WO2010036407A2 - Antiviral nucleoside analogs - Google Patents

Abstract

The invention provides compounds as described herein, as well as pharmaceutical compositions comprising the compounds, and synthetic methods and intermediates that are useful for preparing the compounds. The compounds are useful as anti-viral agents and/or as anti-cancer agents.

Description

ANTIVIRAL NUCLEOSIDE ANALOGS

Cross-reference to Related Application (s)

This patent application claims the benefit of priority of the following application, which application is herein incorporated by reference: U.S. application serial No. 61/053,488, filed May 15, 2008.

Background

Viral diseases are a major cause of death and economic loss in the world. The Flaviviridae family of viruses includes the three genera flaviviruses (including dengue, West Nile, and yellow fever viruses), hepacivirus (including hepatitus C virus (HCV)), and pesti viruses (including bovine viral diarrhea virus, BVDV). The disease states and conditions caused by members of this family include yellow fever, dengue, Japanese encephalitis, St. Louis encephalitis, Hepatitis B and C, West Nile disease, and AIDS. Currently, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are responsible for the largest number of viral related deaths worldwide. Although there are some drugs useful for treating HIV, there are only a few drugs useful for treating HBV, and no drugs that are broadly useful for treating HCV. Ribavirin (l-β-D-ribofuranosyl-l-l,2,4-triazole-3-carboxamide) is a synthetic, non-interferon-inducing, broad spectrum antiviral nucleoside. Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses including Flaviviridae (Davis. Gastroenterology 118:S1O4-S114, 2000). Ribavirin reduces serum amino transferase levels to normal in 40% of patients, but it does not lower serum levels of HCV-RNA (Davis. Gastroenterology 118:S104-S114, 2000). Thus, ribavirin alone is not effective in reducing viral RNA levels. Additionally, ribavirin has significant toxicity and is known to induce anemia.

Interferons (IFNs) are compounds which have been commercially available for the treatment of chronic hepatitis for nearly a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, including HCV. When used as the sole treatment for hepatitis C infection, IFN suppresses serum HCV-RNA to undetectable levels. Additionally, IFN normalizes serum amino transferase levels. Unfortunately, the effects of IFN are temporary and a sustained response occurs in only 8%-9% of patients chronically infected with HCV (Davis. Gastroenterology 118:S104-Sl 14, 2000). HCV is a positive stranded ss RNA virus with a well characterized RNA- dependent RNA polymerase (RdRp) and a well characterized disease progression. HCV has infected an estimated 170 million people worldwide, leading to a major health crisis as a result of the disease. Indeed, during the next few years the number of deaths from HCV-related liver disease and hepatocellular carcinoma may overtake those caused by AIDS. Egypt is the hardest hit country in the world, with 23% of the population estimated to be carrying the virus; whereas, in the USA the prevalence of chronic infections has recently been determined to be around 1.87% (2.7 million persons). HCV infections become chronic in about 50% of cases. Of these, about 20% develop liver cirrhosis that can lead to liver failure, including hepatocellular carcinoma.

The NS5B region of HCV encodes a 65 KDa RdRp thought to be responsible for viral genome replication. RdRps function as the catalytic subunit of the viral replicase required for the replication of all positive-strand viruses. The NS5B protein has been well characterized, shown to possess the conserved GDD motif of RdRps and in vitro assay systems have been reported. Cellular localization studies revealed that NS5B is membrane-associated in the endoplasmic reticulum like NS5A, suggesting that those two proteins may remain associated with one another after proteolytic processing. Additional evidence suggests that NS3, NS4A and NS5B interact with each other to form a complex that functions as part of the replication machinery of HCV.

The X-ray crystal structure of NS 5 B apoenzyme has been determined and three recent publications describe the unusual shape of the molecule. This unique shape for a polymerase, resembling a flat sphere, is attributed to extensive interactions between the fingers and thumb subdomains in such a way that the active site is completely encircled, forming a cavity 15 A across and 20 A deep. Modeling studies showed that the NS5B apoenzyme can accommodate the template-primer without large movement of the subdomains, suggesting that the structure is preserved during the polymerization reaction. The RdRp polypeptides from various members of the Flaviviridae family and other viral families have been shown to be conserved (J. A. Bruenn, Nucleic Acids Research, Vol. 19, No. 2 p. 217, 1991).

Currently, there are no safe and effective therapeutic agents on the market that target HCV polymerase. There is currently a need for therapeutic agents and therapeutic methods that are useful for treating viral infections, such as HCV, HIV, and HBV.

In addition, there is also a current need for therapeutic agents and therapeutic methods that are useful for treating cancer. Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. It has been reported that cancer is the cause of death of up to one of every four Americans. Notwithstanding the advances in treatments for cancer and other diseases there is still a need for novel drugs that are effective to treat cancer.

Summary of Certain Embodiments

Certain embodiments of the present invention provide compounds that are inhibitors of viral RNA and DNA polymerases (e.g., polymerases from hepatitis B, hepatitis C, human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile virus) and that are useful for treating HCV, as well as other viral infections (e.g., flaviviral infections), and cancer. Accordingly, certain embodiments of the present invention provide a novel compound of Formula I to III as described here below, or a pharmaceutically acceptable salt or prodrug thereof.

Certain embodiments of the present invention provide a pharmaceutical composition comprising a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. The composition can optionally comprise one or more additional anti-viral or anti-cancer agents.

Certain embodiments of the present invention provide a method for treating a viral infection in an animal comprising administering to the animal an effective amount of a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof.

Certain embodiments of the present invention provide a method for inhibiting a viral RNA or DNA polymerase comprising contacting the polymerase (in vitro or in vivo) with an effective inhibitory amount of a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof.

Certain embodiments of the present invention provide a method for treating cancer in an animal comprising administering to the animal an effective amount of a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof.

Certain embodiments of the present invention provide a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof, for use in medical therapy (e.g., for use in treating a viral infection or for use in treating cancer).

Certain embodiments of the present invention provide the use of a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof, to prepare a medicament useful for treating a viral infection in an animal (e.g., a human). Certain embodiments of the present invention provide the use of a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof, to prepare a medicament useful for treating cancer in an animal (e.g., a human).

Certain embodiments of the present invention provide a compound of the invention for use in therapy.

Certain embodiments of the present invention provide a compound of the invention for treating a viral infection.

Certain embodiments of the present invention provide a compound of the invention for treating cancer. Certain embodiments of the present invention provide novel synthetic intermediates and synthetic methods that are disclosed herein as being useful for preparing compounds of Formula I to III, or a salt or prodrug thereof. Some compounds of Formula I to III may be useful as synthetic intermediates for preparing other compounds of Formula I to III. Certain embodiments of the present invention provide a compound as described herein for use in medical treatment or diagnosis.

Certain embodiments of the present invention provide the use of a compound as described herein to prepare a medicament useful for treating a viral infection in an animal. Certain embodiments of the invention provide the use of a compound as described herein to prepare a medicament useful for treating cancer in an animal.

Certain embodiments of the invention provide a compound as described herein for use in therapy. Certain embodiments of the invention provide the use of a compound as described herein for treating a viral infection in an animal.

Certain embodiments of the invention provide the use of a compound as described herein for treating cancer in an animal.

Detailed Description Definitions

The term "pharmaceutically acceptable salt" as used herein refers to a compound of the present disclosure derived from pharmaceutically acceptable bases, inorganic or organic acids. Examples of suitable acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic, trifluoroacetic and benzenesulfonic acids. Salts derived from appropriate bases include, but are not limited to, alkali such as sodium and ammonia. Te terms "treat", "treating" and "treatment" as used herein include administering a compound prior to the onset of clinical symptoms of a disease state/condition so as to prevent any symptom, as well as administering a compound after the onset of clinical symptoms of a disease state/condition so as to reduce or eliminate any symptom, aspect or characteristic of the disease state/condition. Such treating need not be absolute to be useful.

The term "animal" as used herein refers to any animal (e.g., an animal in need of treatment), including mammals, such as, but not limited to, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and primates. In one specific embodiment of the invention the animal is a male or female human. The term "therapeutically effective amount", in reference to treating a disease state/condition, refers to an amount of a compound either alone or as contained in a pharmaceutical composition that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease state/condition when administered as a single dose or in multiple doses. Such effect need not be absolute to be beneficial.

The term "alkyl" as used herein refers to alkyl groups having from 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like. In a specific embodiment, the alkyl groups have from 1-4 carbon atoms and are referred to as lower alkyl.

The term "substituted alkyl" as used herein refers to an alkyl group having from 1 to 3 substituents, said substituents being selected from the group consisting of alkoxy, alkoxyalkyl, tri(C₁-C₄alkyl)silyl, substituted alkoxy, acyl, substituted acyl, acylamino, acyloxy, oxyacyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, N₃, carboxyl, carboxyl esters, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloallcyl, thioheterocyclic, substituted thioheterocycliccycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. In one specific embodiment of the invention, the term "substituted alkyl" refers to an alkyl group substituted with 1 to 3 substituents, said substituents being selected from the group consisting of alkoxy, alkoxyalkyl, tri(CrC₄alkyl)silyl, acyl, acylamino, acyloxy, oxyacyl, amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N₃, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and heterocyclic. The terms "alkenyl" or "alkene" as used herein refers to an alkenyl group having from 2 to 10 carbon atoms and having at least 1 site of alkenyl unsaturation. Such groups are exemplified by vinyl(ethen-l-yl), allyl, but-3-en- 1-yl, and the like.

