This application is being filed on 29 November 2011, as a PCT International Patent application in the name of Pharmasset, Inc., a U.S. national corporation, applicant for the designation of all countries except the US, and Jinfa Du and

Michael Joseph Sofia, both citizens of the U.S., applicants for the designation of the US only.

Priority

Priority is claimed to U.S. provisional patent application 61/417,946, filed on

November 30, 2010.

Field of the Invention Disclosed herein are 2'-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections.

Background Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. According to the U.S. Center for Disease Control, there are an estimated 4.5 million infected people in the United States alone. According to the World Health

Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver- destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection.

The HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids. The protein products of the HCV gene consist of the structural proteins C, El, and E2, and the non- structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are believed to provide the catalytic machinery for viral replication. The NS3 protease releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain. HCV NS5B polymerase is required for the synthesis of a double-stranded RNA from a single-stranded viral RNA that serves as a template in the replication cycle of HCV. Therefore, NS5B polymerase is considered to be an essential component in the HCV replication complex (K. Ishi, et al, Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249: 108-118). Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.

HCV belongs to a much larger family of viruses that share many common features. Dengue viral infections are problematic in the tropical and subtropical regions of the word. Shi et al. Top. Med. Chem. (2001) 7: 243-276. The dengue virus (DENV) is transmitted to humans by certain mosquitos, and it is has been estimated that up to about 50 million infections occur each year. Parkinson et al. Future Med. Chem. (2010) 2(7): 1181-1203. At the present, there are no specific treatments for dengue viral infections. Fagundes et al. Drug Development Research (2011) 72: 480-500. DENV is comprised of ten proteins that includes three structural proteins (C, prM, and E) and seven non-structural proteins (NS 1 , NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Of these ten proteins, only NS3 and NS5 are known to possess enzymatic activity. A desirable drug substance is one that interferes with the action or function of any one of these ten viral proteins. Flaviviridae Viruses

The Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; flavivruses, which are the primary cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole member is HCV. The flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993,70,37-43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever {Fields Virology, Editors: Fields, B. N., Knipe, D. M, and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter 31 , 931 -959). Flaviviruses of global concern that are associated with human disease include the Dengue Hemorrhagic Fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6, 251 -264; Halstead, S. B., Science, 239:476-481 , 1988; Monath, T. P., New Eng. J. Med, 1988, 319, 64 1-643). The pestivirus genus includes bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called hog cholera virus) and border disease virus (BDV) of sheep (Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, H.J., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41 , 53-98). Human pestiviruses have not been as extensively

characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans. Pestiviruses and hepaciviruses are closely related virus groups within the

Flaviviridae family. Other closely related viruses in this family include the GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV). The hepaci virus group (hepatitis C virus; HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are at least 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus.

The genetic organization of pestiviruses and hepaciviruses is very similar. These positive stranded RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins. The viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed

nonstructural (NS) proteins. The genetic organization and polyprotein processing of the nonstructural protein portion of the ORF for pestiviruses and hepaciviruses is very similar. For both the pestiviruses and hepaciviruses, the mature nonstructural (NS) proteins, in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5 A, and NS5B.

The NS proteins of pestiviruses and hepaciviruses share sequence domains that are characteristic of specific protein functions. For example, the NS3 proteins of viruses in both groups possess amino acid sequence motifs characteristic of serine proteinases and of helicases (Gorbalenya et al., Nature, 1988, 333, 22; Bazan and Fletterick Virology, 1989,171 ,637-639; Gorbalenya et al., Nucleic Acid Res., \989, 17, 3889-3897). Similarly, the NS5B proteins of pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E.V. and Dolja, V.V., Crir. Rev. Biochem. Molec. Biol. 1993, 28, 375-430).

The actual roles and functions of the NS proteins of pestiviruses and hepaciviruses in the lifecycle of the viruses are directly analogous. In both cases, the NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors downstream of its position in the ORF (Wiskerchen and Collett,

Virology, 1991, 184, 341-350; Bartenschlager et al., J. Virol. 1993, 67, 3835-3844; Eckart et al. Biochem. Biophys. Res. Comm. 1993,192, 399-406; Grakoui et al., J. Virol. 1993, 67, 2832-2843; Grakoui et al., Proc. Natl. Acad Sci. USA 1993, 90, 10583-10587; Hijikata et al., J. Virol. 1993, 67, 4665-4675; Tome et al., J. Virol., 1993, 67, 4017-4026). The NS4A protein, in both cases, acts as a cofactor with the NS3 serine protease (Bartenschlager et al., J Virol. 1994, 68, 5045-5055; Failla et al., J. Virol. 1994, 68, 3753-3760; Xu et al., J. Virol., 1997, 71 :53 12-5322). The NS3 protein of both viruses also functions as a helicase (Kim et al., Biochem.

Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson, Arch. Biochem.

Biophys., 1995, 323, 47-53; Warrener and Collett, J. Virol. 1995, 69,1720-1726). Finally, the NS5B proteins of pestiviruses and hepaci viruses have the predicted RNA-directed RNA polymerases activity (Behrens et al, EMBO, 1996, 15, 12-22; Lechmann et al., J. Virol, 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J. Virol, 1998, 72, 9365-9369).

A number of potential molecular targets for drug development of direct acting antivirals as anti-HCV therapeutics have now been identified including, but not limited to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase and the NS5B polymerase. The RNA-dependent RNA polymerase is absolutely essential for replication of the single-stranded, positive sense, RNA genome and this enzyme has elicited significant interest among medicinal chemists.

Inhibitors of HCV NS5B as potential therapies for HCV infection have been reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881 ; Walker, M.P. et al., Exp. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., et al., Current Opinion in Drug Discovery and Development, 2004, 7, 446-459; Beaulieu, P. L., et al., Current Opinion in Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current Drug Targets-Infectious Disorders, 2003, 3, 207-219; Griffith, R.C., et al, Annual Reports in Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., et al., Infectious Disorders-Drug Targets, 2006, 6, 17-29. The potential for the emergence of resistant HCV strains and the need to identify agents with broad genotype coverage supports the need for continuing efforts to identify novel and more effective nucleosides as HCV NS5B inhibitors.

Nucleoside inhibitors of NS5B polymerase can act either as a non-natural substrate that results in chain termination or as a competitive inhibitor which competes with nucleotide binding to the polymerase. To function as a chain terminator the nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site. This conversion to the triphosphate is commonly mediated by cellular kinases which imparts additional structural requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation. In some cases, the biological activity of a nucleoside is hampered by its poor substrate characteristics for one or more of the kinases needed to convert it to the active triphosphate form. Formation of the monophosphate by a nucleoside kinase is generally viewed as the rate limiting step of the three phosphorylation events. To circumvent the need for the initial phosphorylation step in the metabolism of a nucleoside to the active triphosphate analog, the preparation of stable phosphate prodrugs has been reported. Nucleoside phosphoramidate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (McGuigan, C, et al., J. Med. Chem., 1996, 39, 1748-1753; Valette, G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al., Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20, 1091-1098; Lee, W.A., et al., Antimicrobial Agents and Chemotherapy, 2005, 49, 1898); US 2006/0241064; and WO 2007/095269. Also limiting the utility of nucleosides as viable therapeutic agents is their sometimes poor physico chemical and pharmacokinetic properties. These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of nucleosides have been employed. Additional phosphate-containing prodrugs are also known: C. Schultz, Biorg. & Med. Chem. (2003) 1 1 :885-898; C. McGuigan et al., Bioorg. & Med. Chem. Lett. (1994) 4(3): 427-430; C. Meier, Synlett (1998) 233-242; R. J. Jones et al., Antiviral Research (1995) 27: 1-17; G. J. Friis et al., Eur. J. Pharm. Sci. (1996) 4: 49-59; C. Meier Mini Reviews in Medicinal Chemistry (2002) 2(3): 219- 234; C. Perigaud et al., Advances in Antiviral Drug Design; DeClerq E., Ed.; Vol. 2; JAI Press, London, 1996. However, there is no general agreement as to which phosphate-containing prodrug provides for the best activity. In an effort to improve treatment of HCV or DENV, it remains of vital interest to identify compounds capable of inhibiting the action of NS5B polymerase of HCV or of inhibiting the action or function of a particular DENV protein.

