provides a method of inhibiting a viral infection in an animal (e.g. a mammal), comprising administering an effective amount a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, to the animal.

The invention also provides a compound of the invention for use in medical therapy (preferably for use in treating a viral infection in an animal), as well as the use of a compound of the invention for the manufacture of a medicament useful for the treatment of a viral infection in an animal (e.g. a mammal).

The invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of the invention are useful to prepare other compounds of the invention.

In another embodiment the invention provides a method for inhibiting a viral infection in a sample comprising treating a sample suspected of containing a virus, with a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figures 1-4 illustrate synthetic processes and intermediates that can be used to prepare compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.

Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to. "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aiyl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Carbocycle" refers to a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

"Heterocycle" as used herein includes, by way of example and not limitation, those heterocycles described in Paquette, Leo A.; Principles of Modem Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem, Soc. (1960) 82:5566. In one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more {e.g., 1, 2, 3, or 4) carbon atoms haVe been replaced with a heteroatom (e.g., O, N, or S).

Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5- thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, lH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β- carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyI, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3- pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazolone, 2-pyrazoline, 3 -pyrazolone, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1- pyrazolyl, and 1-piperidinyl.

Heterocycle encompasses "heteroaryl," which includes a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C₁-C₆)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.

The term "substituted heterocycle" includes heterocycles as described herein that are substituted with one or more (e.g. 1, 2, 3, or 4) substituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, oxo, NRx_xR_yy -C(=O)NR_xxR_yy, cyano, halo, hydroxy, nitro, carboxy, (C₃-Cs)cycloalkyl, (C₃-C₈)cycloalkoxy, guanidino, trifluoromethoxy, mercapto, or trifluoromethyl; wherein Rx_x and R_yy are each independently H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl_s or aryl(C₁-C₆)alkyl.

The terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3) single-bonded to a heteroatom, and 4) single-bonded to another heteroatom, wherein each heteroatom can be the same or different. The terms "phosphonate" and "phosphonate group" also include functional groups or moieties that comprise a phosphorous in the same oxidation state as the phosphorous described above, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having the characteristics described above. For example, the terms "phosphonate" and "phosphonate group" include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups. In one specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double- bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to another oxygen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteristics. In another specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics. The tenn "treatment" or "treating," to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. Prodrugs

The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically- active compound.

"Prodrug moiety" refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation mechanism with a phosphate prodrug of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to modulate (e.g. enhanse) solubility, absorption, lipophilicity, drug delivery, bioavailability, and efficacy.

Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH₂OC(=O)R^x and acyloxymethyl carbonates

-CH₂OC(=O)OR^X where R^x is (C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, C₆-C₂₀ aryl or C₆-C_2O substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. ScI 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability of a compound of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) -CH₂OC(=O)C(CH₃)₃. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) -CH₂OC(=O)OC(CH₃)₃.

Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J Med. Chein. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J Med. Chem. 39:4109- 4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-ox jtrørø-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and a quinone methide compound. Examples of this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc.

Perkin Trans. //2345; and Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721).

Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphorous containing drugs. Certain of these proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate, which subsequently breaks down to the phosphoric acid and an episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med. Chem. 39: 4958).

Prodrug moities that can be incorporated into compounds of the invention include those described by Mackman, R.L. and Cihlar, Tomas, Annual Reports in Medicinal Chemistry, 2004, 39, 305-321. Other prodrug moities that can be incorporated into compounds of the invention include those described by Peyrottes et. al., Minireviews in Medicinal Chemistry, 2004, 4(4), 395-408; and Meier, Chris, Advances in Antiviral Drug Design, 2004, 4, 147-213.

Protecting Groups

In the context of the present invention, protecting groups include prodrug moieties and chemical protecting groups.

"Protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups and to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects are also prodrugs.

Various functional groups of the compounds of the invention may be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) include "ether- or ester- forming groups". Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.

A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994). In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like. Specific Embodiments

Specific values described for radicals, substituents, and ranges, as well as specific embodiments of the invention described herein, are for illustration only; they do not exclude other defined values or other values within defined ranges. For example, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C₃-C₆)cycloalkyl(C₁- C₆)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopeiitylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl; hydroxy(C₁-C₆)alkyl can be hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3- hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5- hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl; (C_!-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C₁-C₆)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). A specific value for R₁ is H.

A specific value for R₂ is H. A specific value for R₃ is H. A specific value for R₄ is H or OH. A specific value for R₅ is H.

A specific value for R₆ is OH.

A specific value for each of R₇ and R₅ is H.

A specific value for R₁₀ is OH.

A specific value for R₁₀ is -OP(=O)(OH)₂.

A specific value for R₁₀ is a phosphonate.

A specific value for R₁₀ has the formula:

wherein:

Y^2b is O or NH; each R¹ is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl; and each R², is independently (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁- C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl.

A specific value for R₁₀ has the formula:

A specific value for R₁Q has the formula:

A specific value for Rio has the formula:

wherein R² is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl. A specific value for Rio has the formula:

wherein: Y^2b is O or N(R⁴); R² is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, aryl(C₁-C₆)alkyl, or (C₂-C₆)alkynyl; and R⁴ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, aryl(C₁-C₆)alkyl, or (C₂-C₆)alkynyl.

A specific value for Rio has the formula:

In one specific embodiment of the invention, the compound of formula I is not (l'5',2^li?,3¹ _iS^r,4^li?,5'5)-4-(6-amino-purin-9-yl)-1-[hydroxymethyl]bi- cyclo[3.1.0]hexane-2,3-diol.

In another specific embodiment of the invention, the compound of formula I is not 4-(6-amino-purin-9-yl)-1-[hydroxymethyl]bi- cyclo[3.1.0]hexane-2,3-diol.

In another specific embodiment of the invention, the compound of formula I is not: (l'S^r,2'i?,3'5,4'i?,5'_ιS)-4-(6-amino-9H-purin-9-yl)-1-

[phosphoryloxymethyl]bi-cyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H-purin-9- yl)-1-[phosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H- purin-9-yl)-1-[hydoxymethyl]bicyclo[3.1.0]hexane-2,3-diol; (l'5^l,2^li?,3W,4'i?,5^I»S)-4-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl]bi- cyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H-purin-9-yl)-1-

[triphosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol; (V S, 2%$' SA' R,5' S)-A-

(2,4(H,3H)-dioxopyrimidin-1-yl)-1-(phosphoryloxymethyl)bi- cyclo[3.1.0]hexane-2,3-diol; (r_lS,2'i?,3'₁S,4'i?,5',S)-4-(2,4(H,3H)-dioxopyrimidin- l-yl)-1- (diphosphoryloxymethyl)bicyclo[3.1.0]hexane-2,3-diol; or (l'5',2'i?,3'₁S',4¹i?,5'5)-4-(2_J4(H,3H)-dioxopyπmidin-1-yl)-1- (triphosphoryloxymethyl)bicyclo[3.1.0]hexane-2,3-diol.

In another specific embodiment of the invention the compounds of formula I exclude compounds wherein: Ri is H; R₂ is H; R₃ is H; R₄ is OH; R₅ is H; Re is OH; R₇ and Rg are each H; R9 is 6-amino-9H-purin-9-yl or

2,4(H,3H)-dioxopyrimidin-1-yl; and R₁₀ is OH, -OP(K))(OH)₂, -OP(=O)(OH)- P(⁸O)(OH)₂, or -OP(=OXOH)-P(=O)(OH)-P(=O)(OH)₂.

In another sprcific embodiment of the invention the compounds of formula II exclude compounds wherein: Rj is H; R₂ is H; R₃ is H; R₄ is OH; R₅ is H; R₆ is OH; R₇ and R₈ are each H; R₉ is 6-amino-9H-purin-9-yl; and Rio is OH, -OP(=O)(OH)₂, -OP(=O)(OH)-P(=O)(OH)₂, or -OP(=O)(OH)-P(=O)(OH)-P(=O)(OH)₂,

Nucleoside base The invention provides compounds of formula I and II wherein R₉ is a nucleoside base. A multitude of nucleoside base analogs have been reported. The compounds of formula I and II may include any nucleoside base, provided the final compound possesses useful therapeutic (e.g. anti-viral) properties. For example, a specific value for R9 is a heterocycle or a substituted heterocycle (e.g. a purine, substituted purine, pyrimidine, or a substituted pyrimidine).

Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in United States Patent Application Publication Number 2004/0147464. Accordingly, a specific value for R₉ has the following formula:

wherein: R₂₀ is OH or (C₁-C₆)alkoxy that is optionally substituted with one or more R₂₂; and R₂j is H or (C₁-C₆)alkyl that is optionally substituted with one or more R₂₂; or R₂₀ and R₂₁ together with the nitrogen to which they are attached form a heterocyclic ring that is optionally subsitituted with one or more R₂₂; each R₂₂ is independently (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR₂₃R₂₄, -C(=O)NR₂3R₂₄, aryl, heteroaryl, cyano, halo, hydroxy, nitro, carboxy, or (C₃- C₈)cycloalkyl;

R₂₃ and R₂₄ are each independently H, (C₁-C₆)alkyl or (CrQs)alkanoyl; wherein each aryl or heteroaryl of R₂₂ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR₂₃R₂₄, -C(=O)NR₂₃R₂₄, cyano, halo, hydroxy, nitro, carboxy, (C₃-Cs)cycloalkyl, trifluoromethoxy, mercapto, or trifluoromethyl; and A, B, D, F, and E are each independently >N or >C-R₂s; each R₂₅ is independently H, cyano, nitro, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, -NHCONH₂, CC=O)NR₂₆R₂₇, COOR₂₈, hydroxy, (C₁-C₆)alkoxy, -NR26R2?, halo, l,3-oxazol-2-yl, l,3-oxazol-5-yl, l,3-thiazol-2-yl, imidazol-2-yl, 2-oxo-[l,3]dithiol-4-yl, furan-2-yl, or 2H-[l,2,3]triazol-4-yl; each R₂₆ and R₂₇ is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, (C₃-C8)cycloalkyl, aryl, heterocycle, hydroxy, (C₁-C₆)alkoxy; or R₂₆ and R₂7 together with the nitrogen to which they are attached form a heterocycle; and each R₂S is independently H, (C₁-C₆)alkyl, (C₁-C₆)allcenyl, (Cr C₆)alkynyl, (C₃-Cs)cycloalkyl, aryl, or heterocycle; wherein each (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₃- C₆)cycloalkyl, aryl, heterocycle, and (C₁-C₆)alkoxy of R₂₆ and R₂₇ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁- C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbony3, NH₂, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₆)cycloalkyl, (C₃-C8)cycloalkoxy, trifluoromethoxy, or mercapto.