The term "substituted alkenyl" as used herein refers to alkenyl groups having from 1 to 3 substituents, said substituents being selected from those describe above for a substituted alkyl.

The term "alkynyl" or "alkyne" as used herein refers to an alkynyl group having from 2-10 carbon atoms and having at least 1 site of alkynyl unsaturation. Such groups are exemplified by, but not limited to, ethyn-1-yl, propyn-1-yl, propyn-2-yl, l-methylprop-2-yn-l-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, and the like.

The term "substituted alkynyl" as used herein refers to alkynyl groups having from 1 to 3 substituents, said substituents being selected those describe above for a substituted alkyl.

The term "alkoxy" refers to the group alkyl-O-.

The term "substituted alkoxy" as used herein refers to the group substituted alkyl-O-.

The term "acyl" as used herein refers to the groups alkyl-C(O) -, alkenyl- C(O) -, alkynyl-C(O) -, cycloalkyl-C(O) -, aryl-C(O) -, heteroaryl-C(O) -, and heterocyclic-C(O).

The term "substituted acyl" as used herein refers to the groups substituted alkyl-C(O)-, substituted alkenyl-C(O) -, substituted alkynyl-C(O) -, substituted cycloalkyl-C(O) -, substituted aryl-C (O)-, substituted heteroaryl-C(O), and substituted heterocyclic-C(O) -.

The term "acylamino" as used herein refers to the group-C(O)NZ!Z2 where each Z₁ and Z₂ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, and the substituents described above in the definition of substituted alkyl.

The term "acyloxy" as used herein refers to the groups alkyl-C(O)O-, substituted alkyl- C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl- C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-.

The term "oxyacyl" as used herein refers to the groups alkyl-OC(O) -, substituted alkyl-OC(O)-, alkenyl-OC(O)-, substituted alkenyl-OC(O) -, alkynyl- OC(O) -, substituted alkynyl-OC(O)-, aryl-OC(O)-, substituted aryl-OC(O)-, cycloalkyl-OC(O)-, substituted cycloalkyl-OC(O)-, heteroaryl-OC(O) -, substituted heteroaryl-OC(O) -, heterocyclic- OC(O)-, and substituted heterocyclic-OC(O)-.

The term "amino" as used herein refers to the group -NH₂. The term "substituted amino" as used herein refers to the group-N Z₁Z₂ where Z₁ and Z₂ are as described above in the definition of acylamino, provided that Z₁ and Z₂ are both not hydrogen.

The term "aminoacyl" as used herein refers to the groups -NZ₃C(O)alkyl, -NZ₃C(O)substituted alkyl, -NZ₃C(O)cycloalkyl, -NZ₃C(O)substituted cycloalkyl, -NZ₃C(O)alkenyl, -NZ₃C(O)substituted alkenyl, -NZ₃C(O)alkynyl, - NZ₃C(O)substituted alkynyl, -NZ₃C(O)aryl, -NZ₃C(O)substituted aryl, - NZ₃C(O)heteroaryl, - NZ₃C(O)substituted heteroaryl, -NZ₃C(O)heterocyclic, and -NZ₃C(O)substituted heterocyclic, where Z₃ is hydrogen or alkyl. The term "aryl" as used herein refers to a monovalent aromatic cyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Exemplary aryls include, but are not limited to, phenyl and naphthyl. The term "substituted aryl" as used herein refers to aryl groups which are substituted with from 1 to 3 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, and those substituents described above in the definition of substituted alkyl.

The term "aryloxy" as used herein refers to the group aryl-O- that includes, by way of example but not limitation, phenoxy, naphthoxy, and the like.

The term "substituted aryloxy" as used herein refers to substituted aryl- O-groups.

The term "carboxyl" as used herein refers to -COOH or salts thereof. The term "carboxyl esters" as used herein refers to the groups-C(O)O- alkyl, -C (O)O-substituted alkyl, -C(O)O-aryl, and-C(O)O-substituted aryl.

The term "cycloalkyl" as used herein refers to a saturated or unsaturated cyclic hydrocarbon ring systems, such as those containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

The term "substituted cycloalkyl" as used herein refers to a cycloalkyl having from 1 to 5 substituents selected from the group consisting of oxo (=0), thioxo (=S), alkyl, substituted alkyl, and those substituents described in the definition of substituted alkyl. The term "cycloalkoxy" as used herein refers to -O-cycloalkyl groups.

The term "substituted cycloalkoxy" as used herein refers to-O-substituted cycloalkyl groups.

The term "formyl" as used herein refers to HC(O)-. The term "halogen" as used herein refers to fluoro, chloro, bromo and iodo.

The term "heteroaryl" as used herein refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur in the ring. The sulfur and nitrogen heteroatoms atoms may also be present in their oxidized forms. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom. Exemplary heteroaryl groups include, but are not limited to, heteroaryls include pyridyl, pyrrolyl, thienyl, indolyl, thiophenyl, and furyl.

The term "substituted heteroaryl" as used herein refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl.

The term "heteroaryloxy" as used herein refers to the group -O- heteroaryl.

The term "substituted heteroaryloxy" as used herein refers to the group - O-substituted heteroaryl.

The term "heterocycle" or "heterocyclic" or "heterocycloalkyl" refers to a saturated or unsaturated group (but not heteroaryl) having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen, sulfur, within the ring wherein, in fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the heterocyclic ring. The sulfur and nitrogen heteroatoms atoms may also be present in their oxidized forms.

The term "substituted heterocycle" or "substituted heterocyclic" or "substituted heterocycloalkyl" refers to heterocycle groups that are substituted with from 1 to 3 of the same substituents as defined for substituted aryl. Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2, 3,4-tetrahydroisoquinoline, 4,5, 6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

The term "heterocyclyloxy" as used herein refers to the group -O- heterocyclic.

The term "substituted heterocyclyloxy" as used herein refers to the group-O-substituted heterocyclic.

The term "phosphate" as used herein refers to the groups- OP(O)(OH)₂ (monophosphate or phospho), -OP(O)(OH)OP(O)(OH)₂ (diphosphate or diphospho) and -OP(O)(OH)OP(O)(OH)OP(O)(OH)₂ (triphosphate or triphospho) or salts thereof including partial salts thereof. It is understood that the initial oxygen of the mono-, di-, and triphosphate may include the oxygen atom of a sugar.

The term "phosphate esters" as used herein refers to the mono-, di-and tri-phosphate groups described above wherein one or more of the hydroxyl groups is replaced by an alkoxy group. The term "phosphonate" refers to the groups -0P(0)(Z4)(0H) or-OP(O)

(Z₄)(OZ₄) or salts thereof including partial salts thereof, wherein each Z₄ is independently selected from hydrogen, alkyl, substituted alkyl, carboxylic acid, and carboxyl ester. It is understood that the initial oxygen of the phosphonate may include the oxygen of a sugar. The term "thiol" as used herein refers to the group -SH.

The term "thioalkyl" or "alkylthioether" or "thioalkoxy" refers to the group- S-alkyl.

The term "substituted thioalkyl" or "substituted alkylthioether" or "substituted thioalkoxy" refers to the group -S-substituted alkyl. The term "thiocycloalkyl" as used herein refers to the group -S- cycloalkyl.

The term "substituted thiocycloalkyl" as used herein refers to the group - S-substituted cycloalkyl. The term "thioaryl" as used herein refers to the group -S-aryl.

The term "substituted thioaryl" as used herein refers to the group-S- substituted aryl.

The term "thioheteroaryl" as used herein refers to the group -S- heteroaryl. The term "substituted thioheteroaryl" as used herein refers to the group -

S-substituted heteroaryl.

The term "thioheterocyclic" as used herein refers to the group -S- heterocyclic.

The term "substituted thioheterocyclic as used herein refers to the group - S-substituted heterocyclic.

The term "amino acid sidechain" refers to the Z₇ substituent of α-amino acids of the formula Z₆NHCH(Z₇)COOH where Z₇ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl and Z₆ is hydrogen or together with Z₇ and the nitrogen and carbon atoms bound thereto respectively form a heterocyclic ring. In one embodiment, the α-amino acid sidechain is the sidechain one of the twenty naturally occurring L amino acids.