Summary

Disclosed herein is a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula I:

is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _1-3 SC(0)(alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _!-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) ₁ _ ₃ SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^ia )(NHCHR ^lb C(0)OR ^lc ),

where

R ^la is

i) hydrogen,

ii) alkyl,

iii) cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) C]- ₆ alkyl,

iii) cycloalkyl,

iv) alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) alkyl,

iii) cycloalkyl, or

iv) alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ ) _1-3 SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide,

1) -P*(O)(OR ^l0 )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ , 0) an acyl,

p) a Ci _-6 -alkylene-oxy-acyl, and

q) a -C(0)-0-alkyl;

) R ² is selected from among

a) hydrogen,

b) fluoro,

c) azido,

d) cyano,

e) a Ci_ ₆ alkyl,

f) a vinyl, and

g) an ethynyl;

) R ³ is selected from among

a) hydrogen,

b) methyl, and

c) cyano,

) Y is selected from among

a) hydrogen,

b) fluoro,

c) -OH,

d) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, e) -O(acyl),

f) -0(C _]-6 -alkylene-oxy-acyl),

g) -0-C(0)-0-alkyl,

h) -NH ₂ ,

1) -NH(acyl),

j) -NH-C(0)-0-alkyl, and

k) azido;

5) X is selected from among

a) -0- b) -S- c) -NH- d) -CH ₂ - e) >C=CH ₂ , and

-NH-C(0)-0-alkyl;

6) is a four- or five-membered ring selected from among radicals a-o

represented by the following structures

b c d where * represents the point of attachment to the 2'-carbon and where

a) A is selected from among

i) -0-,

ii) -S- iii) -S(O)-,

iv) -S(0) ₂ - and

v) -NH-,

b) D is selected from among

i) -O- ii) -S- except for rings i and j,

iii) -S(O)- except for rings i and j,

iv) -S(0) ₂ - except for rings i and j, and

v) -NH- except for rings i and j, vi) -N-,

vii) a methylene except for rings i and j,

viii) a methine, and

ix) a vinylidene except for rings i and j,

c) R ⁴ , R ^4' , R ⁵ , R ^5' , R ⁶ , R ⁷ , R ⁸ , R ⁸ , R ⁹ , and R ^9' are independently selected from among

i) hydrogen,

ii) halo,

iii) C, _-6 alkyl,

iv) hydroxy,

v) alkoxy,

vi) cycloalkoxy,

vii) -O(acyl),

viii) -0(C _1-6 -alkyleneoxyacyl), ix) -0-C(0)-0-alkyl,

x) Ci _-6 alkylene-oxy(alkyl),

xi) alkenyl,

xii) ethynyl,

xiii) -NH ₂ ,

xiv) -NH(alkyl), xv) -NH(cycloalkyl),

xvi) heterocyclyl,

xvii) aryl, and

xviii) heteroaryl; and

7) B is selected from among Bl, B2, and B3 represented by the following structures:

Bl B2 B3 where for B 1 n is 0 or 1 ,

a) when n is 0, is a double-bond and R ¹⁰ is selected from among i) -NH ₂ ,

ii) -NH(alkyl),

iii) -NH(acyl),

iv) -NH-C(0)-0-alkyl,

v) - cycloheteroalkyl,

vi) -heteroaryl,

vii) -O(alkyl),

viii) -O(acyl),

ix) -0(Ci. ₆ alkylene-oxyacyl), and

x) -0-C(0)-0-alkyl, or

b) when n is 1, is a single-bond and R ¹⁰ is selected from among i) =0,

ii) =NH, and

iii) =N(alkyl), and

c) independent of the value of n, R and R are independently selected from among

i) hydrogen,

ii) halo,

iii) cyano,

iv) C _1-6 alkyl,

v) C _2-5 alkenyl, and

vi) C _2-5 alkynyl,

where for B2,

a) R is selected from among

i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH ₂ ,

v) C _1-6 alkyl,

vi) vinyl, and vii) ethynyl,

where for B3 m is 0 or 1 , and is a single or double bond

16 17

a) when m is 0, is a double-bond and R and R are independently selected from among

i) hydrogen,

ii) -NH ₂ ,

iii) -NH(alkyl),

iv) -NH(acyl),

iv) -NH-C(0)-0-alkyl,

v) - cycloheteroalkyl,

vi) -O(alkyl),

vii) -O(acyl),

viii) -CXC^alkyleneoxyacyl), and

ix) -0-C(0)-0-alkyl,

x) -S(alkyl), or

b) when m is 1 , is a single-bond

bl) R ¹⁶ is selected from among

i) =0,

ii) =NH, and

iii) =N(alkyl), and

b2) R ¹⁷ is selected from among

i) -NH ₂ ,

ii) -NH(alkyl),

iii) -NH(acyl),

iv) -NH-C(0)-0-alkyl, and

v) - cycloheteroalkyl,

c) independent of the value of m, each bonding pair, W ¹ -— W ² , W ² _: -C, W ⁴ , W ⁴ ^W ³ , and W^W ¹ , contained in the five- membered ring comprises a single or a double bond and

i) W ¹ is O, S, N, or CR ¹⁴ ,

ii) W ² is N or CR ¹⁵ ,

iii) W ³ is C or N, and

iv) W ⁴ is C or N

and where R ¹⁴ and R ¹⁵ , if present, are independently selected from among

i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH ₂ ,

iv) C _1-6 alkyl,

vii) vinyl, and

viii) ethynyl.

Detailed Description of the Invention

Definitions

The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

The terms "optional" or "optionally" as used herein means that a

subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.

The term "stereoisomer" has its plain and ordinary meaning.

The term "*" denotes the presence of a chiral center. Instances where "*" are not explicitly included in a radical does not necessarily mean that the radical does not contain a chiral center.

The term "P*" means that the phosphorus atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of "R" or "S" which have their accepted plain meanings. In some instances, a phosphorus-containing radical does not expressly include an "*" next to the phosphorus atom, e.g., -P(0)(0(CH ₂ )i. ₃ OC(0)(alkyl)) ₂ ,

-P(0)(0(CH ₂ ) _1-3 SC(0)(alkyl)) ₂ , -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

-P(0)(0(CH ₂ )i _-3 SCH ₂ (aryl)) ₂ . In these (and other) instances, it will be understood that chirality at phosphorus will be dictated by the substituent pattern. That is, when the substituents bound to phosphorus are the same, then achirality at phosphorus will exist, but when the substituents bound to the phosphorus are not the same, then chirality at phosphorus will exist.