A specific value for R₂o is OH, methoxy, or propoxy; and for R₂i is H. A specific value for R₂₀ and R₂i together with the nitrogen to which they are attached form a pyrrolidin-1-yl, l,3,4,9-tetrahydro-beta-carbolin-2-yl, piperidinyl, azetidinyl, 3,6-dihydro-2H-pyridin-1-yl, or 3,4-dihydro-lH- isoquinolin-2-yl ring, which ring is optionally substituted with -(X=O)NH₂. Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in United States Patent Application Publication Number 2005/0215511. Accordingly, a specific value for R₉ has the following formula:

wherein:

R₃₀ is -C≡ CR31, -CH=CHR₃₂, formyl, -CH=NHNR₃₃, -CH=N(OR₃₃), -CH(OR₃₄), Or-B(OR₃₃); R₃i is tri(C₁-C₆)alkylsilyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, heteroaryl, aryl,

Carboxy, or (C₁-C₆)alkoxycarbonyl;

R₃₂ is hydrogen or czs-(C₁-C₆)alkoxy;

R₃₃ is H or (C₁-C₆)alkyl; and

R₃₄ is (C₁-C₆)alkyl; wherein each aryl or heteroaryl of R₃₁ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR₃₅R₃₆, -C(K))NR₃₅R₃₆, cyano, halo, hydroxy, nitro, carboxy, (C₃-Cs)cycloalkyl, (C₃-C₆)cycloalkoxy, guanidino, trifluoromethoxy, mercapto, -S(=O)_mR₃₇, or trifluoromethyl; m is 0, 1, or 2;

R₃₅ and R₃₆ are each independently H, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl;

R₃₇ is (C₁-C₆)alkyl, aryl, hetrocycle, or NR₃gR₃₉; and

R₃₈ and R₃9 are each independently H, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl; wherein each aryl or heterocycle OfR₃₇ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR₃₅R₃₆, -Ct=O)NR₃₅R₃₆, cyano, halo, hydroxy, nitro, carboxy, (C₃-Cs)cycloalkyl, (C₃-C8)cycloalkoxy, guanidino, trifluoromethoxy, mercapto, or trifluoromethyl.

A specific value for R30 is 2-trimethylsilylethynyl, 2-(2-pyridyl)ethynyl, 2-(4-pyridyl)ethynyl, 2-(4-methoxy)ethynyl, 2-(aminocarbonyl)ethynyl, 3,3- diethoxypropyn-1-yl, 2-(dimethylaminocarbonyl)ethynyl, 2-(N- amino(aminocarbonyl)ethynyl, 2-carboxyetliynyl, 2-ethoxycarbonylethynyl, 2- methoxycarbonylethynyl, 2-phenylethynyl, 2-(4-fluorophenyl)ethynyl, 2-(4- methylphenyl)ethynyl, vinyl, 2-methoxyvinyl, formyl, -CH=N-NH₂, -CH=NOH, 1,1-diisopropoxymethyl, or -B(OH) ₂.

Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 03/061385. Accordingly, a specific value for R9 has one of the the following formulae:

wherein:

R₄₀ is H, NR_4aR_4b, NHC(=O)R_4b, (C₁-C₆)alkylNR_4aR_4b, NHNH₂, cyano, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl(C₁-C₆)alkyl, heterocycle(C₁- C₆)alkyl, halo, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, hydroxy, or mercapto;

R₄₁ is H, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂- C₆)alkynyl, heterocycle, aryl, aryl(C₁-C₆)alkyl; each R₄₂ is independently H, hydroxy, mercapto, cyano, -SNR_4cR_4d, -C(NH)NR_4cR_4d, -C(=NH)NHOH, -C(NH)NHO_4c, -C(=NH)NHNR_4cR_4d,

NHCOR_4c, SR_4c, OR_4c, SOR_4c, SO₂R_4c, -C(=O)NR_4cR_4d, -C(=S)NR_4cR_4d, or R_4c;

R₄₃ is H, hydroxy, NR_4cR_4d, NHC(=O)NR_4c, NHNHR_4c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, heterocycle, aryl, aryl(C₁-C₆)alkyl, halo, COOR_4c, CONR_4cR_4d, or absent when Y is N; R₄₃ and R_4b are each independently hydrogen, (C₁-C₆)alkyl, (C₂-

C₆)alkenyl, (C₂-C₆)alkynyl, heterocycle, or aryl;

R_4c, and R_4d are each independently hydrogen, (C₁-C₆)alkyl, (C₂- C₆)alkenyl, (C₂-C₆)alkynyl, heterocycle, or aryl;

X, Y, and W are each independently N, C, CR_4c, S or P; R₄₄ is H, hydroxy, mercapto, cyano, -SNR_4cR_4d, -C(NH)NR_4cR_4d, -C(=NH)NHOH, -C(NH)NHOR_4c, -C(=NH)NHNR4oR_4d, NHCOR_4c, SR_4c, OR_4c, SOR_4c, SO₂R_4c, -C(=O)NR_4cR_4d, -C(=S)NR_4cR_4d, Or R_4c;

R₄5 is H, hydroxy, mercapto, cyano, -SNR_4cR_4d, -C(NH)NR_4cR_4d, -C(=NH)NHOH, -C(NH)NHO_4c, -C(N=H)NHNR_4cR_4c1, NHCOR_4c, SR_4c, OR_4c, SOR_4c, SO₂R_4c, -C(O=)NR_4cR_4d, -C(=S)NR_4cR_4d, or R_4c;

R₄₆, and R₄₇ together with the atoms to which they are attached form a heterocyclic ring; and

U is S or O; wherein each aryl or heterocycle is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₈)cycloalkyl, (C₃-C₆)cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl.

Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 03/062257. Accordingly, a specific value for R₉ has one of the following formulae:

wherein:

R₅₀ is NR_5aR_5b, ONR_5aR_5b, NR_5aNR_5aR_5b, SR_5b, OR_5b, H, hydroxy, (Cr C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)all<ynyl, or aryl;

R₅) is (C,-C₆)alkyl, (C₁-C₆)alkanoyl, or aryl;

R₅₂ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl;

R₅₃ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)a]kynyl, or aryl;

R₅₄ is H or NH₂; R₅₅ is NR_5aR_5b, ONR_5aR_5b, NR_5aNR_5aR_5b, SR_5b, OR_5b, H, hydroxy, (C₁- C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl;

R₅₆ is H, halo, (C₁-C₆)alkyl, or (C₁-C₆)alkenyl;

R₅₇ and R₅g are each independently -L-R_5c; each L is independently a direct bond, -N(R_5J1)-, O or S; each R_5a and R_5b is independently H, hydroxy, (C₁-C₆)alkyl, (C₁- C₆)alkenyl, (C_!-C₆)alkynyl, or aryl; and each R_5c is NR_5aR_5b, H, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, or aryl; wherein each (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl of R₅o-Rsg and Rs_a-Rs_c is optionally substituted with one or more (C₁-C₆)alkyl, (C₁- C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁- C₆)alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C₃-C8)cycloalkyl, (C₃- C8)cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl.

Specific nucleoside base sti-uctures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 03/072757. Accordingly, a specific value for R₉ has one of the following formulae:

wherein:

X_2, X_3; and X₄, are each independently N, CH, or C-R6_a; R₆₀, R₆₁, and R_6a are each independently H, halo, NR_6bR_6c, hydroxyamino, NR_6bNR_6bR_6c, N₃, NO, NO₂, formyl, cyano, -C(=O)NR_6bR_6c, -C(=S)NR_6bR_6c; -C(=O)OR_6b, R_6b, OR_6b, or SR_6b; and

R_6b, and R_6c are each independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl. Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 03/073989. Accordingly, a specific value for R₉ has the following formula:

wherein:

X₅, X₆, and X₇, are each independently N, CH, or C-R_7a; R₇₀ and R_7a are each independently H, halo, NR_7bR_7c, hydroxyamino, NR_7bNR_7bR_7c, N₃, NO, NO₂, formyl, cyano, -C(=O)NR_7bR_7c, -C(=S)NR_7bR_7c, -C(=O)OR_7b, R_7b, OR_7b, or SR_7b; and

R_7b, and R₇₀ are each independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl. Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 2004/080466. Accordingly, a specific value for R₉ has the following formula:

wherein:

Y₁=Y₂ is -N=N-, -CH=N-, -N=CR_8a-, or -CH=CR₈₃-; and each R_8a is independently H, halo, or (C₁-C₆)alkyl.

Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in

International Patent Application Publication Number WO 2005/021568.

Accordingly, a specific value for R₉ has one of the following formulae:

wherein: each Z₁ is independently N, C-R_9a, O, S, NR₉₁₃, >C=O, >C=S, >C=NR₉b, >S=O, >S(O)₂ or CH-R₉₃; provided that if a Z₁ participates in an optional bond represented by a dotted line — in the formula, then that Zi is N or C-R_9a; and provided that if a Zi does not participate in an optional bond represented by a dotted line — in the formula, then that Z\ is O, S, NR_9b, >C=O, >C=S, >C=NR_%, >S=O, >S(O)₂ or CH-R₉₃;

X_5a is O, S, SO, SO₂, Se, SeO, SeO₂ or NR_9b; each W₁ is C, CH, or N; wherein if a W₁ participates in an optional bond represented by a dotted line — in the formula, then that W₁ is C; and if a W1 _does not participate in an optional bond represented by a dotted line — in the formula, then that W₁ is CH, or N; each R_9a is independently H, halo, NR_9cR₉d, hydroxyamino, NR₉cNR_9cR_9d, N₃, cyano, -C(=O)NR_9cR_9d, -C(=S)NR_9cR9d, -C(=S)NR_9cR_9d, -C(=NH)0R_9c, R₉C, OR₉C, or SR_9c; each R_9b is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl; and

R_9a, and R_9d are each independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl.