Sugars described herein may either be in D or L configuration. Compounds of Formula III

In one embodiment the invention provides a compound of Formula III:

R²

III wherein:

X is N, Y is N and Z is CH; or X is C, Y is CR³ and Z is O; R is OR_a, SR₃, NR_aR_b, NR₃NR_bR₀, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH₂)_n- CH(NHR₃)CO₂R_b, (CH₂)_n-S-alkyl,_,(CH₂)_n-S-aryl, Cl, F, Br, I, CN, COOR_a, CONR₃R_b, NHC(=NR_a)NHR_b, NR₃OR_b, NR₃NO, NHCONHR₃, NR_aN=NR_b, NR_aN=CHR_b, NR₃C(O)NR_bR₀, NR₃C(S)NR_bR_c, NR₃C(0)0R_b, CH=N-OR₃, NR_aC(=NH)NR_bR_c, NR₃C(O)NR_bNR₀R_d, 0-C(O)R₃, OC(O)-OR₃, ONH- C(0)0-alkyl, 0NHC(0)0-aryl, 0NR₃R_b, SNR₃R_b, S-0NR₃R_b, CHO, C(=S)N R_aR_b, nitro, C (=NR₃)0R_b, or SO₂NR₃R_b; and R³ is H, CN, NO₂, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH=CF₂, CH(=N R₃)OR_b, CHO, CH=CH-OCH₃, NHCONH₂, NHCSNH₂, CONR₃R_b, CSNR₃R_b, CO₂R₃, alkoxy, NH₂, alkylamino, dialkylamino, halogen, (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), (foran-2-yl), (2H[l,2,3]triazol-4-yl), C(=NH)NH₂, C(=NH)NH0H, C(=N0H)NH₂, acyl, substituted acyl, OR₃, C(=NR_a)R_b, CH=NNR₃R_b, CH=NOR₃, CH(OR₃)₂, B(OR_a)₂, C≡C-C(=O)NR_aR_b, CH=NNR₃R_b, CH=NOR₃, CH(OR_a)₂, B(OR_a)₂, C≡C-C(=O)NR_aR_b, (CH₂)_n-S- alkyl, (CH₂)_n-S-aryl, (CH₂)_n-S(O)-alkyl, (CH₂)_n-S(O)-aryl, (CH₂)_n-S(O₂)-alkyl, (CH₂)_n-S(O₂)-aryl, (CH₂)_n-SO₂NR₃R_b, or (CH₂)_n-OR₃; or R and R³ together with atoms to which they are attached may form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; n is 0-5;

R¹ is H, NR₃R_b, Cl, F, 0R_a, SR₃, NHCOR₃, NHSO₂R₃, NHCONHR₃, CN, alkyl, aryl, 0NR₃R_b, or NR₃C(0)0R_b;

R is a nucleoside sugar group; and

R₃, R_b, R_c, and R_d are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO₂-alkyl, amino, substituted amino, substituted cycloalkyl, heteroaryl, substituted heteroaryl , and NO; or R₃ and R_b together with the nitrogen to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or R_b and R₀ together with the nitrogen to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or R₀ and R_d together with the nitrogen to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment the invention provides a compound of Formula III:

III wherein:

X is N, Y is N and Z is CH; or X is C, Y is CR³ and Z is O; R is OR_a, SR₃, NR_aR_b, NR_aNR_bR_c, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH₂)_n- CH(NHR_a)CO₂R_b, (CH₂)_n-S-alkyl, (CH₂)_n-S-aryl, Cl, F, Br, I, CN, COOR_a, CONR₃Rb, NHC(=NR_a)NHR_b, NR_aOR_b, NR₃NO, NHCONHR₃, NR_aN=NR_b, NR_aN=CHRb, NRaC(O)NRbRc, NR₃C(S)NRbRc, NR₃C(O)OR₁,, CH=N-OR₃, NR_aC(=NH)NR_bR_c, NR₃C(O)NR_bNR_cR_d, 0-C(O)R₃, OC(O)-OR₃, ONH- C(O)O-alkyl, ONHC(O)O-aryl, ONR₃R₅, SNR₃R_b, S-ONR_aR_b, CHO, C(=S)N R₃Rb, nitro, CH(=NR₃)0R_b, or SO₂NR₃R_b; and R³ is H, CN, NO₂, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH=CF₂, CH(=N R₃)OR₅, CHO, CH=CH-OCH₃, NHCONH₂, NHCSNH₂, CONR₃R_b, CSNR₃R_b, CO₂R₃, alkoxy, NH₂, alkylamino, dialkylamino, halogen, (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), (2H[l,2,3]triazol-4-yl), C(=NH)NH₂, C(=NH)NH0H, C(=N0H)NH₂, acyl, substituted acyl, OR₃, C(=NR_a)R_b,

CH=NNR_aR_b, CH=NOR₃, CH(0R_a)₂, B(OR₃)₂, C≡C-C(=0)NR₃R_b, (CH₂)_n-S- alkyl, (CH₂)_n-S-aryl, (CH₂)_n-S(O)-alkyl, (CH₂)_n-S(O)-aryl, (CH₂)_n-S(O₂)-alkyl, (CH₂)_n-S(O₂)-aryl, (CH₂)_n-SO₂NR_aR_b, or (CH₂)_n-0R_a; or R and R³ together with atoms to which they are attached may form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; n is 0-5;

R¹ is H, NR_aR_b, Cl, F, OR₃, SR₃, NHCOR₃, NHSO₂R₃, NHCONHR₃, CN, alkyl, aryl, 0NR_aR_b, or NR₃C(0)0R_b; R² is a nucleoside sugar group; R_a, R_b, R_c, and R_d are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, Sθ₂-alkyl, amino, substituted amino, and NO; or R_aand R_b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R_b and R₀ together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; and

R_c, and R_d are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R₀, and R_d together with N atom to which they are attached may form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof. Compounds of Formula I and II

Compounds of the invention include compounds of Formula I and II:

I II.

In certain embodiments:

R is OR₃, SR_a, NR₃R_b, NR_aNR_bR_c, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH₂)_n- CH(NHR_a)CO₂R_b, (CH₂)_n-S-alkyl, (CH₂)_n-S-aryl, Cl, F, Br, I, CN, COOR₃, CONR₃Rb, NHC(=NR₃)NHR_b, NR_aOR_b, NR₃NO, NHCONHR₃, NR_aN=NR_b, NR_aN=CHR_b, NR₃C(O)NR_bR₀, NR₃C(S)NR_bR_c, NR_aC(O)OR_b, CH=N-OR₃, NR_aC(=NH)NR_bRc, NR_aC(O)NR_bNRcR_d, 0-C(O)R₃, OC(O)-OR₃, ONH- C(O)O-alkyl, ONHC(O)O-aryl, 0NR₃R_b, SNR_aR_b, S-0NR_aR_b, CHO, C(=S)N R_aR_b, nitro, CH(NR₃)OR_b, or SO₂NR₃R_b; and R³ is H, CN, NO₂, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH=CF₂, CH(=NR_a)0R_b, CHO, CH=CH-OCH₃, NHCONH₂, NHCSNH₂, CONR₃Rb, CSNR_aR_b, CO₂R₃, alkoxy, NH₂, alkylamino, dialkylamino, halogen, (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), (2H[l,2,3]triazol-4-yl), C(=NH)NH₂, C(=NH)NHOH, C(=NOH)NH₂, acyl, substituted acyl, OR_a, C(=NR_a)R_b, CH=NNR_aR_b, CH=NOR_a, CH(OR_a)₂, B(OR_a)₂, C≡C-C(=O)NR_aR_b, (CH₂VS- alkyl, (CH₂)_n-S-aryl, (CH₂)_n-S(O)-alkyl, (CH₂)_n-S(O)-aryl, (CH₂)_n-S(O₂)-alkyl, (CH₂)_n-S(O₂)-aryl, (CH₂)_n-SO₂NR_aR_b, or (CH₂)_n-0R_a; or R and R³ together with atoms to which they are attached may form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; n is 0-5;

R¹ is H, NR₃R_b, Cl, F, OR_a, SR₃, NHC0R_a, NHSO₂R₃, NHCONHR₃, CN, alkyl, aryl, 0NR_aR_b, or NR_aC(0)0R_b;

R² is a nucleoside sugar group;

R_a, R_b, R_c, and Ra are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO₂-alkyl, amino, substituted amino, and NO; or R₃ and R_b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R_b and R₀ together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; and

R_c, and Ra are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R₀, and R_d together with N atom to which they are attached may form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R is OR₃, Cl, SR_a, NR₃R_b, or NR₃NRbRc; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R is NR₃R_b; R₈ is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO₂-alkyl and NO; and R_b is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO₂-alkyl and NO; or R_a and R_b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring.

In one embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R is NR₃NR_bR_c, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH₂)_n-CH(NHR_a)CO₂R_b, Cl, F, Br, I, CN, COOR_a, CONR_aR_b,

NHC(=NR_a)NHR_b, NR_aOR_b, NR_aNO, NHCONHR₃, NR_aN=NR_b, NR_aN=CHR_b, NRaC(O)NR_bR₀, NR_aC(S)NR_bR_c, NR_aC(O)OR_b, CH=N-OR₃, NR_aC(=NH)NR_bRc, NR₃C(O)NR_bNR₀R₁₁, 0-C(O)R₃, OC(O)-OR₃, ONH- C(O)O-alkyl, ONHC(O)O-aryl, 0NR_aR_b, SNR₃R_b, S-ONR₃Rb, or SO₂NR₃Rb. In one embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R₁ is H or NR_aR_b; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R² is a nucleoside sugar group of Group A, B, C, D, E, or F described herein below; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R² is ribose, 2-methylribose, 2- deoxyribose; 2-deoxy-2-fluororibose; arabinose; 2-deoxy-2-fluoroarabinose; 2,3- dideoxyribose; 2,3-dideoxy-2-fluoroarabinose; 2,3-dideoxy-3-fluororibose; 2,3- dideoxy-2,3-didehydroribose; 2,3-dideoxy-3-azidoribose; 2,3-dideoxy-3- thiaribose; or 2,3-dideoxy-3-oxaribose; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R² is thioribose, 2-deoxythioribose; 2- deoxy-2-fluorothioribose; thioarabinose; 2-deoxy-2-fluorothioarabinose; 2,3- dideoxythioribose; 2,3-dideoxy-2-fluorothioarabinose; 2,3-dideoxy-3- fluorothioribose; 2,3-dideoxy-2,3-didehydrothioribose; or 2,3-dideoxy-3- azidothioribose; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R² is 4-hydroxymethylcyclopent-2-ene; 2,3-dihydroxy-4-hydroxyrnethylcyclopent-4-ene; 3-hydroxy-4- hydroxymethylcyclopentane; 2-hydroxy-4-hydroxymethylcyclopentene; 2- fluoro-3-hydroxy-4-hydroxymethylcyclopentane; 2,3-dihydroxy-4- hydroxymethyl-5-methylenecyclopentane; 4-hydroxymethylcyclopentane, 2,3- dihydroxy-4-hydroxymethylcyclopentane; or 2,3 -dihydroxymethylcyclobutane; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I, II, or III as described above, wherein R² is 4-hydroxymethylpyrrolidine; 2,3- dihydroxy-4-hydroxymethylpyrrolidine; 2/3-hydroxy-4- hydroxymethylpyrrolidine; 2-fluoro-3 -hydroxy-4-hydroxymethylpyrrolidine; or 3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment the invention provides a compound of Formula I,

II, or III as described above, wherein R_a, R_b, R_c, and Rd are independently selected from the group consisting of H, alkyl, and substituted alkyl; or R_aand R_b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R_b and R₀ together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring.