The term "salts" or "salt thereof as described herein, refers to a compound comprising a cation and an anion, which can prepared by any process known to one of ordinary skill, e.g., by the protonation of a proton-accepting moiety and/or deprotonation of a proton-donating moiety. Alternatively, the salt can be prepared by a cation/anion metathesis reaction. It should be noted that protonation of the proton-accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a anion, whereas deprotonation of the proton- donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a cation. It is understood that salt formation can occur under synthetic conditions, such as formation of pharmaceutically acceptable salts, or under conditions formed in the body, in which case the corresponding cation or anion is one that is present in the body. Examples of common cations found in the body include, but are not limited to: H ⁺ , Na ⁺ , K ⁺ , g ²⁺ , Ca ²⁺ , etc. Examples of common anions found in the body include, but are not limited to, C1-, HCO3 ^" , C0 ₃ ^2" , H ₂ P0 ₄ ^" , HP0 ₄ ^2" , etc.

The phrase "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. It is understood that the term "pharmaceutically acceptable salt" is encompassed by the expression "salt." Examples of

pharmaceutically acceptable salts include, but are not limited to acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like. Additional examples of anionic radicals of the pharmaceutically acceptable salt include but are not limited to: acetate,

benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, citrate, edetate, edisylate (1 ,2- ethanedisulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycollylarsanilate (p- glycollamidophenylarsonate), hexylresorcinate, hydrabamine (Ν,Ν'- di(dehydroabietyl)ethylenediamine), hydroxynaphthoate, iodide, isethionate (2- hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate

(embonate), pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, and teoclate (8- chlorotheophyllinate). Basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ , Al ³⁺ , NH _g R _4-g ⁺ , in which R is a Ci _-3 alkyl and g is a number selected from among 0, 1 , 2, 3, or 4. Additional examples of cationic radicals of the pharmaceutically acceptable salt, include but are not limited to: penzathine, phloroprocaine, pholine, piethanolamine,

pthylenediamine, meglumine, and procaine. The term "metabolite," as described herein, refers to a compound produced in vivo after administration of a compound or its stereoisomer or its salt or its deuteride thereof represented by formula I to a subject in need thereof or as formed in vitro in an assay. Said metabolite may exist as a salt.

The term "deuteride," as described herein, refers to a deuterated analog of the compound represented by formula I where a hydrogen atom is enriched with its ² H- isotope, i.e., deuterium (D). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium. .

The term "halo" or "halogen" as used herein, includes chloro, bromo, iodo and fluoro.

The term "alkyl" refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term "CI_M alkyl" refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

The term "Ci- alkyl" refers to an alkyl containing 1 to 6 carbon atoms.

Examples of a C _1- alkyl group include, but are not limited to, methyl, ethyl, n- propyl, /-propyl, n-butyl, z ^' -butyl, s-butyl, /-butyl, n-pentyl, isopentyl, neopentyl, t- pentyl, and hexyl.

The term "C _1-6 -alkylene" refers to an alkylene radical containing 1 to 6 carbon atoms. Examples of a C _1-6 -alkylene include, but are not limited to, a methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), methyl-ethylene (-CH(CH ₃ )CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), methyl-propylene (-CH(CH ₃ )CH ₂ CH ₂ - or - CH ₂ CH(CH ₃ )CH ₂ -), etc. It is understood that a branched C _]-6 -alkylene, such as methyl-ethylene or methyl-propylene, contains a chiral center, in which case the individual stereoisomers are contemplated. It is contemplated that a methylene may be substituted with one or two C _1-6 alkyls.

The term "cycloalkyl" refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., a C _3-8 -cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., a C _3-6 -cycloalkyl). In the instance of a substituted carbocycle containing 3 to 10, 3 to 8, or 3 to 6 carbon atoms, the substituents are not to be counted for the carbocycle carbon count. For instance, a cyclohexyl substituted with one or more Q^-alkyl is still, within the meaning contemplated herein, a C ₃ _ ₆ -cycloalkyl. Examples of a C _3-6 cycloalkyl include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, 2- methyl-cyclobutyl, cyclopentyl, 2-methyl-cylcopentyl, cyclohexyl, 2-methyl- cyclohexyl, etc.

The term "cycloalkylamino" refers to a unsubstituted or substituted carbocycle comprising an "amino" (-NH-) functional group. The carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., a C _3-8 - cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., a C _3-6 -cycloalkyl). In the instance of a substituted carbocycle containing 3 to 10, 3 to 8, or 3 to 6 carbon atoms, the substituents are not to be counted for the carbocycle carbon count. For instance, a cyclohexyl substituted with one or more C _1-6 -alkyl is still, within the meaning contemplated herein, a C _3-6 -cycloalkyl. Examples of a C _3-6 cycloalkylamino (alternatively referred to as -NHC _3-6 cycloalkyl) include, but are not limited to, cyclopropylamino, 2-methyl-cyclopropylamino, cyclobutylamino, 2-methyl- cyclobutylamino, cyclopentylamino, 2-methyl-cyclopentylamino, cyclohexylamino, 2-methyl-cyclohexylamino, etc. One of ordinary skill will know that said cycloalkylaminos are derived from cycloalkylamines, i.e., cycloalkyls substituted by an amine (-NH ₂ ) functional group.

The term "alkoxy" refers to an -O-alkyl group or an -O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above. Examples of -O-alkyl groups include, but are not limited to, methoxy, ethoxy, «-propyloxy, z ^' -propyloxy, n- butyloxy, -butyloxy, -butyloxy, etc. Examples of -O-cycloalkyl groups include, but are not limited to, -O-opropyl, -O-c-butyl, -O-c-pentyl -O-c-hexyl, etc.

The term "Ci _-6 -alkoxy" refers to an -0-Ci _-6 -alkyl group, wherein C _1-6 alkyl is defined herein.

The term "C ₃ . ₆ -cycloalkoxy" refers to an -0-C _3-6 -cycloalkyl group

The term "C) _-6 -alkylene-oxy" refers to an -0-Ci _-6 -alkylene group, wherein Ci _-6 -alkylene is defined as above. Examples of a C] _-6 -alkylene-oxy include, but are not limited to, methylene-oxy (-CH ₂ 0-), ethylene-oxy (-CH ₂ CH ₂ 0-), methyl- ethylene-oxy (-CH(CH ₃ )CH ₂ 0-), propylene-oxy (-CH ₂ CH ₂ CH ₂ 0-), methyl- propylene-oxy (-CH(CH ₃ )CH ₂ CH ₂ 0- or -CH ₂ CH(CH ₃ )CH ₂ 0-), etc.

The terms "alkaryl" or "alkylaryl" refer to an alkylene group having 1 to 10 carbon atoms with an aryl substituent, such as benzyl. The term "Ci _-3 alkaryl" refers to a Ci _-3 alkylene group with an aryl substituent. Benzyl is embraced by the term Cj. ₃ alkaryl.

The term "-OCi _-3 alkaryl" refers a oxygen (-0~) bound to a Ci _-3 alkaryl group. Benzyloxy (-OCH ₂ Ph) is embraced by the term -OCi _-3 alkaryl.

The term "aryl," as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl. The aryl group can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.

The term "heteroaryl" refers to an unsubstituted or substituted aromatic heterocycle containing carbon, hydrogen, and at least one of N, O, and S. Examples of heteroaryls include, but are not limited to, a pyrrole, an imidazole, a diazole, a triazole, a tetrazole, a furan, an oxazole, an indole, a thiazole, etc. Additional examples of heteroaryls can be found in T.L. Gilchrist, in "Heterocyclic Chemistry," John Wiley & Sons, 1985. The heteroaryl group can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.