Another specific value for R₉ has one of the following formulae:

Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 2005/123087. Accordingly, a specific value for R₉ has one of the following formulae:

wherein:

X₄ is CRgo_& or N;

X₅ is O, S, orNR₉i_a ; Rp₀ and R9₁ are each independently H, halo, hydroxy, (C₁-C₆)alkoxy,

NRgobR9ib, or heterocycle;

R₉o_a is H, halo, methyl, azido, or amino;

R_91a is H, or (C₁-C₆)alkyl; and

R_9Ob and R_91b are each independently H, (C₁-Ce^IlCyI, (C₃-C8)cycloalkyl, or aryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl, (C₃-Cs)cycloalkyl, aryl(C₁-C₆)alkyl, and heterocycle of R9₀-R9₁, R_9U, and R₉o_b-R9ib are optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo, hydroxy, amino, (C₁-C₆)alkyl, and (C₁-C₆)alkoxy.

Specific nucleoside base structures that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 2006/002231. Accordingly, a specific value for R₉ is a 9-deazapurine derivative, such as, for example, a group of the following formulae:

wherein:

X₆ is O, S, orNR_70a;

R.₇₀ and R_7J are each independently H, halo, hydroxy, niercapto, aryl, heterocycle, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)alkylthio, arylthio, -S(=O)(C,-C₆)alkyl, -S(=O)₂(C₁-C₆)alkyl, -S(=O)₂NR₇o_bR₇ib, NR₇obR7i_b) (C₁-C₆)alkoxy, aryloxy, (heterocycle)oxy;

R_7Oa is H, methyl, ethyl, or acetyl; and

R_7Ob and R₇] _b are each independently H, (C₁-C₆)alkyl, aryl, aryl(Cj- C₆)alkyl, (C₁-C₆)alkanoyl, or aryl-C(=O)-;

Specific nucleoside base structoes that can be incorporated into the compounds of the invention include the nucleoside bases reported in International Patent Application Publication Number WO 2006/000922. Accordingly, a specific value for R₉ a specific value for R₉ has one of the following formulae:

wherein:

Ago, Bso, and Yso, are each independently H, halo, OR₈O, S(O)_nRsO, NRsoRst, cyano, trifluoromethyl, C(=W)OR₈₀, C(=W)SR₈₀, C(=W)NR₈₀ Rsi, nitro, azido, carbocyclic, (C₁-C₆^IlCyI, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, aryl, aryl(C₁-C₆)alkyl, or heterocycle; or A₈₀ and Bso taken together with the carbon atoms to which they are attached from a 4-7 membered carbocyclic or heterocyclic ring; n is O, I, or 2

Z₈₀ is O, S, NR₈₀, or CR₈₀R₈I; each V is independently N or CR₈₀; and each R₈₀ and Rsi is independently H, carbocycle, (C₁-C₆)alkyl, (C₁-

C₆)alkenyl, (C₁-C₆)alkynyl, halo, (C_!-C₆)alkoxy, amino, methylamino, dimethylamino, cyano, (C₁-C₆)alkanoyl, aryl, a₁yl(C₁-C₆)alkyl, an amino acid residue (e.g. a natural amino acid residue) or heterocycle; or R₈₀ and Rsi taken together with the atom(s) to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring.

Another specific value for R₉ has one of the following formulae:

wherein:

R9₇ is H, hydroxy, mercapto, (C₁-C₆)alkyl, (C₁-C₆)aIkoxy, (C₂- C₆)alkenyl, (C₃-C₈)cycloalkyl, aryl(C₁-C₆)alkyl, aryl or (C₂-C₆)alkynyl; R₉₈ is H, hydroxy, mercapto, or (C₁-C₆)alkyl; R₉₉ is H, halo, azido, cyano, nitro, O R_99a, SR_99a, NR_99bR_99c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₈)cycloaikyl, aryl(C₁-C₆)alkyl, aryl or (C₂-C₆)alkynyl; each R_99a is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_99b and R_99c is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; wherein each (C₂-C₆)alkyl, (C₁-C₆)alkoxy (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl, and aryl(C₁-C₆)alkyl of R₉₇, R₉₈, R₉₉ , R_99a, R_99b, and R_99c, is optionally substituted with one or more (C₁-C₆)alkyl, (C₁- C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁- C₆)alkoxycarbonyl, NH₂, cyano, azido, halo, hydroxy, nitro, carboxy, trifluoromethoxy, aryl, or mercapto.

Another specific value for R₉ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8- azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2- amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, or pyrazolo[3,4- D]pyrimidine; Another specific value for R₉ is 6-amino-2-chloro-purin-9-yl; 6-amino-2- iodo-purin-9-yl; 6-amino-2-fluoro-purin-9-yl; 6-amino-2-methylthio-purin-9-yl; 6-amino-purin-9-yl; or 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl. Another specific value for Rg is adenine or cytosine, which adenine or cytosine is optionally substituted with one or more (C₁-C₆)all<yl, (Cr C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁- C₆)alkoxycarbonyl, NH₂, cyano, halo, hydroxy, nitro, cavboxy, trifluoromethoxy, aryl, or mercapto.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and ElIeI, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents ( Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and WiI en, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yleld the free, enantiomerically enriched xanthene. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, α-methoxy-α- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (199O) J. ofChromatogr. 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

The compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

The compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or aminonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. Monovalent salts maybe preferred if a water soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, ^SO^ H₃PO₄ or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any amino acid can be used, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. For therapeutic use, salts of active ingredients of the compounds of the invention will typically be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.

Pharmaceutical Formulations

Pharmaceutical formulations according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifylng agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of viral infections as described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compounds of the invention can also be formulated to provide controlled release of the active ingredient(s) to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient(s). Accordingly, the invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.

An effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.

Combination Therapy

Active ingredients of the invention can also be used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. For example, when treating a viral infection the compositions of the invention can be combined with other agents that are effective to treat a viral infection (such as other antiviral agents).

It is also possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combination therapy may provide "synergy" and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co- formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate foπnulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yleld a metabolic product thereof. Such products typically are identified by preparing a radiolabeled {e.g., C^ or H^) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no antiviral activity of their own.

Methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37 °C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the invention typically will be stable in the digestive system but are substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.

Antiviral Activity

Another aspect of the invention relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject suspected of needing such inhibition with a composition of the invention.

Within the context of the invention samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as an tumor virus. Samples can be contained in any medium including water and organic solventVwater mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures. If desired, the anti-virus activity of a compound of the invention after application of the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semiquantitative methods of determining such activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.

The antiviral activity of a compound of the invention can be measured using standard screening protocols that are known. For example, the antiviral activity of a compound can be measured using the following general protocol. HCV IC_5O Determination

Assay Protocol: NS5b polymerase assay (40 μL) was assembled by adding 28 μL polymerase mixture (final concentration: 50 mM Tris-HCl at pH 7.5, 10 mM KCL, 5 mM MgCl₂, 1 mM DTT, 10 mM EDTA, 4 ng/μL of RNA template, and 75 nM HCV Δ21 NS5b polymerase) to assay plates followed by 4 μL of compound dilution. The polymerase and compound were pre-incubated at 35 ⁰C for 10 minute before the addition of 8 μL of nucleotide substrate mixture (33P-α-labeled competing nucleotide at K_M and 0.5 mM of the remaining three nucleotides). The assay plates were covered and incubated at 35 ⁰C for 90 min. Reactions were then filtered through 96-well DEAE-81 filter plates via vacuum. The filter plates were then washed under vacuum with multiple volumes of 0.125 MNaHPO₄, water, and ethanol to remove unincorporated label. Plates were then counted on TopCount to assess the level of product synthesis over background controls. The IC50 value was determined using Prism fitting program

HCV EC₅₀ Determination

Replicon cells were seeded in 96-well plates at a density of 8 x 10³ cells per well in 100 μL of culture medium, excluding Genetic in. Compound was serially diluted in 100% DMSO and then added to the cells at a 1 :200 dilution, achieving a final concentration of 0.5% DMSO and a total volume of 200 μL. Plates were incubated at 37°C for 3 days, after which culture medium was removed and cells were lysed in lysis buffer provided by Promega's luciferase assay system. Following the manufacturer's instruction, 100 μL of luciferase substrate was added to the lysed cells and luciferase activity was measured in a TopCount luminometer.

Typically, compounds of the invention that were tested were found to have an EC50 of less than about 1000 μM (Huh7). Some compounds demonstrated an EC₅0 of less than about 250 μM (Huh 7). The cytotoxicity of a compound of the invention can be determined using the following general protocol. Cytotoxicity Cell Culture Assay (Determination of CC50):

The assay is based on the evaluation of cytotoxic effect of tested compounds using a metabolic substrate. Assay protocol for determination ofCC50: 1. Maintain MT-2 cells in RPMI-1640 medium supplemented with 5% fetal bovine serum and antibiotics.

2. Distribute the cells into a 96-well plate (20,000 cell in 100 μl media per well) and add various concentrations of the tested compound in triplicate (100 μl/well). Include untreated control. 3. Incubate the cells for 5 days at 37 ⁰C.

4. Prepare XTT solution (6 ml per assay plate) in dark at a concentration of 2mg/ml in a phosphate-buffered saline pH 7.4. Heat the solution in a water- bath at 55⁰C for 5 min. Add 50 μl of N-methylphenazonium methasulfate (5 μg/ml) per 6 ml of XTT solution. 5. Remove 100 μl media from each well on the assay plate and add 100 μl of the XTT substrate solution per well. Incubate at 37 ⁰C for 45 to 60 min in a CO₂ incubator. 6. Add 20 μl of 2% Triton X-100 per well to stop the metabolic conversion of

XTT. 7. Read the absorbance at 450 nm with subtracting off the background at 650 nm.

8. Plot the percentage absorbance relative to untreated control and estimate the CC50 value as drug concentration resulting in a 50% inhibition of the cell growth. Consider the absorbance being directly proportional to the cell growth.

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compounds of the invention. The compounds are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic

Synthetic Methods (John Wiley & Sons, New York), Vol. I, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol.

3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980;

Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as

March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategy &

Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost,

Editor-in-Chief (Pergamon Press, New York, 1993 printing).

Exemplary methods for the preparation of the compounds of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods. Exemplary methods for the preparation of the compounds of the invention are also illustrated in Figures 1-6.