In another embodiment the invention provides a compound of Formula I, II, or III which is a compound of the following formula (11a or lib).

11a lib or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment the invention provides a compound of Formula II, which is a compound of the following formula (IV):

IV or a pharmaceutically acceptable salt or prodrug thereof; wherein X is H or alkyl.

In certain embodiments the invention, the compound of the invention is not a compound of the following formula:

wherein:

B is selected from:

W is O, S, or NH;

X is N, Y is N and Z is CH; or X is C, Y is CR²³ and Z is O;

R is OR₃, SR₃, NR₃R₄, NR₃NR₄R₅, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH₂),,- CH(NHR₃)CO₂R₄, (CH₂)_n-S-alkyl, (CH₂)_n-S-aryl, Cl, F, Br, I, CN, COOR₃, CONR₃R₄, MKX=NR₃)NHR₄, NR₃OR₄, NR₃NO, NHCONHR₃, NR₃N=NR₄, NR₃N=CHR₄, NR₃C(O)NR₄R₅, NR₃C(S)NR₄R₅, NR₃C(O)OR₄, CH=N-OR₃, NR₃Q=NH)NR₄R₅, NR₃C(O)NR₄NR₅R₆, 0-C(O)R₃, OC(O)-OR₃, ONH- C(O)O-alkyl, ONHC(O)O-aryl, ONR₃R₄, SNR₃R₄, S-ONR₃R₄, or SO₂NR₃R₄; n is 0-5; R¹ is H, NR₃R₄, Cl, F, OR₃, SR₃, NHCOR₃, NHSO₂R₃, NHCONHR₃, CN, alkyl, aryl, ONR₃R₄, Or NR₃C(O)OR₄;

R₃, R₄, R₅, and R₆ are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO₂-alkyl and NO; or R₃ and R₄ together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R₄ and R₅ together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; and

R^c is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from halo, amino, hydroxy, and alkoxy; or a pharmaceutically acceptable salt thereof.

Prodrugs

The term "prodrug" as used herein refers to a compound that can be metabolized in vivo to provide a compound of Formula I to III. Thus prodrugs include compounds that can be prepared by modifying one or more functional groups in a compound of Formula I to III to provide a corresponding compound that can be metabolized in vivo to provide a compound of Formula I to III. Such modifications are known in the art. For example, one or more hydroxy groups or amine groups in a compound of Formula I to III can be acylated with alkyl- C(=O)-groups or with residues from amino acids to provide a prodrug. Alternatively, one or more pendent hydroxyl groups from a mono-, di-, or triphosphate functionality in a compound of Formula I to III can be converted to an alkoxy, substituted alkoxy, aryloxy, or substituted aryloxy group.

In one embodiment, the term prodrug includes a compound wherein one or more hydroxy groups on a nucleoside sugar group (e.g., a 2', 3', or 5' hydroxy group) have been converted to a group that can be metabolized in vivo to provide a compound of Formula I to III. For example, the invention provides a compound wherein one or more hydroxy groups on a nucleoside sugar group (e.g., a 2', 3', or 5' hydroxy group) have been converted to an acyloxy, acylamino or R-O group, wherein R is a carboxy-linked amino acid. In one embodiment, the term prodrug includes a compound wherein one or more pendent hydroxyl groups from a mono-, di-, or tri-phosphate functionality in a compound of Formula I to III is converted to a group Ry-O-; wherein each R_y is independently a 1-20 carbon branched or unbranched, saturated or unsaturated chain, wherein one or more (e.g., 1, 2, 3, or 4) of the carbon atoms is optionally replaced with -O- or -S- and wherein one or more of the carbon atoms is optionally substituted with oxo (=0) or thioxo (=S) (See Lefebvre et al, J. Med. Chem. 1995, 38, 3941-50).

In another embodiment, the term prodrug includes a compound wherein one or more pendent hydroxyl groups from a mono-, di-, or tri-phosphate functionality in a compound of Formula I to III is converted to a group R₂-N-; wherein each R₂ is a residue of an amino acid. Thus, in the methods of treatment of the present invention, the term "administering" includes administration of a compound of Formula I to III, as well as administration of a prodrug which converts to a compound of Formula I to III or a salt thereof in vivo.

Conventional procedures for the selection and preparation of prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and in International Patent Application Publication Number WO 2005/084192. A variety of prodrugs are also described in International Patent Application Number PCT US2004/013063 , which was published as International Publication Number WO 2004/096286 and PCT US2006/030549, which was published as International Publication Number WO 2007/021610.

In another embodiment the prodrug comprises one of more groups of formula:

wherein:

R₁₅ is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and an amino acid;

R₁₆ is H, optionally substituted monocyclic aryl, or optionally substituted monocyclic heteroaryl; and R₁₇ is H, halogen, CN, -CO-R₂₀, -CON(R₂O₂, - CO₂R₂₀, -SO₂R₂₀, -SO₂N(R₂₁)₂, -OR₂I, -SR₂₁, -R₂₁, -N(R₂₁)₂, -0-COR₂₀, -O- CO₂R₂₀, -SCOR₂₀, -S-CO₂R₂₀, -NHCOR₂₁, -NHCO₂R₂₁, -(CH₂)_P-OR₂₂, or - (CH₂)_P-SR₂₂; or R₁₆ and R₁₇ are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; or R₁₇ and R₁₈ are connected as described below;

R₁₈ and R₁₉ are each independently H, alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or R₁₈ and R₁₉ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms; or R₁₇ and R₁₈ are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom and R₁₉ is H, alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; and R₂₀ is alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₁ is H, alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₂ is H or lower acyl; n is an integer from 2-5; m is an integer from 10-20; and p is an integer from 2-3.

Prodrug forms of a compound bearing various nitrogen functions (amino, hydroxyamino, amide, etc.) may include the following types of derivatives where each R_p group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl or cycloalkenyl groups as defined earlier.

(a) Carboxamides, represented as -NHC(O)Rp

(b) Carbamates, represented as -NHC(O)ORp

(c) (Acyloxy)alkyl Carbamates, represented as NHC(O)OROC(O)Rp

(d) Enamines, represented as -NHCR(=CHCO₂R_P) or -NHCR(=CHCONR_pR_p)

(e) Schiff Bases, represented as -N=CR_PR_P

(f) Mannich Bases (from carboximide compounds), represented as RCONHCH₂NR_pR_p Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al, J. Med. Chem. 1988, 31, 318; Aligas- Martin et al, PCT WO0041531, p.30).

Prodrug forms of carboxyl -bearing compounds include esters (-CO₂R_m) where the R_m group corresponds to any alcohol whose release in the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels. Another prodrug derived from a carboxylic acid form of the disclosure may be a quaternary salt type of structure described by Bodor et al. , J. Med. Chem. 1980, 23, 469.

R

Nucleoside Sugar Groups

The term "nucleoside sugar group" as used herein includes cyclic and acyclic groups that can be included as the sugar portion of a nucleoside analog of Formula I to III. Many examples of such groups are known in the field of nucleoside chemistry (See for example Antiviral Drugs by John S. Driscoll (2002) published by Ashgate Publishing Ltd.).

The term nucleoside sugar group includes substituted and unsubstituted tetrahydrofuranyl and dihydrofuranyl compounds including those set forth in group (A) below, substituted and unsubstituted tetrahydrothiophenyl and dihydrothiophenyl compounds including those set forth in group (B) below, substituted and unsubstituted alkyl compounds including those set forth in group (C) below, substituted and unsubstituted cycloalkyl and cycloalkenyl compounds including those set forth in group (D) below, substituted and unsubstituted dihydropyrrolidinyl and tetrahydropyrrolidinyl compounds including those set forth in group (E) below, and substituted and unsubstituted dioxolane, substituted and unsubstituted thioxolane, and substituted and unsubstituted dithiolane compounds including those set forth in group (F) below. Group A

Examples of substituted tetrahydro and dihydrofuranyl compounds include those compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

(d) (1) (d) (1)

Group B

Examples of substituted tetrahydrothiophenyl and dihydrothiophenyl compounds include those compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

Group C

Examples of substituted alkyl compounds include those compounds represented by:

Specific examples include, but are not limited to, the following compounds:

Group D Examples of substituted cycloalkyl and cycloalkenyl compounds include those compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

Group E

Examples of substituted dihydropyrrolidinyl and tetrahydropyrrolidinyl compounds include those compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

Group F

Examples of substituted dioxolane, substituted thioxolane and substituted dithiolane compounds include those compounds represented by the general structures:

R .q9 _π n / / R IVq_{9 ς} /

Specific examples include, but are not limited to, the following compounds:

For the structures in Groups A-F, the following definitions apply: R₇ is H, OR₁₄, N₃, NH₂, or F; and R'₇ is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₇ and R₇ together may be =CH₂, =CHF; wherein both R₇ and R₇ are not OH; and when one of R₇ and R₇ is NH₂, the other is not OH; and when one of R₇ and R'₇ is N₃, the other is not OH; R₇" is alkyl or substituted alkyl. R₈ is H, OR₁₄, N₃, NH₂, or F; and R'₈ is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₈ and R₈ together may be =CH₂, =CHF; wherein both R₈ and R'₈ are not OH; and when one of R₈ and R₈ is NH₂, the other is not OH; and when one of R₈ and R'₈ is N₃, the other is not OH; or R₇ and R₈ together can form

O O

^R100

wherein: R_JOO is C_1-12 alkyl C_3-8 cycloalkyl, aryl or heteroaryl; wherein any C_1-12 alkyl and C_3-8 cycloalkyl OfR₁₀₀ is unsubstituted or is substituted with 1-3 substituents selected from halogen, hydroxy, carboxy, and C_1-4 alkoxy; and wherein any aryl or heteroaryl of R_1Oo is unsubstituted or is substituted with 1-5 substituents independently selected from R_1Oi; each R₁₀₁ is independently halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-

4 alkylsulfoyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4 alkylamino, di(C_1-4 alkyl) amino, C_1-4 alkanoyl, C_1-4 alkanoyloxy, or C_1-4 alkyloxycarbonyl; R₉ is H, CH₃, C₂H₅, or N₃; R₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

— o-C -P-OR₁₀ ;

R₁₀ and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_nl-O-(CH₂)_mCH₃; nl is 2-5; m is 10-20;

Ri₂ is an N-linked amino acid residue (e.g., -NH-CH(CH₃)C0₂alkyl or - NH-CH(isopropyl)-CO₂alkyl);

R₁₃ is H, CH₃, C₂H₅, CH₂F, CH₂OH, CH₂CH₂F, CH₂CH₂OH, CH₂N₃, CH₂CH₂N₃, CH₂NH₂, or CH₂CH₂NH₂; and R₁₄ is H.

In one embodiment, for the structures in Groups A-F, R₇ is H, OR₁₄, N₃, NH₂, or F; and R'₇ is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₇ and R₇ together may be =CH₂, =CHF; wherein both R₇ and R₇ are not OH; and when one of R₇ and R₇ is NH₂, the other is not OH; and when one of R₇ and R₇ is N₃, the other is not OH; R₇" is alkyl or substituted alkyl; and R₈ is H, OR₁₄, N₃, NH₂, or F; and R'₈ is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₈ and R'₈ together may be =CH₂, =CHF; wherein both R₈ and R'₈ are not OH; and when one of R₈ and R₈ is NH₂, the other is not OH; and when one of R₈ and R'₈ is N₃, the other is not OH; In one embodiment, for a compound of Formula I to III, R₁₄ is replaced to form a pharmaceutically acceptable prodrug, for example, a prodrug selected from the group consisting of: acyl, oxyacyl, phosphonate, phosphate, phosphate esters, phosphonamidate, phosphorodiamidate, phosphoramidate mono ester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, C(O) CHR₁₅NH₂,

wherein:

R₁₅ is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or an amino acid; R₁₆ is H, optionally substituted monocyclic aryl, or optionally substituted monocyclic heteroaryl; and R₁₇ is H, halogen, CN, -CO-R₂₀, -CON(R₂₁)₂, - CO₂R₂₀, -SO₂R₂₀, -SO₂N(R₂₁)₂, -OR₂₁, -SR₂₁, -R₂₁, -N(R₂₁)₂, -0-COR₂₀, -O- CO₂R₂₀, -SCOR₂₀, -S-CO₂R₂₀, -NHCOR₂₁, -NHCO₂R₂₁, -(CH₂)_P-OR₂₂, or - (CH₂)_P-SR₂₂; or R₁₆ and R₁₇ are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; or R₁₇ and R₁₈ are connected as described below;

Ri₈ and R₁₉ are each independently H, alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or R₁₈ and R₁₉ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms; or R₁₇ and R₁₈ are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom and R₁₉ is H, alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; and R₂₀ is alkyl, aryl, heterocycloalkyl, or arylalkyl; R₂₁ is H, alkyl, aryl, heterocycloalkyl, or arylalkyl; R₂₂ is H or lower acyl; n is an integer from 2-5; m is an integer from 10-20; and p is an integer from 2-3.

Synthetic Processes

Processes for preparing compounds of Formula I-III, or a pharmaceutically acceptable salts or prodrugs thereof, as well as processes for preparing intermediate compounds that can be used to prepare compounds of Formula I-III or pharmaceutically acceptable salts or prodrugs thereof are provided as further embodiments of the invention. For example in one embodiment the invention provides a method for preparing a pharmaceutically acceptable salt of compound of Formula I-III comprising converting a corresponding compound of Formula I-III to the salt.

In another embodiment the invention provides a method for preparing a prodrug of a compound of Formula I-III comprising converting a corresponding compound of Formula I-III to the prodrug. In another embodiment the invention provides a method for preparing a compound of Formula I-III comprising deprotecting a corresponding compound of Formula I-III that comprises one or more protecting groups to provide the compound of Formula I-III.

A representative compound of formula III (and formula I), compound lib, can be prepared as follows.

Synthetic schemes for the preparation of (3R,4R)-2-(4-aminoimidazo[l,2- f][l,2,4]triazin-7-yl)-5-(hydroxymethyI)-3-methyltetrahydrofuran-3,4-diol

A representative compound of formula III (and formula II), compound lie, can be prepared as follows. Synthetic scheme for the preparation of (2R,3R,4R,5R)-2-(4-aminofuro[3,4- d]pyrimidin-7-yI)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol

J. Chem. Soc. Perkin Trans. 1 ; 1982; 903-908

44 45

BnO OBn Synthesis, 2004, 1359-1362

46

1 , NaOH

1, NaOH 2,DPPA 2,EDCI/H0Bt NEt₃, Toluene NH₄CI, DIPEA t-BuOH

Synthetic Intermediates

The invention also provides synthetic intermediates that are useful for preparing compounds of Formula I to III or a salt or prodrug thereof. For example, the invention provides novel synthetic intermediates such as those described in the Schemes and Examples herein. Isomers and Physical Forms

It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixtures thereof, of a compound of the invention (e.g., a compound of Formula I to III, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine anti-viral or anti-cancer activity using the standard tests described herein, or using other similar tests which are well known in the art. Although the invention includes all isomeric forms of the compounds described herein, one embodiment of the invention provides compounds having the absolute stereochemistry depicted in the Examples herein below. Pharmaceutical Compositions, Modes of Administration and Methods of Treatment

The present disclosure provides compounds of the general Formula I to III as detailed above which are inhibitors of DNA and/or RNA viral polymerases and anticancer agents. Various forms of DNA and RNA viral polymerases are inhibited by the compounds disclosed, such as but not limited to viral RdRps. The compounds of the present disclosure therefore have utility in treating and/or preventing viral infections in a host and in treatment and/or preventing a variety of disease states and/or conditions caused by or related to such viral infections. In one embodiment, the compounds are useful in the above mentioned treating and/or preventing by inhibiting a viral RNA and DNA polymerases. Such viral agents include, but are not limited to, hepatitis B, hepatitis C, human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile virus. In a particular embodiment, the causative agent of the viral infection is a flavivirus.

The present disclosure provides for a compound of the general Formula I to III and a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of general Formula I toIII as described herein. Such compounds and/or pharmaceutical compositions may be used in the manufacture of a medicament for treating and/or preventing a disease or condition in which it is desirable to inhibit a viral RNA and DNA polymerases. Such pharmaceutical compositions may also comprise a pharmaceutically acceptable carrier and other ingredients known in the art, or may comprise solely a compound of the general Formula I to III. The pharmaceutically acceptable carriers described herein, including, but not limited to, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art. Typically, the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no detrimental side effects or toxicity under the conditions of use. The pharmaceutically acceptable carriers can include polymers and polymer matrices.

The compounds described in the instant disclosure can be administered by any conventional method available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with additional therapeutic agents.

The compounds described are administered in a pharmaceutically effective amount. The pharmaceutically effective amount of the compound and the dosage of the pharmaceutical composition administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the severity and stage of the disease state or condition; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to

1000 milligrams (mg) per kilogram (kg) of body weight per day. In one embodiment, the total amount is between about 0.1 mg/kg and about 100 mg/kg of body weight per day; in an alternate embodiment between about 1.1 mg/kg and about 50 mg/kg of body weight per day; in yet another alternate embodiment between 0.1 mg/kg and about 30 mg/kg of body weight per day. The above described amounts may be administered as a series of smaller doses over a period of time if desired. The pharmaceutically effective amount can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity in itself, the pharmaceutically effective amount can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art. The dosage of active ingredient may be given other than daily if desired.

The total amount of the compound administered will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one skilled in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations. Dosage forms of the pharmaceutical compositions described herein (forms of the pharmaceutical compositions suitable for administration) contain from about 0.1 mg to about 3000 mg of active ingredient (i.e., the compounds disclosed) per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% weight based on the total weight of the composition. Multiple dosage forms may be administered as part of a single treatment. The active ingredient may be administered to achieve peak plasma concentrations of the active ingredient of from about 0.2 to 70 μM, or from about 1.0 to 10 μM. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. The active ingredient can also be administered intranasally (nose drops) or by inhalation via the pulmonary system, such as by propellant based metered dose inhalers or dry powders inhalation devices. Other dosage forms are potentially possible such as administration transdermally, via patch mechanisms or ointment.