The term "heterocycle" or "heterocyclyl" refers to an unsubstituted or substituted radical containing carbon, hydrogen and at least one of N, O, and S.

Examples of heterocycles, include, but are not limited to, an aziridine, an azetidine, a pyrrolidine, a piperidine, a piperazine, etc. Additional examples of heterocycles can be found in T.L. Gilchrist, in "Heterocyclic Chemistry," John Wiley & Sons, 1985. The heterocycle can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999. The terms "alk(heteroaryl)" and "alk(heterocyclyl)" refers to a Ci _-6 -alkylene group with a heteroaryl and heterocyclyl substituent, respectively.

The term "cycloheteroalkyl" refers to an unsubstituted or substituted heterocycle, in which the heterocycle contains 2 to 9 carbon atoms; preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms. Examples of cycloheteroalkyls include, but are not limited to, aziridin-l-yl, aziridin-2-yl, iV-Ci, ₃ -alkyl-aziridin-2-yl, azetidinyl, azetidin-l-yl, N-Ci_ ₃ -alkyl-azetidin-m'-yl, pyrrolidin-m'-yl, pyrrolidin-1- yl, 7V-Ci _-3 -alkyl-pyrrolidin-m'-yl, piperidin-m'-yl, piperidin-l -yl, and N-Ci _-3 -alkyl- piperidin-m'-yl, where m' is 2, 3, or 4 depending on the cycloheteroalkyl. Specific examples of N-Ci _-3 -alkyl-cycloheteroalkyls include, but are not limited to, N- methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl- pyrrolidin-4-yl, N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, and N-methyl- piperidin-4-yl. In the instance of R ¹⁰ , R ¹⁶ , and R ¹⁷ , the point of attachment between the cycloheteroalkyl ring carbon and the ring occurs at any one of m'.

The term "acyl" refers to a substituent containing a carbonyl moiety and a non-carbonyl moiety and is meant to include an amino-acyl. The carbonyl moiety contains a double-bond between the carbonyl carbon and a heteroatom, where the heteroatom is selected from among O, N and S. When the heteroatom is N, the N is substituted by a

Ci- ₆ - The non-carbonyl moiety is selected from straight, branched, and cyclic alkyl, which includes, but is not limited to, a straight, branched, or cyclic Ci-20 alkyl, CMO alkyl, or a Ci _-6 -alkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyl optionally substituted with halogen (F, CI, Br, I), hydroxyl, Q to C ₄ alkyl, or Ci to C ₄ alkoxy, sulfonate esters, such as alkyl or aralkyl sulphonyl, including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least one aryl group is present in the non-carbonyl moiety, it is preferred that the aryl group comprises a phenyl group.

The term "C _2-7 acyl" refers to an acyl group in which the non-carbonyl moiety comprises a Ci _-6 alkyl. Examples of a C _2-7 -acyl, include, but are not limited to: -C(0)CH ₃ , -C(0)CH ₂ CH ₃ , -C(0)CH(CH ₃ ) ₂ , -C(0)CH(CH ₃ )CH ₂ CH ₃ , - C(0)C(CH ₃ ) ₃ , etc. The term "aminoacyl" includes Ν,Ν-unsubstituted, N,N-monosubstituted, and Ν,Ν-disubstituted derivatives of naturally occurring and synthetic α, β γ or δ amino acyls, where the amino acyls are derived from amino acids. The amino- nitrogen can be substituted or unsubstituted or exist as a salt thereof. When the amino-nitrogen is substituted, the nitrogen is either mono- or di-substituted, where the substituent bound to the amino-nitrogen is a Ci_ ₆ alkyl or an alkaryl. In the instance of its use for the compound of formula I, it is understood that an

appropriate atom (O or N) is bound to the carbonyl carbon of the aminoacyl.

The term "amino acid" includes naturally occurring and synthetic α, β γ or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β- threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β- glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of α, β γ or δ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the D and L-configurations.

The term "Ci_ ₆ -alkylene-oxy-acyl" refers to an -0-C). ₆ -alkylene-acyl group, wherein Ci _-6 -alkylene and acyl are defined as above. Examples of a Cj. ₆ -alkylene- oxy-acyl include, but are not limited to, methylene-oxy-acyl (-CH ₂ 0-C(0)alkyl), ethylene-oxy-acyl (-CH ₂ CH ₂ 0-C(0)alkyl), methyl-ethylene-oxy-acyl (- CH(CH ₃ )CH ₂ 0-C(0)alkyl), propylene-oxy-acyl (-CH ₂ CH ₂ CH ₂ 0- C(O)alkyl), methyl-propylene-oxy-acyl (-CH(CH ₃ )CH ₂ CH ₂ 0- C(0)alkyl or -

CH ₂ CH(CH ₃ )CH ₂ 0- C(O)alkyl), etc. As the expression "acyl" encompasses "aminoacyl," further contemplated radicals include but are not limited to C _1-6 -alkyl- oxy-aminoacyl, where aminoacyl is defined above. The term "alkenyl" refers to an unsubstituted or a substituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or more olefinic double bonds. The term "C _2- N alkenyl" refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. For example, the term "C2- 10 alkenyl" refers to an alkenyl comprising 2 to 10 carbon atoms. The term "C _2-4 alkenyl" refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl) or 2- butenyl (crotyl). It is understood that the alkenyl or C _2- N-alkenyl can be substituted with one or more radicals selected from among alkyl, halo, alkoxy, aryloxy, nitro, and cyano.

The term "vinyl," which is embraced by the term "C _2-4 alkenyl," refers to -CR— CR"R"', where R', R", and R'" are independently selected from among hydrogen, Ci _-6 -alkyl, halo, and Ci _-6 -alkoxy. Examples of a vinyl include, but are not limited to, ethenyl (-CH=CH ₂ ), 2-bromo-ethenyl (-CH=CHBr), etc.

The term "ethynyl," as used herein, refers to -C≡CR', where R' is selected from among hydrogen, Ci _-6 -alkyl, halo, and C]_ ₆ -alkoxide.

The term "methine," as used herein, refers to the radical -CR— , where R' is selected from among hydrogen, Ci _-6 alkyl, halo, and Ci_ ₆ -alkoxide.

The term "vinylidene," as used herein, refers to >C=CRR', where R and R are independently selected from among hydrogen, Ci_ -alkyl, halo, and Ci- - alkoxide.

The expressions -P(0)(OH) ₂ , -P(0)(OH)-OP(0)(OH) ₂ , and -P(0)(OH)-0- P(0)(OH)-0-P(0)(OH) ₂ , refer to mono- (P,), di- (P ₂ ), and tri- (P ₃ ) phosphate radicals, respectively.

O O O O O O

I I I I I I I I I I I I

P P P P P P

OH OH OH OH OH OH

Pl ^P 2 ^P 3

The Pi, P ₂ , and P ₃ phosphate radicals may be introduced at the 5'-OH of a nucleoside compound either by synthetic means in the lab or by enzymatic (or metabolic) means in a cell or biological fluid (either in vivo or in vitro). It is understood that the acidities of the hydroxyl (-OH) substituents vary and that salts of the phosphate radicals are possible. The term "-P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc )" or "phosphoramidate" as used herein is represented by the following structure:

where R ^la , R ^lb , and R ^lc are as defined above. Examples of phosphoramidate moieties are described in U.S. Patent No. 7,964,580. It will be understood that the ~NHCH*(R ^lb )C(0)OR ^lc fragment can be derived from an amino acid, which is defined above.