Synthetic intermediates and methods that are useful for preparing compounds of the invention are described by Joshi et al., J.Org. Chem., 2005, 70, 439-447; Gallos et al., Tetrahedron, 2002, 58, 8043-8053; Paquette et al., J.

Org. Chem., 1995, 60, 7849-7856; and Kim et al., J. Med. Chem., 2002, 45, 208-

218.

Representative compounds of the invention were prepared as described below. An intermediate compound 9 was prepared as illustrated below.

L-Ribose 1 was converted into the iodides 2, which were reductively cleaved with Zn to afford the aldehyde 3. This aldehyde was unstable and was reacted directly with ethyl diazoacetate to afford keto ester 4. The keto ester was reacted with tosyl azide to afford the diazo derivative 5, which underwent a thermally-induced intramolecular cyclopropanation to give the bicyclo[3.1.0]hexan-2-one derivatives 6 and 7 with a diastereoisomeric ratio of (3:1) favoring isomer 6. The bicyclo derivative 6 was isolated by chromatography and reduced stereospecifically with NaBH₄ to give alcohol 8 as a single product in 69% yleld. This alcohol 8 was subjected to an acid-catalyzed equilibration to produce the isomeric acetonide 9, which was isolated in 35% yleld by crystallization from cyclohexane. The remaining alcohol 8 was recycled.

Preparation of compounds 2-9

Ethyl (4S,5S)-3-[2,2-dimethyI-5-vinyl(lβ-dioxolan-4-yl)]-3- oxopropanoate 4: Concentrated HCl was added to a solution containing L- Ribose 1 (75g, 0.5 mol) in acetone (200 ml) and methanol (200 ml) at room temperature. The resulting reaction mixture was refluxed for 2 hours, cooled to room temperature, neutralized with pyridine, and concentrated. The residue was partitioned between water (300 ml ) and ethyl acetate (300 ml three times); the combined organic phase was washed with saturated solution of copper sulphate, followed by brine, and the resulting solution was dried over sodium sulphate and concentrated. The crude residue was used directly in the next step ( 82 g).

The crude residue was dissolved in toluene (800 ml) and was added with imidazole (51 g, 0.75 mol), triphenylphosphine (197g, 0.75 mol), and acetonitrile 175 ml). The resulting reaction mixture was heated to 70 ⁰C, and Iodine (13 Ig, 0.5 mol) was added portion wise and carefully till the reaction mixture remained dark brown. The reaction mixture was maintained at 70 ⁰C for 1 hour. The top clear organic layer was decanted; and the residue was washed with toluene (200 ml). The combined organic layer was washed with 5% sodium thiosulphate solution, water, and brine and concentrated. The crude residue was treated with mixture containing hexane and ethyl acetate (3:1). Solid triphenylphosphine oxide separated out, was filtered, and the filtrate was concentrated. Further purification was effected by flash column chromatography, with ethyl acetate and hexane (5: 95 ) as the eluant, to give the iodo derivative 2 as a mixture of anomers. ( 95g, 64% in two steps).

Powdered Zn ( 16.2g, 0.25 mol) was added to the solution containing the iodides 2 (15.7 g, 0.05 mol) in methanol (25ml ) and isopropanol (75 ml). The resulting reaction mixture was allowed to reflux for 1 hour and was cooled at room temperature. The solution was decanted and concentrated (under reduced pressure). The residue was treated with water (100 ml) containing 5% acetic acid, extracted with dichloromethane (100 ml) , dried, and concentrated under reduced pressure to give the crude aldehyde 3 (7 g).

Aldehyde 3 (7 g) in dichloromethane (40 ml) was treated with SnCl₄ (3.8g, 0.02 mol) and ethyldiazoacetate (7.6 g, 0.04 mol) at 0 ⁰C, and the mixture was allowed to stir at room temperature for 8 hours. The mixture was filtered through a pad of celite, concentrated, and purified by column chromatography (silica gel, hexane: ethylacetate, 95:5) to afford 4, ( 5g, 42% based on the iodide derivative) as an oil. ¹H NMR (CDCl₃) δ 12.08 (s, 0.1 H, D₂O exchangeable, enolic OH), 5.92-6.06 (m, 1 Η), 5.37-5.56 (m, 2 Η), 4.46-4.62 (m, 1 Η), 4.18- 438 (m, 3 H), 3.75 (AB q, 2 H, J= 16.4 Hz), 1.54-1.57 (m, 6 H, 2), 1.34-1.41 (m, 3 H); FAB MS m/z (relative intensity) 185 (7.2), 243 (MH⁺, 2).

Ethyl (45',55)-3-[2,2-dimethyI-5-vinyl(l,3-dioxolan-4-yl)]-2-diazo-3- oxopropanoate 5. To a stirred solution of keto ester 4 (9,68 g, 0.04 mol) in acetonitrile (40 mL) was successively added tosyl azide (8.26 g, 0.042mol) and Et₃N (8.8 g, 80 mmol). The resulting reaction mixture was concentrated after stirring for 1 hour at room temperature The diazo derivative was directly purified by column chromatography (silica gel; hexanes:EtOAc, 90:10) to furnish 5 (7.5 g, 70%) as an oil ¹H NMR (CDCl₃) δ 5.79(ddd, 1 H, J= 17.3, 10.1, 7.3 Hz), 5.70 (d, 1 H, J= 7.6 Hz), 5.45 (d, 1 H, J= 17.1 Hz), 5.33 (d, 1 H, J= 10.2 Hz), 5.07 (t, 1 H, J= 7.5 Hz), 4.34 (q, 2 H, J= 7.1 Hz), 1.74 (s, 3 H), 1.51 (s, 3 H), 1.41 (t, 3 H, J= 7.1 Hz); FAB MS m/z (relative intensity) 269 (MH⁺, 86).

Ethyl (l£β5;4£;5£)-3,4-0-isopropyIidene-2-oxobicyclo[3.1.0]- hexanecarboxylate 6. To a stirred solution of diazo compound 5 (5.36 g, 20 mmol) in dry toluene (30 mL) was added CuI (0.190 g, 1 mmol) at room temperature. The reaction mixture was refluxed for 8 hours, cooled to room temperature, concentrated, and purified by column chromatography (silica gel; hexanes.ΕtOAc, 75:25) to provide bicylic compound 6 (1.72 g, 36%) and compound 7 (0.57 g, 12%). Compound 6: ¹HNMR (CDCl₃) δ 5.13 (ddd, 1 H, J = 8.3, 5.4, 1.0 Hz), 4.39 (d, 1 H, J= 8.3 Hz), 4.29 (q, 2 H, J= 7.1 Hz), 2.84 (dt, 1 H, J= 8.3, 5.3 Hz), 2.18 (dd, 1 H, J= 8.1, 5.1 Hz), 1.89 (t, 1 H, J- 5.2 Hz), 1.59 (s, 3 H), 1.39 (s, 3 H), 1.36 (t, 3 H, J= 7.1 Hz); FAB MS m/z (relative intensity) 241 (MH⁺, 100). 7: ¹HNMR (CDCl₃) δ 4.81 (d, 1 H, J= 5.1 Hz), 4.38 (dd, 1 H, J= 4.8, 1.7 Hz), 4.32 (dq, 2 H, J= 7.1, 1.5 Hz), 2.96 (dd, I H, J= 8.7, 5.7 Hz), 2.21 (ddd, 1 H, J- 8.8, 5.7, 1.7 Hz), 1.53 (s, 3 H), 1.45 (s, 3 H), 1.37 (t, 3 H, J= 4.1 Hz), 1.35 (irregular t, 1 H); FAB MS m/z (relative intensity) 241 (MH⁺, 100).

Ethyl (l^^iϊβ^^S^-S^-O-isopropylidene-1-hydroxybicycloIS.l.O]- hexane-carboxylate (8). To a stirred solution of compound 6 (2.4 g, 10 mmol) in ethanol (20 mL) at room temperature was added NaBH₄ (0.38 g, 5 mmol) and stirring was continued for an additional 1 hour. The reaction mixture was treated with acetone (2 mL) and concentrated to dryness. The residue was purified by column chromatography (silica gel; hexanes:£tOAc, 70:30) to give compound 8 (1.68g, 69%) as a white solid; m.p.109 °C (cyclohexane); ¹H NMR (CDCl₃) δ 4.95 (t, 1 H, J= 7.5 Hz), 4.88 (t, 1 H, J= 6 Hz), 4.60 (t, 1 H, J= 7 Hz), 4.12- 4.24, (m, 2 H), 2.48 (d, 1 H, J= 12 Hz, OH), 2.16-2.26 (m, 1 H), 1.48-1.61 (m, 5 H), 1.32 (s, 3 H), 1.26 (t, 3 H, J= 6.5 Hz). FAB MS m/z (relative intensity) 243 (MH⁺, 100).

Ethyl (15',2i?,35',45',55)-2,3-O-(isopropyHdene)-4-hydroxybicyclo[3.1.0]- hexane-carboxylate 9. A solution of compound 8 (0.96 g, 4.0 mmol) andp- TsOH*H₂O (0.38 g, 2 mmol) in acetone (20 mL) was refluxed for 8 hours. Following the addition OfNEt₃ (2 mL), the solution was concentrated under reduced pressure. Flash column chromatography (silica gel; CHCl₃MeOH, 9:1) of the residue furnished a mixture of isomerized alcohols 8 and 9 in a 6:4 ratio based on NMR. This crude mixture was further purified by careful crystallization from cyclohexane to obtain pure 9 (0.340 g, 35%) as colorless crystals. The remaining alcohol 8 was recycled. Compound 9: ¹H NMR (CDCI₃) δ 5.38 (d, 1 H, J= 5.5 Hz), 4.42-4.64 (m, 2 H), 4.08-4.21 (m, 2 H), 2.39-2.45 (m,

2 H), 1.42-1.62 (m, 5 H), 1.35 (s, 3 H), 1.12 (t, 2 H, J= 3.2 Hz); FAB MS m/z (relative intensity) 243.1 (MH⁺, 100).

As described in Examples 1-6 representative compounds of the invention were prepared from Compound 9 as illustrated in Figure 1. Alcohol 9 was subjected to a Mitsunobu coupling conditions using variety of purine bases 10- 16 to afford the condensed products 17-22. Reduction with DIBAL-H afforded compounds 23-28. The chloro functionality was substituted with an amino group to afford compounds 29-34. The final hydrolysis of the isopropylidene group using 10% TFA in MeOH at 70 °C afforded compounds 35-40, which are compounds of formula I.