Formulations suitable for oral administration can include (a) liquid solutions, such as a pharmaceutically effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined pharmaceutically effective amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.

Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the patient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutically acceptable carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4- methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

Oils, which can be used in parenteral formulations, include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl .beta.- aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof. The parenteral formulations typically contain from about 0.5% to about

25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. Pharmaceutically acceptable excipients are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following methods and excipients are merely exemplary and are in no way limiting. The pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects. Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.

The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. Such aerosol formulations may be administered by metered dose inhalers. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutically acceptable carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986).

Formulations suitable for topical administration include pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art. Furthermore, transdermal patches can be prepared using methods known in the art. Additionally, formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

One skilled in the art will appreciate that suitable methods of administering a compound of the present invention to an patient are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route.

Useful embodiments of pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows.

A large number of hard-shell capsules are prepared by filling standard two-piece hard gelatine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix. A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Immediate release tablets/capsules are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. Moreover, the compounds of the present invention can be administered in the form of nose drops, or metered dose and a nasal or buccal inhaler. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol. In one embodiment, the teachings of the present disclosure provide for the use of such pharmaceutical compositions and medicaments in a method of treating a viral infection or treating a disease state and/or condition caused by or related to such viral infection. In one embodiment, the treatment is the result of the inhibition of a viral RNA or DNA polymerase, such as but not limited to a RdRp. Such treatment or inhibition need not be complete to be useful. The method of treatment comprises the steps of: (i) identifying a patient in need of such treatment; (ii) providing such pharmaceutical composition containing at least one compound of the invention; and (iii) administering such pharmaceutical composition in a therapeutically effective amount to treat the viral infection in a patient in need of such treatment or to inhibit the activity of a viral RNA or DNA polymerase in a patient in need of such treatment. The teachings of the present disclosure provide for, among other things, the use of such pharmaceutical compositions and medicaments in a method of preventing or suppressing a viral infection or preventing or suppressing a disease state and/or condition caused by or related to such viral infection. In one embodiment, the prevention or suppression is the result of the inhibition of a viral RNA or DNA polymerase, such as but not limited to a RdRp. Such prevention, suppression or inhibition need not be complete to be useful. The method of preventing or suppressing can optionally comprises the steps of: (i) identifying a patient in need of such prevention; (ii) providing such pharmaceutical composition containing at least one compound of the general Formula I to III; and (iii) administering such pharmaceutical composition in a therapeutically effective amount to prevent or suppress the viral infection in a patient in need of such treatment or to inhibit the activity of a viral RNA and DNA polymerase in a patient in need of such treatment. The methods of the treating and preventing a viral infection or a disease state and/or condition caused by or related to said viral infection may further comprise administering a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of another anti-viral agent which , in particular, may be active against HCV. Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of HCV NS3 serine protease, an inhibitor of inosine monophosphatedehydrognease, interferon-α, pegylated interferon-α (peginterferon-α), a combination of interferon-α and ribavirin, a combination of peginterferon-α and ribavirin, a combination of interferon-α and levovirin, and a combination of peginterferon-α and levovirin. Interferon-α includes, but is not limited to, recombinant interferon-α2a, interferon-α2b, a consensus interferon, and a purified interferon-α product.

The compounds and pharmaceutical compositions of the present disclosure can be administered to patients to prevent and/or treat a number of cancers. Cancers include, but are not limited to, leukemias and lymphomas such as acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chrome myelogenous leukemia, Hodgkin's Disease, non- Hodgkin's lymphomas, and multiple myeloma, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms Tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as lung cancer, colon and rectum cancer, breast cancer, prostate cancer, urinary cancers, uterine cancers, oral cancers, pancreatic cancer, melanoma and other skin cancers, stomach cancer, ovarian cancer, brain tumors, liver cancer, laryngeal cancer, thyroid cancer, esophageal cancer, and testicular cancer. The cancer may be related to a viral infection or an activity of a viral DNA or RNA polymerase.

The methods of the treating and preventing cancer may also comprises further administering of a chemotherapeutic agent in combination with any of the compounds or pharmaceutical compositions of the present disclosure. Any suitable chemotherapeutic agent can be employed for this purpose. The chemotherapeutic agent is typically selected from the group consisting of alkylating agents, antimetabolites, natural products, hormonal agents, and miscellaneous agents.

Examples of alkylating chemotherapeutic agents include carmustine, chlorambucil, cisplatin, lomustine, cyclophosphamide, melphalan, mechlorethamine, procarbazine, thiotepa, uracil mustard, triethylenemelamine, busulfan, pipobroman, streptozocin, ifosfamide, dacarbazine, carboplatin, and hexamethylmelamine.

Examples of chemotherapeutic agents that are antimetabolites include cytosine arabinoside, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, azaserine, thioguanine, floxuridine, fludarabine, cladribine and L- asparaginase.

Examples of chemotherapeutic agents that are natural products include actinomycin D, bleomycin, camptothecins, daunomycin, doxorubicin, etoposide, mitomycin C, TAXOL™ (paclitaxel), taxotere, teniposide, vincristine, vinorelbine, mithramycin, idarubicin, MITHRACIN™. (plicamycin), and deoxycoformycin.

An example of a hormonal chemotherapeutic agent includes tamoxifen. Examples of the aforesaid miscellaneous chemotherapeutic agents include mitotane, mitoxantrone, vinblastine, and levamisole.

Representative prodrugs of the invention can be been tested in vitro or in vivo to confirm that the prodrug is converted, e.g., by hydrolysis, to provide an active compound. The ability of a compound to inhibit viral polymerases can be evaluated using known assays. The ability of a compound to inhibit HCV NS5B polymerase can be evaluated using the following assay. HCV NS5B Polymerase Assay Antiviral activity of the test compounds can be assessed (Okuse et al ,

Antiviral Res. 2005, 65, 23-34) in the stably HCV RNA-replicating cell line, AVA5, derived by transfection of the human hepatoblastoma cell line, Huh7 (Blight et al, Sci. 2000, 290, 1972). Compounds can be added to dividing cultures once daily for three days. Media can be changed with each addition of compound. Cultures generally start the assay at 30-50% confluence and reach confluence during the last day of treatment. Intracellular HCV RNA levels and cytotoxicity can be assessed 24 hours after the last dose of compound.

Triplicate cultures for HCV RNA levels (on 48-well and 96-well plates) and cytotoxicity (on 96-well plates) can be used. A total of six untreated control cultures, and triplicate cultures treated with α-interferon and ribavirin can serve as positive antiviral and toxicity controls.

Intracellular HCV RNA levels can be measured using a conventional blot hybridization method in which HCV RNA levels are normalized to the levels of B-actin RNA in each individual culture (Okuse et al, Antivir. Res. 2005, 65, 23- 34). Cytotoxicity can be measured using a neutral red dye uptake assay (Korba and Gerin, Antivir. Res. 1992, 19, 55). HCV RNA levels in the treated cultures can be expressed as a percentage of the mean levels of RNA detected in untreated cultures. Compound Synthesis Compounds of Formula I-III can be prepared using synthetic intermediates and synthetic procedures that are known, or they can be prepared using the synthetic intermediates and synthetic procedures described in the Schemes and Examples herein.

The invention will now be illustrated by the following non-limiting Example. Example 1

The following illustrate representative pharmaceutical dosage forms, containing a compound of Formula I to III, or a pharmaceutically acceptable salt or prodrug thereof ('Compound X'), for therapeutic or prophylactic use in humans.

Ci) 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

(iϊ) Tablet 2 mg/tablet

Compound X= 20.0

Microcrystalline cellulose 410.0

Starch 50.0

Sodium starch glycolate 15.0

Magnesium stearate

500.0

(iii) 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

(iv) Injection 1 Cl mR/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) Injection 2 (10 mε/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 niL

(vi) Aerosol mR/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 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

CLAIMS What is claimed:

1. A compound of Formula III :

III wherein:

X is N, Y is N and Z is CH; or X is C, Y is CR³ and Z is O;

R is OR₃, SR₃, NR₃R_b, NR₃NR_bR₀, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH₂)_n- CH(NHR₃)CO₂R_b, (CH₂)_n-S-alkyl, (CH₂)_n-S-aryl, Cl, F, Br, I, CN, COOR_a, CONR_aR_b, NHC(=NR_a)NHR_b, NR_a0R_b, NR₃NO, NHCONHR₃, NR_aN=NR_b, NR_aN=CHR_b, NR₃C(O)NRbRc, NR₃C(S)NRbRc, NR₃C(O)OR_b, CH=N-OR₃, NR₃Q=NH)NR_bR_c, NR_aC(O)NR_bNR_cR_d, 0-C(O)R₃, OC(O)-OR₃, ONH- C(O)O-alkyl, ONHC(O)O-aryl, 0NR₃R_b, SNR₃R_b, S-ONR_aR_b, CHO, C(=S)N R₃Rb, nitro, C (=NR₃)0R_b, or SO₂NR₃R_b; and R³ is H, CN, NO₂, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH=CF₂, CH(=N R₃)OR_b, CHO, CH=CH-OCH₃, NHCONH₂, NHCSNH₂, CONR₃R_b, CSNR₃R_b, CO₂R₃, alkoxy, NH₂, alkylamino, dialkylamino, halogen, (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), (2H[l,2,3]triazol-4-yl), C(=NH)NH₂, C(=NH)NH0H, C(=N0H)NH₂, acyl, substituted acyl, OR₃, C(=NR_a)R_b, CH=NNR₃Rb, CH=NOR₃, CH(OR₃)₂, B(OR₃)₂, C≡C-C(=O)NR_aR_b, CH=NNR₃R_b, CH=NOR₃, CH(0R_a)₂, B(OR_a)₂, C≡C-C(=0)NR_aR_b, (CH₂)_n-S- alkyl, (CH₂)_n-S-aryl, (CH₂)_n-S(O)-alkyl, (CH₂)_n-S(O)-aryl, (CH₂)_n-S(O₂)-alkyl, (CH₂)_n-S(O₂)-aryl, (CH₂)_H-SO₂NR₃R_b, or (CH₂)_n-0R_a; or R and R³ together with atoms to which they are attached may form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; n is 0-5; R¹ is H, NR₃R_b, Cl, F, OR_a, SR_a, NHCOR₃, NHSO₂R₃, NHCONHR_a, CN, alkyl, aryl, ONR_aR_b, or NR₃C(0)0R_b;