Under the Summary, certain definitions related to R ¹ , 1)1), and Y, 4)d), include the expressions "-P*(0)(OR ^lc )~" (see R ¹ , 1)1)) and "-0~" (see Y, 4)d)). It is understood that when R ¹ is "-P*(0)(OR ^lc )~" and Y is "-0~" or when Y is "-0~' and R ¹ is "-P(0)(OR ^lc )~", then compound I has the structure shown on the left, where the R ¹ and Y substituents are identified on the ri ht:

Y

It is understood that use of the expression "cyclophosphate" or "cyclic-phosphate" is meant to embrace the left-hand structure. These expressions likewise have the same meanings when recited as definitions for certain embodiments and aspects of those embodiments.

The term " a l ,3,2-dioxaphosphinane-2-oxide," as used herein is represented by an unsubstituted form (jl) or a substituted form (j2), as represented by the following structures:

jl) j2) where R _n is selected from among hydroxy, an alkyl, a hydroxyalkyl, an aryloxide, an aryl, such as phenyl, a heteroaryl, such as pyridinyl, where the aryl and the heteroaryl can be substituted by 1 -3 substituents independently selected from among an alkyl, an alkoxy, and a halo. A preferred R _n is pyridinyl which can be substituted by 1-3 substituents independently selected from among a Ci- alkyl, a Ci _-6 -alkoxy, and a halo.

The term "aryloxide," or "aryloxy" as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenoxide (PhO-), p-phenyl- phenoxide (p-Ph-PhO-), or naphthoxide, preferably the term aryloxide refers to substituted or unsubstituted phenoxide. The aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, -C(0)(Ci _-6 alkyl), -C(0)0(Ci _-6 alkyl), amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.

The term "4H-benzo[d][l,3,2]dioxaphosphine-2-oxide," as used herein is represented by an unsubstituted form (kl) or a substituted form (k2), as represented by the followin

kl) k2)

where R _n and R' _n , where R _n is hydrogen and one alkyl radical, or two alkyl radicals independent of one another, and R' _n is one, two, or three radicals selected from among alkyl, alkoxy, aryloxy, and halo. Preferably, R' _n is one, two, or three radicals selected from among a Ci _-6 alkyl, a C _1-6 , alkoxy, and a halo. More preferably, R' _n is one radical selected from among a C _1-6 -akyl, a Ci _-6 -alkoxy, and a halo.

In the structure B3, as a possible radical for B, the language "each bonding pair, W ^] ™W ² , W ² ^C, C^W ⁴ , W ⁴ ^W ³ , and W^W ¹ , contained in the five- membered ring comprises a single or a double bond" is presented above.

B3

In the event that resolution problems or printing errors might obscure the pictoral representation of B3, it is contemplated that there exists a bonding configuration represented by "^" between each one of w'^W ² , W ² ^C, C^W ⁴ , W^W ³ , and W ³ — W ¹ , within the five-membered ring framework, where "^^" is understood to be a single- or double-bond. It is not contemplated that all bonding pairs contained in the five-membered ring therein are all double bonds or all single bonds. Rather, it is contemplated that when a certain definitional requirement is selected, then the bonding arrangement of the five-membered ring satisfies Huckel's rule, i.e., the total number of pi-bond and lone-pair electrons for the selected radicals is 6. For example, when W ¹ is O or S, W ² is CR ¹⁵ , W ³ is C, and W ⁴ is C (see 1-3-12 or 1-3-13), then the contemplated structure is:

Formula I is recited above. Implicit to formula I is the exclusion of compounds disclosed in B. R. Babu et al. Org. Biomol. Chem. (2003) 1 : 3514-3526, whether said compounds are explicitly or implicitly disclosed therein. For instance, the compounds identified there as 9b, 14b, 21, and 27, are not contemplated to be within the sco e of formula I (as well as formula 1-1 resented below

9b 14b 21 27

However, these compounds, as well as derivatives embraced by formula I, are contemplated for treating a subject infected by HCV or DENV and are contemplated for compositions useful for treating a subject infected by HCV or DENY, as explained in further detail below. The compound numbering for compounds 9b, 14b, 21, and 27 is as found in Babu et al. It should be noted that compounds 21 and 27 are exemplified herein with the numbering here of 36 and 32, respectively.

The term "effective amount" as used herein means an amount required to reduce symptoms of the disease in a subject.

The term "subject," as used herein means a mammal.

The term "medicament," as used herein means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof.

The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.

The term "excipient" as used herein refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.

As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. "Treatment" is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. The term "treatment" of an HCV infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.

The term "protecting group" which is derived from a "protecting compound," has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., -OH, -NH ₂ , etc.) that allows chemical modification of at least one other functional group. Examples of protecting groups, include, but are not limited to, benzoyl, acetyl, phenyl-substituted benzoyl, tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl) group, thiopixyl (9- phenylthioxanthen-9-yl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)- alkyl, C(0)Ph, C(0)aryl,

C(0)0(C _1-6 alkyl), C(0)0(C _]-6 alkylene)aryl (e.g., -C(0)OCH ₂ Ph), C(0)Oaryl, CH ₂ 0-alkyl, CH ₂ 0-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, a protecting group comprising at least one silicon atom, such as, teri-butyldimefhylsilyl, feri-butyldiphenylsilyl,

Si(Ci _-6 alkyl) ₂ OSi(C _1-6 alkyl) ₂ OH, such as, -Si PrhOSiCPrhOH or

~OSi('Pr) ₂ OSi('Pr) ₂ 0~. Additional examples are disclosed in e.g., Protective Groups in Organic Synthesis, 3 ^nd ed. T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, N.Y., 1999).

The term "leaving group" ("LG") as used herein, has its plain and ordinary meaning for one of ordinary skill in this art. Examples of leaving groups include, but are not limited to: halogen (CI, Br, or I); tosylate, mesylate, triflate, acetate, etc.

Embodiments

A first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula I-l

I-l wherein R ¹ , R ² , Y, R ³ , ¾ X, R ¹⁰ , R ¹¹ , R ¹² , n, and™ have the meanings described above.

A first aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula I-l

wherein

1) R is selected from among

a) hydrogen, b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) ₁ . ₃ OC(0)(C _I _ ₆ alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _1-3 SC(0)(C ₁ . ₆ alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) Ci_ ₆ alkyl,

iii) C ₃ _ ₆ cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) Ci_ ₆ alkyl,

iii) C _3-6 cycloalkyl,

iv) C^alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) Ci_ ₆ alkyl,

iii) C _3-6 cycloalkyl, or

vi) Ci _-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ ) _1-3 SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide,

1) -P*(O)(OR ^l0 )~, when Y is -0~, where R ^lc is defined above, m) -Ρ(0)(ΟΗ)-0-Ρ(0)(ΟΗ) ₂ ,

n) -Ρ(0)(ΟΗ)-0-Ρ(0)(ΟΗ)-0-Ρ(0)(ΟΗ) ₂ ,

o) a C _2-7 acyl,

p) an aminoacyl

q) a C] _-6 -alkylene-oxy-C _2-7 acyl, and

r) a -C(0)-0-C _I-6 alkyl;

2) R ² is selected from among

a) hydrogen,

b) fluoro,

c) azido, and

d) cyano;