Examples 1-6

The following general procedure was used to prepare the compounds of Examples 1-6. A mixture containing an isopropylidene analog 29-34 (0.04 mmol), 10% trifluoroacetic acid /MeOH (5 mL), and H₂O (0.5 mL) was heated at 70 ⁰C for

3 hours. The solvent was removed and the residue was dried by coevaporation with toluene. The residue was purified using preparative TLC (CHCl₃:MeOH, 9:1) to afford the title compound 35-40 as a colorless solid in 62-67% ylelds.

Example 1 (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloro-purin-9-yl)-1- [hydroxymethyl]bicycIo[3.1.0]hexane-2,3-dioI 35. ¹H NMR (CD₃OD, 300 MHz) 50.71-0.78 (m, 1H), 1.50-1.64 (m, 2H), 3.85 (d, J= 6.9, Hz, 1H), 3.25 (d, J= 12, Hz, 1H), 4.75 (dd, J= 1.5, 1.5 Hz 1H), 4.76-4.79 (m, 2H), 8.49 (s, 1H). HRMS (M + I)⁺: calculated 312.0863, found 312.0871.

Example 2 (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-iodo-purin-9-yl)-1-

[hydroxymethyI]bicyclo[3.1.0]hexane-2,3-diol 36. ¹HNMR (CD₃OD, 300 MHz) S 0.72-0.78 (m, 1H), 1.51-1.62 (ra, 2H), 3.33-3.37 (m, 1H), 3.86 (d, J= 6.6, Hz, 1H), 4.25 (d, J= 13.5, Hz 1H), 4.76-4.79 (m, 2H), 8.42 (s, 1H). HRMS (M + I)⁺: calculated 404.0220, found 404.0204.

Example 3 (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-fluoro-purin-9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-diol 37. ¹HNMR (CD₃OD, 300 MHz) 50.72-0.76 (m, 1H), 1.51-1.63 (m, 2H), 3.33-3.37 (m, 1H), 3.85 (d, J= 6.9, Hz, 1H), 4.24 (d, J= 12, Hz 1H), 4.76-4.79 (m, 2H), 8.45 (s, 1H). HRMS (M + I)⁺: calculated 296.1159, found 296.1162.

Example 4 (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-methylthio-purin-9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-diol 38. ¹H NMR (CD₃OD, 300 MHz) 30.72-0.78 (m, 1H), 1.52-1.63 (m, 2H), 2.57 (s, 3H), 3.43-3.56 (m, 1H), 3.85-3.92 (m, 1H), 4.25 (d, J= 11.4, Hz, 1H), 4.76-4.79 (m, 2H), 8.41 (s, 1H). HRMS (M + I)⁺: calculated 324.1130, found 324.1120.

Example 5 (1'S,2'R,3'S,4'R,5'S)-4-(6-amino -purin-9-yI)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-diol 39. ¹H NMR (CD₃OD, 300 MHz) 50.73-0.79 (m, 1H), 1.52-1.66 (m, 2H), 3.28-3.33 (m, 1H), 3.88 (d, J= 3.6, Hz, 1H), 4.26 (d, J= 12, Hz, 1H), 4.76-4.79 (m, 2H), 8.20 (s, 1H), 8.51 (s, 1H). HRMS (M + I)⁺: calculated 278.1253, found 278.1252. Example 6 (1'S,2'R,3'S,4'R,5'S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yI)4-[hydroxymethyl]bicycIo[3.1.0]hexane-2,3-diol 40. ¹H NMR (CD₃OD, 300 MHz) S 0.66-0.74 (m, 1H), 1.48-1.58 (m, 2H)₃ 3.28-3.33 (m, 1H), 3.76 (d, J = 6.9, Hz, 1H), 4.26 (d, J= 10.8, Hz, 1H), 4.75 (d, J= 6.6, Hz, 1H), 4.97 (s, 1H), 6.57-6.58 (m, 1H), 7.45 (s, 1H), 8.12 (s, 1H). HRMS (M + I)⁺: calculated 277.1301, found 277.1283.

The starting isopropylidene analogs 29-34 used in Examples 1 -6 were prepared as follows.

Examples la-6a

The following general procedure was used for the Mitsunobu coupling reaction of nucleoside purine bases 10-16 and the sugar moiety 9.

A mixture of triphenyl phosphine (0.104 g, 0.4 mmol), and the substituted purine 10-16 (0.4 mmol) in dry THF (2 niL) was treated with diisopropylazodicarboxylate (0.080 g, 0.4 mmol) at room temperature. After 20 minutes stirring, a solution of sugar 9 (0.048 g, 0.2 mmol) in THF (1 mL) was added and the mixture was stirred further for 8 hours. Concentration and purification of the residue by column chromatography (silica gel; Ethylacetate:- Hexane, 3:1) provided nucleoside ester analogues 17-22 in 35% to 42 % ylelds.

Example Ia Ethyl (1'S,2'R,3'S,4'R,5'S)-4'-(2,6-dichloropurin-9-yl]-2',3'-O- (isopropylidene)-bicyclo[3.1.0]hexanecarboxylate 17. Compound 17 was obtained from 2,6-dichloro purine 10. ¹HNMR (CDCl₃) δ 8.09 (s, 1 H), 5.85 (d, 1 H, 6.5 Hz), 4.91 (s, 1 H), 4.72 (d, 1 H, J= 5.5 Hz), 4.05-4.38 (m, 2 H), 2.14- 2.2 (m, 1 H), 1.75-1.82 (m, 1 H), 1.52-1.62 (m, 4 H), 1.15-1.38 (m, 6 H); FAB MS m/z (relative intensity) 413.1 (MH⁺, 100).

Example 2a (1'S,2'R,3'S,4'S,5'S)-4'-[6-ChIoro-2-iodopurin-9-yI]-2',3'- isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic Acid Ethyl Ester 18.

Compound 18 was obtained from 2-iodo-6-chloro-purine 11. ¹HNMR (CDCI3, 300 MHz) 61.30-1.36 (m, 4H), 1.57 (s, 6H), 1.75-1.80 (m, 1H), 2.12-2.22 (m, 1H), 4.1-4.2 (m, 2H)₃ 4.75 (d, J= 14 Hz, 1H), 4.92 (s, 1H), 5.85 (d, J= 15 Hz, 1H), 7.98 (s, 1H). MS (m/e) (positive-FAB) 505.0 (M + I)⁺.

Example 3a (1'S,2'R,3'S,4'R,5'S-4)^I-[6-Chloro-2-fluoropuπn-9-yI]-2^l,3'- isopropylidenebicyclo[3.1.0]hexane-r-carboxylic Acid Ethyl Ester 19.

Compound 19 was obtained from 2-fluoro-6-chloiO-purine 12. ¹HNMR (CDCI3, 300 MHz) 51.23-1.36 (m, 4H), 1.55 (s, 6H), 1.76-1.82 (m, 1H), 2.42-2.46 (m, 1H), 4.14-4.28 (m, 2H), 4.73 (d, J= 10 Hz, 1H), 4.93 (s, 1H), 5.88 (d, J= 7 Hz, 1H), 8.07 (s, 1H). HRMS (M + I)⁺: calculated 397.1079, found 397.1083.

Example 4a (lW,2^3tf,4W,5^SH46-Chloro-2-methylthiopurin-9-yl]-2',3'- isopropylidenebicyclo[3.1.0]hexane-l'-carboxylic Acid Ethyl Ester 20. Compound 20 was obtained from 2-methylthio-6-chloro purine 13. ¹H NMR (CDCl₃, 300 MHz) 51.25-1.55 (m, 4H), 1.56 (s, 6H), 1.75-1.82 (m, 1H), 2.25- 2.32 (m, 1H), 2.64 (s, 3H), 4.18-4.29 (m, 2H), 4.82 (d, J= 12 Hz, 1H), 4.92 (s, 1H), 5.85 (d, J= 11 Hz, 1H), 7.90 (s, 1H). MS (m/e) (positive-FAB) 425.10 (M

+ D⁺.

Example 5a (lW,2'Λ,3'5',4W,5^l5)-4^I-{6-ChIoropurin-9-yl]-2',3'- isopropylidenebicyclo[3.1.0]hexane-l'-carboxylic Acid Ethyl Ester 21.

Compound 21 was obtained from 6-chloropurine 15. ¹HNMR (CDCl₃, 300 MHz) 51.26-1.57 (m, 4H), 1.59 (s, 6H), 1.75-1.8 (m, 1H), 2.24-2.32 (m, 1H), 4.12-4.38 (m, 2H), 4.76 (d, J= 8 Hz, 1H), 5.08 (s, 1H), 5.89 (d, J= 7 Hz, 1H), 8.10 (s, 1H), 8.71 (s, 1H). HRMS (M+ I)⁺: calculated 379.1173, found 379.1188.

Example 6a (l'_iS,2'Λ,3W,4W,5'₎S)-4'-[4-chIoro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl] ^'^'-isopropylidenebicyclo [3.1.0] hexane- 1 -car boxylic Acid Ethyl Ester 22. Compound 22 was obtained from 4-chloro-7H-pyrrolo[2,3- d]pyrimidine 16. ¹HNMR (CDCl₃, 300 MHz) 51.22-1.38 (m, 4H), 1.56 (s, 3H), 1.59 (s, 3H) 1.76-1.80 (m, 1H), 2.18-2.26 (m, 1H), 4.14-4.23 (m, 2H), 4.69 (d, J = 8 Hz, 1H), 5.05 (s, 1H), 5.83 (d, J= 8Hz, 1H), 6.64 (s, 1H), 7.15 (d, J= 3.6Hz, 1H), 8.60 (s, 1H) . HRMS (M + I)⁺: calculated 378.1221, found 378.1245. Examples 1b-6b

The following general procedure was used for the DIBAL-H reduction of esters 17-22. A stirred solution of ester 17-22 (0.5 mmol) in toluene (10 mL) was cooled to -78 ⁰C and treated dropwise with diisobutylaluminum hydride (DIBAL-H, 1 mL, 1.5 M solution in THF). After 1 hour, methanol (1.5 mL) and 1 M cold sulfuric acid (10 ml) (pH = 4), were added carefully. The reaction mixture was filtered through a pad of Celite and the filtrate was collected, separated, and the aqueous phase was extracted with dichloromethane. The combined organic layer was evaporated and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (CHCl₃ :MeOH, 10:1) to give the corresponding alcohols 23-28 in 35 to 56 % ylelds.