R² is a nucleoside sugar group; and

R_a, R_b, R_c, and Rj are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO₂-alkyl, amino, substituted amino, substituted cycloalkyl, heteroaryl, substituted heteroaryl , and NO; or R₃ and R_b together with the nitrogen to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or R_b and Rς together with the nitrogen to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or R₀ and R_d together with the nitrogen to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1 wherein the compound of formula III is a compound of Formula I or II:

II.

3. The compound of claim 2 wherein the compound of formula III is a compound of Formula I:

I.

4. The compound of claim 2 wherein the compound of formula III is a compound of Formula II:

5. The compound of any one of claims 1-4 wherein R is OR_a, Cl, SR_a, NR_aR_b5 Or NR_aNR_bR₀.

6. The compound of any one of claims 1-4 wherein R is hydroxy, chloro, methoxy, mercapto, amino, methylamino, isopropylamino, propylamino, ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino, l-(2- hydroxyethyl)hydrazino, hydrazino, 1-methylhydrazino, azetidino, or pyrrolidino.

7. The compound of any one of claims 1 -6 wherein R¹ is H or NR_aR_b.

8. The compound of any one of claims 1-7 wherein R² is

wherein:

R₇ is H, OR₁₄, N₃, NH₂, or F; and R₇ is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₇ and R₇ together may be =CH₂, =CHF; wherein both R₇ and R'₇ are not OH; and when one of R₇ and R'₇ is NH₂, the other is not OH; and when one of R₇ and R'₇ is N₃, the other is not OH;

R₈ is H, OR₁₄, N₃, NH₂, or F; and R'₈ is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₈ and R₈ together may be =CH₂, =CHF; wherein both R₈ and R₈ are not OH; and when one of R₈ and R'₈ is NH₂, the other is not OH; and when one of R₈ and R'₈ is N₃, the other is not OH; or R₇ and R₈ together can form

wherein: R_1Oo is C_1-12 alkyl C_3-8 cycloalkyl, aryl or heteroaryl; wherein any C_1-12 alkyl and C_3-8 cycloalkyl of R_1O0 is unsubstituted or is substituted with 1-3 substituents selected from halogen, hydroxy, carboxy, and C_1-4 alkoxy; and wherein any aryl or heteroaryl OfR₁₀₀ is unsubstituted or is substituted with 1-5 substituents independently selected from R₁₀₁; each R₁₀₁ is independently halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1- 4 alkylsulfoyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4 alkylamino, di(C_1-4 alkyl) amino, C_1-4 alkanoyl, C_1-4 alkanoyloxy, or C_1-4 alkyloxycarbonyl;

R₉ is H, CH₃₅ C₂H₅, or N₃;

R'₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

—

R_1O and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_nl-O-(CH₂)_mCH₃;

R₁₂ is an N-linked amino acid residue (e.g., -NH-CH(CH₃)Cθ₂alkyl or NH-CH(isopropyl)-CO₂alkyl); and

Ri₄ is H; nl is 2-5; and m is 10-20.

9. The compound of any one of claims 1-7 wherein R² is selected from:

(d) (1) (d) (1)

10. The compound of any one of claims 1-7 wherein R² is:

wherein:

R₇ is H, OR₁₄, N₃, NH₂, or F; and R₇ is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₇ and R'₇ together may be =CH₂, =CHF; wherein both R₇ and R₇ are not OH; and when one of R₇ and R₇ is NH₂, the other is not OH; and when one of R₇ and R₇ is N₃, the other is not OH;

R₈ is H, OR₁₄, N₃, NH₂, or F; and R'₈ is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₈ and R₈ together may be =CH₂, =CHF; wherein both R₈ and R₈ are not OH; and when one of Rg and R₈ is NH₂, the other is not OH; and when one of R₈ and R'₈ is N₃, the other is not OH; or R₇ and R₈ together can form

wherein: R₁₀₀ is C_1-12 alkyl C_3-8 cycloalkyl, aryl or heteroaryl; wherein any C_1-12 alkyl and C_3-8 cycloalkyl OfR_1O0 is unsubstituted or is substituted with 1-3 substituents selected from halogen, hydroxy, carboxy, and C_1-4 alkoxy; and wherein any aryl or heteroaryl OfR₁₀₀ is unsubstituted or is substituted with 1-5 substituents independently selected from Ri₀₁; each Rιoi is independently halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_{1- 4} alkylsulfoyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, trifluoromethoxy, Ci_-4 alkylamino, di(C_1-4 alkyl) amino, C_1-4 alkanoyl, C_1-4 alkanoyloxy, or C_1-4 alkyloxycarbonyl;

R₉ is H, CH₃, C₂H₅, or N₃;

R'₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

— o-C -P-OR₁₀ ;

R_IO and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_nl-O-(CH₂)_mCH₃;

R₁₂ is an N-linked amino acid residue (e.g., -NH-CH(CH₃)C0₂alkyl or - NH-CH(isopropyl)-CO₂alkyl);

R₁₄ is H; nl is 2-5; and m is 10-20.

11. The compound of any one of claims 1 -7 wherein R is selected from:

12. The compound of any one of claims 1-7 wherein R² is:

wherein

R₇" is alkyl or substituted alkyl;

R₁₀ and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_nl-O-(CH₂)_mCH₃; nl is 2-5; and m is 10-20;

R₁₂ is an N-linked amino acid residue (e.g., -NH-CH(CH₃)C0₂alkyl or NH-CH(isopropyl)-CO₂alkyl); and

R₁₃ is H, CH₃, C₂H₅, CH₂F, CH₂OH, CH₂CH₂F, CH₂CH₂OH, CH₂N₃, CH₂CH₂N₃, CH₂NH₂, or CH₂CH₂NH₂.

13. The compound of any one of claims 1 -7 wherein R² is:

14. The compound of any one of claims 1-7 wherein R is:

wherein:

R₇ is H, OR₁₄, N₃, NH₂, or F; and R'₇ is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₇ and R'₇ together may be =CH₂, =CHF; wherein both R₇ and R'₇ are not OH; and when one of R₇ and R'₇ is NH₂, the other is not OH; and when one of R₇ and R₇ is N₃, the other is not OH;

R₈ is H, OR₁₄, N₃, NH₂, or F; and R'₈ is H, F, OH, 0 alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₈ and R₈ together may be =CH₂, =CHF; wherein both R₈ and R₈ are not OH; and when one of R₈ and R₈ is NH₂, the other is not OH; and when one of R₈ and R's is N₃, the other is not OH; or R₇ and R₈ together can form

wherein: R_1O0 is C_1-12 alkyl C_3-8 cycloalkyl, aryl or heteroaryl; wherein any C_1-12 alkyl and C_3-8 cycloalkyl OfR₁₀₀ is unsubstituted or is substituted with 1-3 substituents selected from halogen, hydroxy, carboxy, and C_1-4 alkoxy; and wherein any aryl or heteroaryl OfR₁₀₀ is unsubstituted or is substituted with 1-5 substituents independently selected from R_1Oi; each R₁₀₁ is independently halo, Cj_-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_{1- 4} alkylsulfoyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4 alkylamino, di(C_1-4 alkyl) amino, C_1-4 alkanoyl, C_1-4 alkanoyloxy, or C_1-4 alkyloxycarbonyl;

R₉ is H, CH₃, C₂H₅, orN₃;

R₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

— ,

R₁₀ and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_nl-O-(CH₂)_mCH₃;

R₁₂ is an N-linked amino acid residue {e.g., -NH-CH(CH₃)C0₂alkyl or - NH-CH(isopropyl)-CO₂alkyl); and

R₁₄ is H; nl is 2-5; and m is 10-20.