3) R ³ is selected from among

a) hydrogen,

b) methyl, and

c) cyano,

4) Y is selected from among

a) hydrogen,

b) fluoro,

c) -ΟΗ,

d) -0~, when R ¹ is -P(O)(OR ^l0 )~, where R ^lc is defined above, e) -0(C _2-7 acyl),

f) -O(aminoacyl), g) -0(Ci.6-alkylene-oxy-acyl),

h) -0-C(0)-0-C _1-6 alkyl,

i) -NH ₂ ,

j) -NH(C _2-7 acyl),

k) -NH(aminoacyl),

1) -NH-C(0)-0-C,. ₆ alkyl and

m) azido;

5) X is selected from among

a) -O- and

-S-;

is a four- or five-membered ring selected from among radicals c,

d, e, f, g, and h, represented by the following structures

where * represents the point of attachment to the 2'-carbon and where

a) A is selected from among

i) -0- ii) -S- iii) -S(O)- iv) -S(0) ₂ - and

v) -NH-,

b) D is selected from among

i) -O- ii) -S- iii) -S(O)- iv) -S(0) ₂ -, and

v) -NH-,

vi) a methylene, and

vii) a vinylidene,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are independently selected from among

i) hydrogen,

ii) halo,

iii) C _1-6 alkyl

iv) hydroxy,

v) alkoxy,

vi) cycloalkoxy,

vii) -O(acyl),

viii) -0(Ci _-6 -alkyleneoxyacyl),

ix) -0-C(0)-0-alkyl,

x) Ci _-6 alkylene-oxy(alkyl),

xi) alkenyl, xii) ethynyl,

xiii) -NH ₂ ,

xiv) -NH(alkyl),

xv) -NH(cycloalkyl),

xvi) heterocyclyl,

xvii) aryl, and

xviii) heteroaryl; and

7a) n is 0, is a double-bond and R ¹⁰ is selected from among

i) -NH ₂ ,

ii) -NH(C, _-6 alkyl),

iii) -NH(acyl),

iv) -NH-C(0)-0-alkyl,

v) - cycloheteroalkyl,

vi) -heteroaryl,

vii) -O(alkyl),

viii) -O(acyl),

ix) -0(Ci _-6 alkylene-oxyacyl), and x) -0-C(0)-0-alkyl, or

7b) n is 1, is a single-bond and R ¹⁰ is selected from among

i) =0,

ii) =NH, and

iii) =N(alkyl); and

7c) independent of the value of n, R ¹¹ and R ¹² are independently selected from among

i) hydrogen,

ii) halo,

iii) cyano,

iv) Ci _-6 alkyl,

v) C _2-5 alkenyl, and

vi) C _2-5 alkynyl.

A second aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-1

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ )i _-3 OC(0)0(C _I-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _1-3 SC(0)(C _1-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) C _1-6 alkyl, iii) C3_ ₆ cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl,

iv) Ci_ ₃ alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) Ci _-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) Ci _-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i- ₃ SC(0)(alkyl)), j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinuie-2-oxide,

1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

o) a C _2-7 acyl,

p) an aminoacyl,

q) a Ci_6-alkylene-oxy-C ₂ - ₇ acyl, and

r) a -C(0)-0-Ci_ ₆ alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C _2-7 acyl),

d) -O(aminoacyl),

e) -0(Ci _-6 -alkylene-oxy-acyl), and

f) -0-C(0)-0-Ci _-6 alkyl; a four- or five-membered ring selected from among radicals

g, and h, represented by the following structures

where * represents the point of attachment to the 2'-carbon and where

a) A is selected from among

-O-,

ii) -S-, iii) -S(O)-,

iv) -S(0) ₂ - and

v) -NH-,

b) D is selected from among

i) -0-,

ii) -S- iii) -S(O)- iv) -S(0) ₂ - v) -NH-,

vi) a methylene, and

vii) a vinylidene,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are independently selected from among i) hydrogen,

ii) halo, and

iii) Ci _-6 alkyl; and

7a) n is 0, is a double-bond and R ¹⁰ is selected from among

i) -NH ₂ ,

ii) -NH(C,_ ₆ alkyl),

iii) -NH(C _2-7 acyl), and

iv) -NH-C(0)-0-C , . ₆ alkyl, or

7b) n is 1 , is a single-bond and R ¹⁰ is selected from among

i) =0 and

ii) =N(alkyl), and

7c) independent of the value of n, R ^{1 1} and R ¹² are independently selected from among

i) hydrogen,

ii) halo,

iv) Ci- ₆ alkyl, and

v) C _2- alkenyl.

A third aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-1

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ )i _-3 SC(0)(C _I-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or iv) aryl,

R ^lb is

i) hydrogen,

ii) Ci _-6 alkyl,

iii) C _3-6 cycloalkyl,

iv) Ci_ ₃ alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or

vi) Ci_ ₃ alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ ) _I-3 SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

o) a C _2-7 acyl,

p) an aminoacyl,

q) a Ci-6-alkylene-oxy-C ₂ - ₇ acyl, and

r) a -C(0)-0-C,. ₆ alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C _2-7 acyl),

d) -O(aminoacyl),

e) -0(Ci _-6 -alkylene-oxy-acyl), and

f) -0-C(0)-0-Ci_ ₆ alkyl; a f° ^ur " ^or five-membered ring selected from among radicals c,

d, e, f, g, and h, represented by the following structures

where * represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -0- or -CH ₂ -,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are each hydrogen; and

7a) n is 0, is a double-bond and R ¹⁰ is selected from among i) -NH ₂ ,

ii) -NH(C _1-6 alkyl),

iii) -NH(C _2-7 acyl), and

iv) -NH-C(0)-0-C _1-6 alkyl, or

7b) n is 1 , is a single-bond and R ¹⁰ is selected from among

i) =0 and

ii) =N(alkyl), and

7c) independent of the value of n, R ^{1 1} and R ¹² are independently selected from among

i) hydrogen,

ii) halo,

iv) Ci_ ₆ alkyl, and

v) C _2-4 alkenyl.

A fourth aspect of the first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-1

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _]-3 OC(0)0(C _I-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _1-3 SC(0)(C _1-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen or

iv) aryl,

R ^lb is

i) hydrogen or

ii) Ci _-6 alkyl, and

R ^lc is

i) hydrogen

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) C _1-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ ) _1-3 SC(0)(alkyl)), j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide, 1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

o) a C _2- acyl,

p) an aminoacyl,

q) a Ci _-6 -alkylene-oxy-C _2-7 acyl, and r) a -C(0)-0-C,. ₆ alkyl;

2) R ² is hydrogen;

3) R is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C ₂ _ ₇ acyl), and

d) -O(aminoacyl); a f° ^ur " ^or five-membered ring selected from among radicals c,

d, e, and f represented by the following structures c d e f where * represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -0- or -CH ₂ -,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are each hydrogen; and

7a) n is 0, is a double-bond and R ¹⁰ is selected from among

i) -NH ₂ ,

ii) -NH(C,_ ₆ alkyl),

iii) -NH(C _2-7 acyl), and

iv) -NH-C(0)-0-C _1-6 alkyl, or

7b) n is 1 , is a single-bond and R ¹⁰ is selected from among

i) =0 and

ii) =N(alkyl), and

7c) independent of the value of n, R ^{1 1} and R ¹² are independently selected from among

i) hydrogen,

ii) halo,

iv) Ci^alkyl, and

v) C _2-4 alkenyl.

A second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2

wherein

wherein R ¹ , R ² , Y, R ^1J have the meanings described above.