Example Ib (1'S,2'R,3'S,4'R,5'S)-4-(2,6-dichIoro-purin-9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidine) 23. ¹H NMR (CDCl₃, 300 MHz) 51.05-1.08 (m, 1H), 1.21-138 (m, 7H), 1.70-1.74 (m, 1H), 3.52(d, J= 12Hz, 1H), 4.21-4.27 (m, 1H), 4.63 (d, J= 7.5Hz, 1H), 4.96 (s, 1H), 5.51 (d, J= 12Hz, 1H), 8.32 (s, 1H). HRMS (M + I)⁺: calculated 371.0678, found 371.0669.

Example 2b (1'S,2'R,3'S,4'R,5'S)-4-(6-chloro-2-iodo-purin-9-yI)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidine) 24. ¹H NMR (CDCl₃, 300 MHz) 51.02-1.05 (m, 1H), 1.21-42 (m, 7H), 1.66-1.71 (m, 1H), 3.60 (d, J= 12Hz, 1H), 4.16(d, J= 12Hz, 1H), 4.65(d, J= 7.2Hz, 1H), 4.97 (s, 1H), 5.47 (d, J= 7.5Hz, 1H), 8.28 (s, 1H). HRMS (M + I)⁺: calculated 463.0034, found 463.0021.

Example 3b (1'S,2'R,3'S,4'R,5'S)-4-(6-chIoro-2-fluoro-purin-9-yl)-1- [hydroxymethyl]bicycIo[3.1.0]hexane-2,3-(O-isopropylidine) 25. ¹H NMR (CDCl₃, 300 MHz) 51.01-1.09 (m, 2H), 1.25 (s, 6H), 1.66-1.74 (m, 1H), 3.50 (d, J= 11Hz, 1H), 4.18-4.23(m, 1H), 4.62(d, J= 4.8Hz, 1H), 4.95 (s, 1H), 5.48 (dd, J= 1.5, 1.6Hz, 1H), 8.35 (s, 1H). HRMS (M + I)⁺: calculated 355.0973, found 355.0971.

Example 4b (1'S,2'R,3'S,4'R,5'S)-4-(6-chIoro-2-methythio-purin-9-yl)-1- [hydroxymethyI]bicycIo[3.1.0]hexane-2,3-(O-isopropyIidine) 26. HRMS (M + I)⁺: calculated 383.0945, found 383.0958.

Example 5b (1'S,2'R,3'S,4'R,5'S)-4-(6-chloropurin-9-yl)-l- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropyIidine) 27. HRMS (M + I)⁺: calculated 337.1067, found 337.1069.

Example 6b (1'S,2'R,3'S,4'R,5'S)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidiπ- 7-yI)-1-[hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropyIidine) 28.

HRMS (M + I)⁺: calculated 336.1115, found 336.1115.

Examples 1c-6c

The following general procedures were used to convert the chloro group in analogs 23-28 to the corresponding amine. The chloro analog was added to a 20 fold excess of 2M NH₃ in THF and the resulting mixture was stirred at room temperature for 16 hours. Alternatively, the chloro analog was added to a 20 fold excess of saturated aminonia in ethanol and the resulting mixture was stirred at 95 °C under pressure in a sealed vessel for 16 hours. Using the above procedures compounds 29-34 were obtained in 60 to 65 % ylelds.

Example 1c (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-chloro-purin-9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropyIidine) 29. HRMS

(M + I)⁺: calculated 352.1176, found 353.1163.

Example 2c (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-iodo-purin~9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropyIidine) 30. HRMS (M + I)⁺: calculated 444.0533, found 444.0522 Example 3c (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-fluoro-purin-9-yl)-1- [hydroxymethyI]bicycIo[3.1.0]hexane-2,3-(O-isopropylidine) 31. HRMS

(M + I)⁺: calculated 336.1472, found 336.1474.

Example 4c (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-2-methyIthiopurine-9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidine) 32. ¹H NMR (CDCI₃, 300 MHz) 50.94-0.99 (m, 1H), 1.13-1.17 (m, 1H), 1.28 (s, 3H), 1.55 (s, 3H), 1.67-1.71 (m, 1H), 2.59 (s, 3H), 3.33 (dd, J= 2.1, 2.1 Hz, 1H), 3.86 (dd, J= 2.4, 2.4 Hz, 1H), 4.22-4.26 (m, 1H), 4.71-4.75 (m, 2H), 5.55-5.61 (m, 2H), 7.72 (s, 1H). HRMS (M + I)⁺: calculated 364.1443, found 364.1447.

Example 5c (1'S,2'R,3'S,4'R,5'S)-4~(6-amino-purine-9-yl)-1- [hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidine) 33. ¹H NMR (CD₃OD, 300 MHz) 50.95-1.10 (m, 1H), 1.14-1.19 (m, 1H), 1.24 (s, 3H), 1.51 (s, 3H), 1.67-1.78 (m, 1H), 3.44 (d, J= 5.7 Hz, 1H), 4.06 (d, J= 11 Hz, 1H), 4.66 (d, J= 4.2 Hz, 1H), 5.02 (s, 1H), 5.40 (d, J= 7.2 Hz, 1H), 8.19 (s, 1H), 8.31 (s, 1H). HRMS (M + I)⁺: calculated 318.1566, found 318.1575.

Example 6c (1'S,2'R,3'S,4'R,5'S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrJmidin- 7-yl)-1-[hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidine) 34. HRMS (M + I)⁺: calculated 317.1614, found 317.1615.

Example 7 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I or II ('Compound X'), for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet

Compound X= 100.0

Lactose 77.5

Povidone 15.0

Croscarmellose sodium 12.0

Microcrystalline cellulose 92.5

Magnesium stearate 3.0

300.0 (if) Tablet 2 ma/tablet

Compound X= 20.0

Microcrystalline cellulose 410.0

Starch 50.0

Sodium starch glycolate 15.0

Magnesium stearate

500.0

(WY) Capsule mg/capsule

Compound X= 10.0

Colloidal silicon dioxide 1.5

Lactose 465.5

Pregelatinized starch 120.0

Magnesium stearate 3.0

600.0

Civ) Injection 1 (I mg/ml) mg/ml

Compound X= (free acid form) 1.0

Dibasic sodium phosphate 12.0

Monobasic sodium phosphate 0.7

Sodium chloride 4.5

1.0 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) q.s.

Water for injection q.s. ad 1 mL

Cv) Iniection 2 (^"10 mg/ml) mg/ml

Compound X= (free acid form) 10.0

Monobasic sodium phosphate 0.3

Dibasic sodium phosphate 1.1

Polyethylene glycol 400 200.0

01 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) q.s.

Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can

Compound X= 20.0

Oleic acid 10.0

Trichloromonofluoromethane 5,000.0

Dichlorodifluoromethane 10,000.0

Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents cited hereinabove are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

ClaimsWe claim:

1. A compound of formula I or II:

wherein:

R₁ is H, halo, OR_a, SR_a, or NR_bR_c;

R₂ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; R₃ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₄ is H, halo, azido, cyano, nitro, OR_a, SR_a, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₃ and R₄ taken together are =O, =NR_d, =CR_fR_g; or R₃ and R₄ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -O-, -S-, or -NRa-;

R₅ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₆ is H, halo, azido, cyano, nitro, OR_a, SR₃, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₅ and R₆ taken together are =O, =NR_d, =CR_fR_g; or R₅ and R₆ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -O-, -S-, or -NR_a-; R₇ and R₈ are each independently H or halo;

R₉ is a nucleoside base;

R₁₀ is OH, -OP(=O)(OH)₂, -OP(=O)(OH)-P(=O)(OH)₂, -OP(=O)(OH)-P(-O)(OH)-P(=O)(OH)₂, or a phosphonate; each R_a is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_b and R_c is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_d is independently H, (C₁-C₆)alkyl, or OH; each R_e is independently H or (C₁-C₆)alkyl; and each R_f and R_g is independently H, (C₁-C₆)alkyl, or halo; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl of R₂-R₆ and R_a-R_g is optionally substituted with one or more halo, hydroxy, or (C₁- C₆)alkoxy; or a pharmaceutically acceptable salt or prodrug thereof; provided the compound is not (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-purin-9- yl)-1-[hydroxymethyljbicyclo[3.1.0]hexane-2,3-diol; and provided the compound is not (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-9H-purin- 9-yl)-1-[phosphoryloxymethyl]bi-cyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H- purin-9-yl)-1-[phosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol; 5-(6-amino- 9H-purin-9-yl)-1-[hydoxymethyl]bicyclo[3.1.0]hexane-2,3-diol; (1'S,2'R,3'S,4'R,5'S)-4-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl]bi- cyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H-purin-9-yl)-1- [triphosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol; (1'S,2'R,3'S,4'R,5'S)-4- (2,4(H,3H)-dioxopyrimidin-1-yl)-1-(phosphoryloxymethyl)bi- cyclo[3.1.0]hexane-2,3-diol; (1'S,2'R,3'S,4'R,5'S)-4-(2,4(H,3H)-dioxopyrimidin- 1-yl)-1- (diphosphoryloxymethyl)bicyclo[3.1.0]hexane-2,3-diol; or (1'S,2'R,3'S,4'R,5'S)-4-(2,4(Η,3Η)-dioxopyrimidin-1-yl)-1- (triphosphoryloxymethyl)bicyclo[3.1.0]hexane-2,3-diol.