15. The compound of any one of claims 1-7 wherein R² is selected from:

16. The compound of any one of claims 1 -7 wherein R² is:

wherein:

R₇ is H, ORi₄, N₃, NH₂, or F; and R'₇ is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₇ and R'₇ together may be =CH₂, =CHF; wherein both R₇ and R'₇ are not OH; and when one of R₇ and R'₇ is NH₂, the other is not OH; and when one of R₇ and R'₇ is N₃, the other is not OH;

R₈ is H, ORi₄, N₃, NH₂, or F; and R'₈ is H, F, OH, O alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R₈ and R₈ together may be =CH₂, =CHF; wherein both R₈ and R'₈ are not OH; and when one of R₈ and R₈ is NH₂, the other is not OH; and when one of R₈ and R'₈ is N₃, the other is not OH; or R₇ and R₈ together can form

O. ,O

Y R M, 00

wherein: R₁₀₀ is C_1-12 alkyl C_3-8 cycloalkyl, aryl or heteroaryl; wherein any C_1-12 alkyl and C_3-8 cycloalkyl of R₁₀₀ is unsubstituted or is substituted with 1-3 substituents selected from halogen, hydroxy, carboxy, and C_1-4 alkoxy; and wherein any aryl or heteroaryl OfRi₀₀ is unsubstituted or is substituted with 1-5 substituents independently selected from Ri₀₁; each Rj_O1 is independently halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1- 4 alkylsulfoyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4 alkylamino, di(C_1-4 alkyl) amino, C_1-4 alkanoyl, Ci_-4 alkanoyloxy, or Ci_-4 alkyloxycarbonyl; R₉ is H, CH₃, C₂H₅, or N₃;

R'₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

— O^~C P-OR₁₀ I

R₁₀ and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_ni-O-(CH₂)_mCH₃;

R₁₂ is an N-linked amino acid residue (e.g., -NH-CH(CH₃)C0₂alkyl or - NH-CH(isopropyl)-CO₂alkyl); and

R₁₄ is H; nl is 2-5; and m is 10-20.

17. The compound of any one of claims 1-7 wherein R² is:

18. The compound of any one of claims 1 -7 wherein R² is:

wherein

R₉ is H, CH₃, C₂H₅, or N₃;

R'₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

— O-C -P-OR₁₀ ;

R_1O and R₁₁ are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl, or (CH₂)_nl-O-(CH₂)_mCH₃; R₁₂ is an N-linked amino acid residue (e.g., -NH-CH(CH₃)C0₂alkyl or - NH-CH(isopropyl)-CO₂alkyl); R₁₄ is H; nl is 2-5; and m is 10-20.

19. The compound of any one of claims 1-7 wherein R is:

20. The compound of any one of claims 1-7 wherein R is ribose, 2- methylribose, 2-deoxyribose; 2-deoxy-2-fluororibose; arabinose; 2-deoxy-2- fluoroarabinose; 2,3-dideoxyribose; 2,3-dideoxy-2-fluoroarabinose; 2,3-dideoxy- 3-fluororibose; 2,3-dideoxy-2,3-didehydroribose; 2,3-dideoxy-3-azidoribose; 2,3-dideoxy-3-thiaribose; or 2,3-dideoxy-3-oxaribose; or a pharmaceutically acceptable salt or prodrug thereof.

21. The compound of any one of claims 1-7 wherein R² is thioribose, 2- deoxythioribose; 2-deoxy-2-fluorothioribose; thioarabinose; 2-deoxy-2- fluorothioarabinose; 2,3 -dideoxythioribose; 2,3 -dideoxy-2-fluorothioarabinose; 2,3-dideoxy-3-fluorothioribose; 2,3-dideoxy-2,3-didehydrothioribose; or 2,3- dideoxy-3-azidothioribose; or a pharmaceutically acceptable salt or prodrug thereof.

22. The compound of any one of claims 1-7 wherein R² is 4-hydroxymethyl- cyclopent-2-ene; 2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene; 3-hydroxy-4- hydroxymethylcyclopentane; 2-hydroxy-4-hydroxymethylcyclopentene; 2- fluoro-3 -hydroxy-4-hydroxymethylcyclopentane; 2,3 -dihydroxy-4- hydroxymethyl-5-methylenecyclopentane; 4-hydroxymethylcyclopentane, 2,3- dihydroxy-4-hydroxymethylcyclopentane; or 2,3 -dihydroxymethylcyclobutane; or a pharmaceutically acceptable salt or prodrug thereof.

23. The compound of any one of claims 1-7 wherein R² is 4-hydroxymethyl- pyrrolidine; 2,3-dihydroxy-4-hydroxymethylpyrrolidine; 2/3-hydroxy-4- hydroxymethylpyrrolidine; 2-fluoro-3-hydroxy-4-hydroxymethylpyrrolidine; or 3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine; or a pharmaceutically acceptable salt or prodrug thereof.

24. The compound of any one of claims 1-23 wherein R_a, R_b, R₀, and Ra are independently selected from the group consisting of H, alkyl, and substituted alkyl; or R_a and R_b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or Rb and R₀ together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring.

25. The compound of claim 1 which is a compound of the following formula 11a or lib:

11a lib. or a pharmaceutically acceptable salt or prodrug thereof.

26. The compound of claim 1 which is a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof; wherein X is H or alkyl.

27. The compound of any one of claims 1 -26 which is a prodrug.

28. The compound of any one of claims 1-26 which comprises one or more mono-, di-, or tri-phosphate groups.

29. The compound of any one of claims 1-26 which comprises one or more mono-phosphate groups.

30. The compound of claim 28 or 29 which is a prodrug.

31. The compound of claim 28 wherein one or more pendent hydroxyl groups from the mono-, di-, or tri-phosphate group has been converted to an alkoxy, substituted alkoxy, aryloxy, or substituted aryloxy group.

32. The compound of claim 28 wherein one or more pendent hydroxyl groups from the mono-, di-, or tri-phosphate group has been converted to a group RyO-; wherein each R_y is independently a 1-20 carbon branched or unbranched, saturated or unsaturated chain, wherein one or more of the carbon atoms is optionally replaced with -O- or -S- and wherein one or more of the carbon atoms is optionally substituted with oxo (=0) or thioxo (=S).

33. The compound of claim 28 wherein one or more pendent hydroxyl groups from the mono-, di-, or tri-phosphate group has been converted to a group R₂-N-; wherein each R₂ is a residue of an amino acid.

34. The compound of claim 33 wherein the amino acid is a natural amino acid.

35. The compound of claim 30 which comprises one or more groups of formula:

wherein:

R₁₅ is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or an amino acid;

R₁₆ is H, optionally substituted monocyclic aryl, or optionally substituted monocyclic heteroaryl; and R₁₇ is H, halogen, CN, -CO-R20, -CON(R₂O₂, - CO₂R₂₀, -SO₂R₂₀, -SO₂N(R₂₁)₂, -OR₂₁, -SR₂₁, -R₂₁, -N(R₂O₂, -0-COR₂₀, -O- CO₂R₂₀, -SCOR₂₀, -S-CO₂R₂₀, -NHCOR₂₁, -NHCO₂R₂₁, -(CH₂)_P-OR₂₂, or - (CH₂)_P-SR₂₂; or R₁₆ and R₁₇ are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; or R₁₇ and R₁₈ are connected as described below;

R₁₈ and R₁₉ are each independently H, alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or R₁₈ and R₁₉ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms; or R₁₇ and R₁₈ are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom and R₁₉ is H, alkyl, aryl, heterocycloalkyl, aralkyl, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;

R₂₀ is alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₁ is H, alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₂ is H or lower acyl; n is an integer from 2-5; m is an integer from 10-20; and p is an integer from 2-3.

36. A pharmaceutical composition comprising a compound as described in any one of claims 1-35 and a pharmaceutically acceptable carrier.

37. The composition of claim 36 which further comprises one or more additional anti- viral agents.

38. The composition of claim 37 wherein the one or more anti-viral agents are selected from ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of a serine proteases, an inhibitor of inosine monophosphatedehydrognease, interferon-α, and pegylated interferon-α (peginterferon-α).

39. The composition of any one of claims 36-38 which further comprises one or more additional HCV polymerase inhibitors.

40. The composition of any one of claims 36-39 which further comprises one or more protease inhibitors.

41. The composition of any one of claims 36-40 which further comprises ribavirin.

42. The composition of any one of claims 36-41 which further comprises interferon-α or pegylated interferon-α (peginterferon-α).

43. The composition of claim 36 which further comprises one or more anticancer agents.

44. The composition of claim 43 wherein the one or more anti-cancer agents are selected from alkylating agents, antimetabolites, natural products, and hormonal agents.

45. A method for treating a viral infection in an animal comprising administering to the animal an effective amount of a compound as described in any one of claims 1-35, or a composition as described in any one of claims 36- 44.

46. The method of claim 45 wherein the viral infection is selected from the group consisting of: hepatitis B, hepatitis C, human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile virus.

47. The method of claim 45 wherein the viral infection is HCV.

48. The method of any one of claims 45-47 which further comprises administering to the animal one or more additional HCV polymerase inhibitors.

49. The method of any one of claims 45-48 which further comprises administering to the animal, one or more protease inhibitors.

50. The method of any one of claims 45-49 which further comprises administering ribavirin to the animal.

51. The method of any one of claims 45-50 which further comprises administering interferon-α or pegylated interferon-α (peginterferon-α) to the animal.

52. A method for treating cancer in an animal comprising administering to the animal an effective amount of a compound as described in any one of claims 1-35, or a composition as described in any one of claims 36 and 43-44.

53. The method of claim 52 wherein one or more additional anti-cancer compounds are administered.

54. The method of any one of claims 45-53 wherein the animal is a human.

55. A method for inhibiting a viral RNA or DNA polymerase comprising contacting the polymerase in vitro or in vivo with an effective inhibitory amount of a compound as described in any one of claims 1-35.

56. The method of claim 55 wherein the viral polymerase is an RdRp.

57. A compound as described in any one of claims 1-35 for use in medical therapy.

58. A compound according to any one of claims 1-35 for use in therapy.

59. The use of a compound according to any one of claims 1-35 for treating a viral infection.

60. The use of a compound according to any one of claims 1-35 for treating cancer.