A first aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2 wherein

is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C ₁ . ₆ alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) ₁ . ₃ SC(0)(C ₁ _ ₆ alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _]-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) Ci _-6 alkyl,

iii) C ₃ _ ₆ cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl,

iv) C _1-3 alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) C _1-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i _-3 SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide, 1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

0) a C _2-7 acyl,

p) an aminoacyl,

q) a Ci _-6 -alkylene-oxy-C ₂ _ ₇ acyl, and

r) a -C(0)-0-C _1-6 alkyl;

2) R ² is selected from among

a) hydrogen,

b) fluoro,

c) azido, and

d) cyano;

3) R ³ is selected from among

a) hydrogen,

b) methyl, and

c) cyano,

4) Y is selected from among

a) hydrogen,

b) fluoro,

c) -OH,

d) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, e) -0(C _2-7 acyl),

f) -O(aminoacyl),

g) -0(Ci _-6 -alkylene-oxy-acyl),

h) -0-C(0)-0-Ci _-6 alkyl,

1) -NH ₂ ,

j) -NH(C _2-7 acyl),

k) -NH(aminoacyl),

1) -NH-C(0)-0-C,. ₆ alkyl, and

m) azido;

5) X is selected from among

a) -O- and

b) -S-;

6) (^^) i ^{s a} f° ^ur " ^or five-membered ring selected from among radicals d, e, f, g, and h, represented by the following structures

where * represents the point of attachment to the 2'-carbon and where

a) A is selected from among

i) -0- ii) -S- iii) -S(O)-,

iv) -S(0) ₂ -, and

v) -NH-,

b) D is selected from among

i) -0- ii) -S-,

iii) -S(O)-,

iv) -S(0) ₂ -, and

v) -NH-,

vi) a methylene, and

vii) a vinylidene,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are independently selected from among

i) hydrogen,

ii) halo,

iii) Ci _-6 alkyl

iv) hydroxy,

v) alkoxy,

vi) cycloalkoxy,

vii) -O(acyl),

viii) -0(Ci_6-alkyleneoxyacyl),

ix) -0-C(0)-0-alkyl,

x) Ci _-6 alkylene-oxy(alkyl),

xi) alkenyl,

xii) ethynyl,

xiii) -NH ₂ ,

xiv) -NH(alkyl),

xv) -NH(cycloalkyl),

xvi) heterocyclyl,

xvii) aryl, and

xviii) heteroaryl; and

7) R ¹³ is hydrogen.

A second aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ )i _-3 SC(0)(Ci _-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^,a is

i) hydrogen, ii) Ci _-6 alkyl,

iii) C _3- cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) C _1-6 alkyl,

iii) C3 _-6 cycloalkyl,

iv) Ci _-3 alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) Ci_ ₆ alkyl,

iii) C ₃ _ cycloalkyl, or

iv) Ci _-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i- ₃ SC(0)(alkyl)), j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l ,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^lc )~ _> when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ , o) a C _2-7 acyl,

p) an aminoacyl,

q) a Ci _-6 -alkylene-oxy-C ₂ _ ₇ acyl, and

r) a -C(0)-0-C,_ ₆ alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C ₂ . ₇ acyl),

d) -O(aminoacyl),

e) -0(Ci _-6 -alkylene-oxy-acyl), and

f) -0-C(0)-0-C _]-6 alkyl;

-;

is a four- or five-membered ring selected from among radicals c,

d, e, f, g, and h, represented by the following structures

g where * represents the point of attachment to the 2 '-carbon and where

a) A is selected from among

-O-, ϋ) -S-,

iii) -S(O)- iv) -S(0) ₂ - and

v) -NH-,

b) D is selected from among

i) -0- ii) -S- iii) -S(O)- iv) -S(0) ₂ - and

v) -NH-,

vi) a methylene, and

vii) a vinylidene,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are independently selected from among i) hydrogen,

ii) halo,

iii) Ci_ ₆ alkyl; and

7) R ¹³ is hydrogen.

A third aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ )i _-3 OC(0)0(Ci _-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ )i _-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ )i _-3 SC(0)(C ₁ . ₆ alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _!-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ )i _-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^Ib C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) Ci _-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl,

iv) C _1-3 alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) C _1-3 alkaryl, i) -P*(0)(NH(alkaryl)(0(CH ₂ )i. ₃ SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^ic )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-O-P(O)(OH)-O-P(O)(OH) ₂ ,

o) a C _2-7 acyl,

p) an aminoacyl,

q) a C _1-6 -alkylene-oxy-C2 _-7 acyl, and

r) a -C(0)-0-C _1-6 alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C ₂ . ₇ acyl),

d) -O(aminoacyl),

e) -0(C _]-6 -alkylene-oxy-acyl), and

f) -0-C(0)-0-Ci _-6 alkyl; a f° ^ur " ^or five-membered ring selected from among radicals c,

d, e, f, g, and h, represented by the following structures

c a e i g n where * represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -O- or -CH ₂ - and

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are each hydrogen; and

7) R is hydrogen.

A fourth aspect of the second embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-2

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C _1-6 alkyl)) ₂ , e) -P(0)(0(CH ₂ ) ₁ . ₃ SC(0)(C _1-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) ₁ _ ₃ OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen or

iv) aryl,

R ^lb is

i) hydrogen or

ii) C _1-6 alkyl, and

R ^lc is

i) hydrogen

ii) C _1-6 alkyl,

iii) C3_ ₆ cycloalkyl, or

iv) Ci _-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i _-3 SC(0)(alkyl)),

j) a l ,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide, 1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

o) an C _2-7 acyl,

p) an aminoacyl,

q) a Ci-6-alkylene-oxy-C _2-7 acyl, and

r) a -C(0)-0-Ci _-6 alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C ₂ - ₇ acyl), and

d) -O(aminoacyl); a f° ^ur " ^or five-membered ring selected from among radicals c,

d, e, and f represented by the following structures c d e f where * represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -O- or -CH ₂ - and

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are each hydrogen; and

7) R ¹³ is hydrogen. A third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3

1-3 wherein R ¹ , R ² , Y, R ³ , 0, X, W ¹ , W ² , W ³ , W ⁴ , R ¹⁶ , R ¹⁷ , m, and™ have meanings described above.

A first aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ),_ ₃ OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _1-3 SC(0)(C _1-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ),. ₃ OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) aryl,

R ^,b is

i) hydrogen,

ii) Ci _-6 alkyl,

iii) C ₃ . ₆ cycloalkyl,

iv) C _1-3 alkaryl, or

v) alk(heteroaryl), and

R ^Ic is

i) hydrogen ii) Ci. ₆ alkyl,

iii) C _3-6 cycloalkyl, or

iv) Ci_ ₃ alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i. ₃ SC(0)(alkyl)),

j) a l ,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l ,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

0) a C ₂ . ₇ acyl,

p) an aminoacyl,

q) a Ci_6-alkylene-oxy-C _2-7 acyl, and

r) a -C(0)-0-Ci _-6 alkyl;

) R ² is selected from among

a) hydrogen,

b) fluoro,

c) azido, and

d) cyano;

) R ³ is selected from among

a) hydrogen,

b) methyl, and

c) cyano;

) Y is selected from among

a) hydrogen,

b) fluoro,

c) -OH,

d) -0~, when R ¹ is -P(0)(OR ^Ic )~, where R ^lc is defined above, e) -0(C ₂ _ ₇ acyl),

f) -O(aminoacyl),

g) -0(C _1- -alkylene-oxy-acyl),

h) -0-C(0)-0-C _1-6 alkyl,

1) -NH ₂ ,

j) -NH(C _2-7 acyl),

k) -NH(aminoacyl),

1) -NH-C(0)-0-Ci. ₆ alkyl, and

m) azido;