2. The compound of claim 1 wherein Ri is H; R₂ is H; R₃ is H; R₄ is H or OH; R₅ is H; and R₆ is OH.

3. The compound of claim 1 wherein R₇ and R₈ are each H.

4. The compound of claim 1 wherein R₉ is a heterocycle or a substituted heterocycle.

5. The compound of claim 1 wherein R₉ has the following formula:

wherein:

R₂₀ is OH or (C₁-C₆)alkoxy that is optionally substituted with one or more R₂₂; and R_2] is H or (C₁-C₆)alkyl that is optionally substituted with one or more R₂₂; or R₂₀ and R₂i together with the nitrogen to which they are attached form a heterocyclic ring that is optionally substituted with one or more R₂₂; each R₂₂ is independently (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR₂₃R₂₄, -C(=O)NR₂3R24, aryl, heteroaryl, cyano, halo, hydroxy, nitro, carboxy, or (C3- Cs)cycloalkyl; R₂₃ and R₂₄ are each independently H, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl; wherein each aryl or heteroaryl OfR₂₂ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR₂₃R₂₄, -C(=O)NR₂₃R₂₄, cyano, halo, hydroxy, nitro, carboxy, (C₃-Cs)cycloalkyl, trifluoromethoxy, mercapto, or trifluoromethyl; and

A, B, D, F, and E are each independently >N or >C-R₂s; each R₂5 is independently H, cyano, nitro, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, -NHCONH₂, C(=O)NR₂₆R₂₇, COOR₂₈, hydroxy, (C₁-C₆)alkoxy, -NR₂₆R₂₇, halo, l,3-oxazol-2-yl, l,3-oxazol-5-yl, l,3-thiazol-2-yl, imidazol-2-yl, 2-oxo-[l, 3]dithiol-4-yl, furan-2-yl, or 2H-[1,2,3]triazol-4-yl; each R₂6 and R₂₇ is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, (C₃-Cs)cycloalkyl, aryl, heterocycle, hydroxy, or (C₁-C₆)alkoxy; or R₂₆ and R₂₇ together with the nitrogen to which they are attached form a heterocycle; and each R₂₈ is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, (C₃-C g)cycloalkyl, aryl, or heterocycle; wherein each (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₃- C₈)cycloall<yl, aryl, heterocycle, and (C₁-C₆)alkoxy of R₂₆ and R₂₇ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁- C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NH₂, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₆)cycloalkyl, (C₃-Cs)cycloalkoxy, trifluoromethoxy, or mercapto.

6. The compound of claim 5 wherein R₂₀ is OH, methoxy, or propoxy; and R21 is H.

7. The compound of claim 5 wherein R₂0 and R₂; together with the nitrogen to which they are attached form a pyrrolidin-1-yl, 1,3,4,9-tetrahydro-beta- carbolin-2-yl, piperidinyl, azetidinyl, 3,6-dihydro-2H-pyridin-1-yl, or 3,4- dihydro-lH-isoquinolin-2-yl ring, which ring is optionally substituted with -C(=O)NH₂.

8. The compound of claim 1 wherein R₉ has the following formula:

wherein: R₃₀ is -C≡ CR₃₁, -CH=CHR₃₂, formyl, -CH=NHNR₃₃, -CH=N(OR₃₃),

-CH(OR₃₄X Or -B(OR₃₃);

R3₁ is tri(C₁-C₆)alkylsilyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, heteroaryl, aryl, Carboxy, or (C₁-C₆)alkoxycarbonyl;

R₃₂ is hydrogen or cis-(Cι-C(s)alkoxy; R₃₃ is H or (C₁-C₆)alkyl; and

R3₄ is (C₁-C₆)alkyl; wherein each aryl or heteroaryl of R₃₁ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-

C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR35R36, -C(=O)NR₃5R36, cyano, halo, hydroxy, nitro, carboxy, (C₃-C8)cycloalkyl, (C₃-C₆)cycloalkoxy, guanidino, trifluoromethoxy, mercapto, -S(=O)_mR₃₇, or trifluoromethyl; m is 0, 1, or 2;

R.₃₅ and R₃₆ are each independently H, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl; R₃₇ is (C₁-C₆)alkyl, aryl, hetrocycle, or NR38R39; and

R38 and R₃₉ are each independently H, (C₁-C₆)alkyl or (C₁-C₆)alkanoyl; wherein each aryl or heterocycle OfR₃₇ is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, NR3₅R₃6, -C(=O)NR₃5R3₆, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₆)cycloalkyl, (C₃-C₈)cycloalkoxy, guanidino, trifluoromethoxy, mercapto, or trifluoromethyl.

9. The compound of claim 8 wherein R₃₀ is 2-trimethylsilylethynyl, 2-(2- pyridyl)ethynyl, 2-(4-pyridyl)ethynyl, 2-(4-methoxy)ethynyl, 2-(aminocarbonyl)ethynyl, 3,3-diethoxypropyn-1-yl,

2-(dimethylaminocarbonyl)ethynyl, 2-(N-amino(aminocarbonyl)ethynyl, 2-carboxyethynyl, 2-ethoxycarbonylethyiiyl, 2-methoxycarbonylethynyl, 2-phenylethynyl, 2-(4-fluorophenyl)ethynyl, 2-(4-methylphenyl)ethynyl, vinyl, 2-methoxyvinyl, formyl, -CH=N-NH₂, -CH=NOH, 1,1-diisopropoxymethyl, or -B(OH)₂.

10. The compound of claim 1 wherein R₉ has one of the the following formulae:

wherein:

R₄₀ is H, NR4_aR_4b, NHC(=O)R_4b, (C₁-C₆)alkylNR_4aR_4b, NHNH₂, cyano, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl(C₁-C₆)alkyl, heterocycle(C₁- C₆)alkyl, halo, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, hydroxy, or mercapto; R₄₁ is H, (C₁-C₆)alkyl, hydroxy (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂- C₆)alkynyl, heterocycle, aryl, or aryl(C₁-C₆)alkyl; each R₄₂ is independently H, hydroxy, mercapto, cyano, -SNR_4cR_4d, -C(NH)NR_4cR_4d, -C(=NH)NHOH, -C(NH)NHO_4c, -C(=NH)NHNR_4cR_4d, NHCOR_4c, SR_4c, OR_4c, SOR_4c, SO₂R_4c, -Ct=O)NR_4cR_4d, -C(=S)NR_4cR_4d, or R_4c;

R₄₃ is H, hydroxy, NR_4cR_4d, NHC(=O)NR_4c, NHNHR_4c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, heterocycle, aryl, aryl(C₁-C₆)alkyl, halo, COOR_4c, CONR_4cR_4c, or absent when Y is N;

R₄₃ and R_4b are each independently hydrogen, (C₁-C₆)alkyl, (C₂- C₆)alkenyl, (C₂-C₆)alkynyl, heterocycle, or aryl; R_4c, and R_4d are each independently hydrogen, (C₁-C₆)alkyl, (C₁- C₆)alkenyl, (C₂-C₆)alkynyl, heterocycle, or aryl;

X, Y, and W are each independently N, C, CR_4c, S or P;

R₄₄ is H, hydroxy, mercapto, cyano, -SNR_4cR_4d, -C(NH)NR_4cR_4d, -C(=NH)NHOH, -C(NH)NHOR_4c, -C(=NH)NHNR_4cR_4C NHCOR_4c, SR_4c, OR_4c, SOR_4c, SO₂R_4c, -C(=O)NR_4cR_4d, -C(=S)NR_4cR_4d, or R_4c;

R₄₅ is H, hydroxy, mercapto, cyano, -SNR_4cR_4d, -C(NH)NR_4cR_4d, -C(=NH)NHOH, -C(NH)NHO_4c, -C(=NH)NHNR_4cR_4d, NHCOR_4c, SR_4c, OR_4c, SOR_4c, SO₂R_4c, -C(=O)NR_4cR_4d, -C(=S)NR_4cR_4d, or R_4c;

R₄₆, and R₄₇ together with the atoms to which they are attached form a heterocyclic ring; and

U is S or O; wherein each aryl or heterocycle is optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁- C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₆)cycloalkyl, (C₃-C₈)cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl.

11. The compound of claim 1 wherein R₉ has one of the following formulae:

wherein:

R₅₀ is NR_5aR_5b, ONR_5aR_5b, NR_5aNR_5aR_5b, SR_5b, OR_5b, H, hydroxy, (C₁- C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl; Rsi is (C₁-C₆)alkyl, (C₁-C₆)aIkanoyl, or aryl; R₅₃ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl; R₅₃ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl;

R₅₄ is H or NH₂;

R₅₅ is NR_5aR_5b, ONR_5aR_5b, NR_5aNR_5aR_5b, SR_5b, OR_5b, H, hydroxy, (C₁- C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl;

R₅₆ is H, halo, (C₁-C₆)alkyl, or (C₁-C₆)alkenyl; R₅₇ and R₅₈ are each independently -L-R_5c; each L is independently a direct bond, -N(R_5a)-, O or S; each R_5a and R_5b is independently H, hydroxy, (C₁-C₆)alkyl, (C₁- C₆)alkenyl, (C₁-C₆)alkynyl, or aryl; and each R_5c is NR_5aR_5b, H, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, or aryl; wherein each (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or aryl of R₅₀-R₅₈ and R_5a-R_5c is optionally substituted with one or more (C₁-C₆)alkyl, (C₁- C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁- C₆)alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C₃-C₈)cycloalkyl, (C₃- C8)cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl.

12. The compound of claim 1 wherein R₉ has one of the the following formulae:

wherein:

X₂, X₃, and X₄ are each independently N, CH, or C-R_6a;

R₆₀, R₆₁, and R_6a are each independently H, halo, NR_6b R_6c, hydroxyamino, NR_6bNR_6bR_6c, N₃, NO, NO₂, formyl, cyano, -C(=O)NR_6b R_6c, -C(=S)NR_6b R_6c, -C(=O)OR_6b, R_6b, OR_6b, or SR_6b; and R_6b, and R_6c are each independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl.

13. The compound of claim 1 wherein R₉ has the following formula:

wherein:

Xs₁ X₆, and X₇, are each independently N, CH, or C-R_7a;

R_7O and R_7a are each independently H, halo, NR_7bR_7c, hydroxyamino, NR₇bNR₇bR7c, N₃, NO, NO₂, formyl, cyano, -C(=O)NR_7bR_7c, -C(=S)NR_7bR_7c, -C(=O)OR_7b, R?b, OR_7b, or SR_7b; and

R_7b, and R₇₀ are each independently H, (C₁-C₆)all<yl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl.

14. The compound of claim 1 wherein R₉ has the following formula:

wherein:

Y₁=Y₂ is -N=N-, -CH=N-, -N=CR_8a-, or -CH=CR₈₃-; and each R_8a is independently H, halo, or (C₁-C₆)alkyl.

15. The compound of claim 1 wherein R₉ has one of the following formulae:

wherein: each Zi is independently N, C-R_9a, O, S, NR_9b, >C=O, >C=S, >C=NR₉b, >S=O, >S(O)₂ or CH-R_9a; provided that if a Zi participates in an optional bond represented by a dotted line — in the formula, then that Zi is N or C-R_9a; and provided that if a Zi does not participate in an optional bond represented by a dotted line — in the formula, then that Zi is O, S, NR_%, >C=O, >C=S, >C=NR_9b, >S=O, >S(O)₂ or CH-R_9a; X₅ is O, S, SO, SO₂; Se, SeO, SeO₂ or NR%; each Wi is C, CH, or N; wherein if a Wi participates in an optional bond represented by a dotted line — in the formula, then that Wi is C; and if a Wi does not participate in an optional bond represented by a dotted line — in the formula, then that Wi is CH, or TSI; each R_9a is independently H, halo, NR₉₀R₉₁J, hydroxyamino,

NR_9cNR_9cR9d, N₃, cyano, -C(=O)NR_9cR_9d, -C(=S)NR_9cR9d, -C(=S)NR_9cR9d, -C(=NH)0R_9c, R₉₀, OR₉₀, or SR_9c; each R₉b is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (Cr C₆)a]kynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl; and R_9c, and R₉d are each independently H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, aryl, (C₁-C₆)alkanoyl, or aryl(C₁-C₆)alkyl.

16. The compound of claim 1 wherein R₉ has one of the following formulae:

wherein:

Rg₇ is H, hydroxy, mercapto., (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₂- C₆)alkenyl, (C₃-C₈)cycloalkyl, aryl(C₁-C₆)alkyl, aryl or (C₂-C₆)alkynyl

R₉8 is H, hydroxy, mercapto, or (C₁-C₆)alkyl; R₉₉ is H, halo, azido, cyano, nitro, OR_99a, SR_99a, NR_99bR_99C, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₈)cycloalkyl, aryl(C₁-C₆)alkyl, aryl or (C₂-C₆)alkynyl; each R_99a is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_99b and R₉₉₀ is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₁-C₆)alkoxy (C₁-C₆)alkenyl, (C₁- C₆)alkynyl, (C₃-C₆)cycloalkyl, aryl, and aryl(C₁-C₆)alkyl of R₉₇, R₉₈, R₉₉ , R_99a, R_99b, and R_99C, is optionally substituted with one or more (C₁-C₆)alkyl, (C₁- C₆)alkylthio, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (d- C₆)alkoxycarbonyl, NH₂, cyano, halo, azido, hydroxy, nitro, carboxy, trifluoromethoxy, aryl, or mercapto.

17. The compound of claim 1 wherein R₉ has the following formula:

wherein: X₄ is CR₉O_a or N;

X₅ is O, S, or NR₉i_a ; Rgo and R₉₁ are each independently H, halo, hydroxy, (C₁-C₆)alkoxy, NRgobRgibj or heterocycle;

R9o_a is H, halo, methyl, azido, or amino;

Rgia is H, or (C₁-C₆)alkyl; and Rgob and Rgib are each independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or aryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl, (C₃-C8)cycloalkyl, aryl(C₁-C₆)alkyl, and heterocycle of R90-R91, R9i_a, and Rgob-R9ib are optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo, hydroxy, amino, (C₁-C₆)alkyl, and (C₁-C₆)alkoxy.

18 The compound of claim 1 wherein R₉ has the following formula:

wherein:

X₆ is O, S, or NR_70a; R₇o and R₇₁ are each independently H, halo, hydroxy, mercapto, aryl, heterocycle, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)alkylthio, arylthio, -S(=O)(C₁-C₆)alkyl, -SC=O)₂(C₁ -C₆)alkyl, -S(=O)₂NR_70bR₇ib, NR₇ObR₇₁b, (C₁-C₆)alkoxy, aryloxy, (heterocycle)oxy;

R₇Oa is H, methyl, ethyl, or acetyl; and R₇Ob and R₇Ib are each independently H, (C₁-C₆)alkyl, aryl, aryl(Cr C₆)alkyl, (C₁-C₆)alkanoyl, or aryl-C(=O)-;

19. The compound of claim 1 wherein R₉ has one of the following formulae:

wherein:

A₈O, B₈₀, and Y₈₀, are each independently H, halo, OR₈₀, S(O)_nR₈O, NR₈₀R₈₁, cyano, trifluoromethyl, C(=W)OR₈₀, C(=W)SR₈₀, C(=W)NR₈₀ R₈₁, nitro, azido, carbocyclic, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, aryl, aryl(C₁-C₆)alkyl, or heterocycle; or A₈₀ and B₈₀ taken together with the carbon atoms to which they are attached from a 4-7 membered carbocyclic or heterocyclic ring; n is 0, 1, or 2

Z₈₀ is O, S, NRs₀, or CR_S0R_8!; each V is independently N or CR₈₀; and each R₈₀ and R₈₁ is independently H, carbocycle, (C₁-C₆^IlCyI, (C₁- C₆)alkenyl, (C₁-C₆)alkynyl, halo, (CVC₆)alkoxy, amino, methylamino, dimethylamino, cyano, (C₁-C₆)alkanoyl, aryl, aryl(C₁-C₆)alkyl, an amino acid residue (e.g. a natural amino acid residue) or heterocycle; or Rso and Rsi taken together with the atom(s) to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring.

20. The compound of claim 1 wherein R₉ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8- azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2- amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouraciL O^-methylguanine, N^-methyladeniiie, (9⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, or pyrazolo[3,4- Djpyrimidine.

21. A prodrug of a compound of claim 1 werein Ri ₀ is OH, or -OP(=O)(OH)₂.

22. A pharmaceutical composition comprising a pharmaceutical excipient and a compound of formula I or II:

wherein:

Ri is H, halo, OR_a, SR_a, or ΝR_bR_c;

R₂ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; R₃ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₄ is

H, halo, azido, cyano, nitro, OR₃, SR_a, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₃ and R₄ taken together are =O, =NR_dR_e, =CR_fR_g; or R₃ and R₄ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -0-, -S-, or -NRa-; R₅ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₆ is

H, halo, azido, cyano, nitro, OR_a, SR_a, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R5 and R₆ taken together are =O, =NR_dR_e, =CR_fR_g; or R₅ and Re taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -O-, -S-, or -NR_a-;

R₇ and Rg are each independently H or halo; R₉ is a nucleoside base;

Rio is OH, -OP(=O)(OH)₂, -OP(=O)(OH)-P(=O)(OH)₂, -OP(=O)(OH)-P(=O)(OH)-P(=O)(OH)₂, or a phosphonate; each R₃ is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_b and R_c is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_d is independently H, (C₁-C₆)alkyl, or OH; each R_e is independently H or (C₁-C₆)alkyl; and each R_f and R_g is independently H, (C₁-C₆)alkyl, or halo; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl of R₂-R₅ and R_a-R_g is optionally substituted with one or more halo, hydroxy, or (C₁- C₆)alkoxy; or a pharmaceutically acceptable salt or prodrug thereof; provided the compound is not (l'S,2'i?,3'S,4'i?,5'S)-4-(6-amino-9H-purin- 9-yl)-1-[phosphoryloxymethyl]bi-cyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H- purin-9-yl)-1-[phosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol; 5-(6-amino- 9H-purin-9-yl)-1-[hydoxymethyl]bicyclo[3.1.0]hexane-2,3-diol; (lW,2'i?,3'<S',4'i?,5^I6}-4-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl]bi- cyclo[3.1.0]hexane-2,3-diol; 5-(6-amino-9H-purin-9-yl)-l - [triphosphoryloxymethyηbicyclo^.l.OJhexane^^-diol^lW^^S'.S'^'^S'.S)^- (2,4(H,3H)-dioxopyrimidin-1-yl)-1-(phosphoryloxymethyl)bi- cyclo[3.1.0]hexane-2,3-diol; (lW,2'i?,3'5^l,4^ti?,5'»S)-4-(2,4(H,3H)-dioxopyrimidin- l-yl)-1- (diphosphoryloxymethyl)bicyclo[3.1.0]hexane-2,3-diol; or (lW,2y?,3W,47?,5\S)-4-(2,4(H,3H)-dioxopyrimidin~l-yl)-1- (triphosphoryloxymethyl)bicyclo[3.1.0]hexane-2,3-diol.

23. A pharmaceutical composition comprising a pharmaceutical excipient and a compound, salt, or prodrug as descrobed in any one of claims 1-22.

24. A method for treating a viral infection in an animal comprising administering to the animal an effective anti-viral amount of a compound of formula I or II:

wherein:

Ri is H, halo, OR_a, SR_a, or NR_bR_c;

R₂ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₁-C₆)alkynyl;

R₃ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₄ is H, halo, azido, cyano, nitro, OR_a, SR_a, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₃ and R₄ taken together are =O, ^NR_dR_e, -CR_fR_g; or R₃ and R₄ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -0-, -S-, or -NRa-;

R₅ is H, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and R₆ is H, halo, azido, cyano, nitro, OR₃, SR₃, NR_bR_c, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R5 and R₆ taken together are =O, =NR_dR_e, =€RfR_g; or R₅ and Rδ taken together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring wherein one carbon atom can optionally be replaced with -Q-, -S-, or -NRaS

R₇ and Re are each independently H or halo;

R₉ is a nucleoside base; R₁₀ is OH, -OP(=O)(OH)₂, -OPC=O)(OH)-PC=O)(OH)₂, -0P(=O)(OH)-P(=O)(OH)-P(=O)(OH)₂, or a phosphonate; each R_a is independently H, (Cι-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_b and R_c is independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; each R_d is independently H, (C₁-C₆)alkyl, or OH; each R_e is independently H or (C₁-C₆)alkyl; and each R_f and R_g is independently H, (C₁-C₆)alkyl, or halo; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl OfR₂-Rs and Ra-Rg is optionally substituted with one or more halo, hydroxy, or (Cj- C₆)alkoxy; or a pharmaceutically acceptable salt or prodrug thereof.

25. The method of claim 24 wherein the viral infection is Hepatitis C.

26. The use of a compound as described in any one of claims 1-22 in medical therapy.

27. The use of a compound as described in claim 26 to prepare a medicament useful for treating a viral infection in an animal.

28. The use of claim 27 wherein the viral infection is Hepatitis C.