5) X is selected from among

a) -O- and

-S-;

6) is a four- or five-membered ring selected from among radicals c,

d, e, f, g, and h, represented by the following structures

where * represents the point of attachment to the 2'-carbon and where

a) A is selected from among

i) -0- ii) -S- iii) -S(O)-,

iv) -S(0) ₂ - and

v) -NH-,

b) D is selected from among

i) -0- ii) -S- iii) -S(O)- iv) -S(0) ₂ - and

v) -NH-,

vi) a methylene, and

vii) a vinylidene, and

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are independently selected from among

i) hydrogen,

ii) halo,

iii) Ci _-6 alkyl

iv) hydroxy,

v) alkoxy,

vi) cycloalkoxy,

vii) -O(acyl),

viii) -CXC^-alkyleneoxyacyl),

ix) -0-C(0)-0-alkyl,

x) Ci_ ₆ alkylene-oxy(alkyl),

xi) alkenyl,

xii) ethynyl,

xiii) -NH ₂ ,

xiv) -NH(alkyl),

xv) -NH(cycloalkyl),

xvi) heterocyclyl,

xvii) aryl, and

xviii) heteroaryl; and

7a) m is 0, is a double-bond and R ¹⁶ and R ¹⁷ are independently selected from among

i) hydrogen,

ii) -NH ₂ ,

iii) -NH(C _1-6 alkyl),

iv) -NH(C _2-7 acyl),

iv) -NH-C(0)-0-C _1-6 alkyl,

v) - cycloheteroalkyl, vi) -0(C,. ₆ alkyl),

vii) -0(C _2-7 acyl),

viii) -0(Ci_ ₆ alkyleneoxyacyl),

ix) -0-C(0)-0-C _1-6 alkyl,

x) -S(Ci _-6 alkyl), and

xi) -OCi _-3 alkaryl,

7b) m is 1 , is a single-bond and

bl) R ¹⁶ is selected from among

i) =0,

ii) =NH, and

iii) =N(C _1-6 alkyl), and

b2) R ¹⁷ is selected from among

i) -NH ₂ ,

ii) -NH(C _1-6 alkyl),

iii) -NH(C ₂ . ₇ acyl),

iv) -NH-C(0)-0-Ci _-6 alkyl, and

v) - cycloheteroalkyl, and

7c) independent of the value of m, each bonding pair, W ¹ — W ² , W ² ~ „C, C^W ⁴ , W^W ³ , and W ³ -~-W contained in the five- membered ring comprises a single or a double bond and i) W ¹ is O, S, N, or CR ¹⁴ ,

ii) W ² is N or CR ¹⁵ ,

iii) W ³ is C or N, and

iv) W ⁴ is C or N, and

where R ¹⁴ and R ¹⁵ , if present, are independently selected from among i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH ₂ ,

iv) Ci-ealkyl,

vii) vinyl, and

viii) ethynyl.

A second aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ) _1-3 OC(0)(C ₁ . ₆ alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _1-3 SC(0)(C _1-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ) _1-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _1-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ¹⁰ ),

wherein

R ^la is i) hydrogen,

ii) Ci _-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) Ci_ ₆ alkyl,

iii) C _3-6 cycloalkyl,

iv) Ci_ ₃ alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) C]. ₆ alkyl,

iii) C _3-6 cycloalkyl, or

iv) Ci_ ₃ alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i _-3 SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l ,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

o) a C _2-7 acyl,

p) an aminoacyl,

q) a Ci _-6 -alkylene-oxy-C ₂ - ₇ acyl, and

r) a -C(0)-0-C _1-6 alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C _2-7 acyl),

d) -O(aminoacyl),

e) -0(Ci- -alkylene-oxy-acyl), and

f) -0-C(0)-0-Ci _-6 alkyl;

5) X is -0-;

6) (^^) i ^{s a} four- or five-membered ring selected from among radicals c, d, e, f, g, and h, represented by the following structures

where * represents the point of attachment to the 2'-carbon and where

a) A is selected from among ii) -S- iii) -S(O)- iv) -S(0) ₂ - and

v) -NH-,

b) D is selected from among

i) -0- ii) -S- iii) -S(O)- iv) -S(0) ₂ - and

v) -NH-,

vi) a methylene, and

vii) a vinylidene,

c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are independently selected from among

i) hydrogen,

ii) halo, and

iii) C _1-6 alkyl; and

1 1

7a) m is 0, is a double-bond and R and R are independently selected from among

i) hydrogen,

ii) -NH ₂ ,

iii) -NH(C _! _ ₆ alkyl),

iv) -NH(C _2-7 acyl),

iv) -NH-C(0)-0-Ci _-6 alkyl,

v) - cycloheteroalkyl,

vi) -0(C _1-6 alkyl),

vii) -0(C ₂ _ ₇ acyl),

viii) -0(C _1-6 alkyleneoxyacyl),

ix) -0-C(0)-0-C _1-6 alkyl,

x) -S(Ci _-6 alkyl), and

xi) -OCi_ ₃ alkaryl,

7b) m is 1 , is a single-bond and

bl) R ¹⁶ is selected from among

i) =0,

ii) =NH, and

iii) =N(Ci_ ₆ alkyl), and

b2) R ¹⁷ is selected from among

i) -N¾,

ii) -NH(C _1-6 alkyl),

iii) -NH(C _2-7 acyl),

iv) -NH-C(0)-0-Ci _-6 alkyl, and

v) - cycloheteroalkyl, and

7c) independent of the value of m, each bonding pair, W ¹ — W ² , W ² — ^„ C, C^W ⁴ , W ⁴ ™W ³ , and W^W ¹ , contained in the five- membered ring comprises a single or a double bond and

i) W ¹ is O, S, N, or CR ¹⁴ ,

ii) W ² is N or CR ¹⁵ ,

iii) W ³ is C or N, and

iv) w s C or ^ and

where R ¹⁴ and R ¹⁵ , if present, are independently selected from among i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH ₂ ,

iv) Ci _-6 alkyl,

vii) vinyl, and

viii) ethynyl.

A third aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ ) _1-3 OC(0)0(C _1-6 alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ), _-3 OC(0)(C _1-6 alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) _{1 -3} SC(0)(C _1-6 alkyl)) ₂ ,

f) -P(0)(0(CH ₂ ),_ ₃ OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ),_ ₃ SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^la is

i) hydrogen,

ii) Ci _-6 alkyl,

iii) C ₃ _ ₆ cycloalkyl, or

iv) aryl,

R ^lb is

i) hydrogen,

ii) Ci_ ₆ alkyl,

iii) C _3-6 cycloalkyl,

iv) Ci_ ₃ alkaryl, or

v) alk(heteroaryl), and

R ^lc is

i) hydrogen

ii) Ci _-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) Ci _-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ )i _-3 SC(0)(alkyl)), j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ ,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

o) a C _2-7 acyl,

p) an aminoacyl,

p) a C _1-6 -alkylene-oxy-C ₂ _ ₇ acyl, and

q) a -C(0)-0-C _]-6 alkyl; 2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C _2-7 acyl),

d) -O(aminoacyl),

e) -0(Ci _-6 -alkylene-oxy-acyl), and

f) -0-C(0)-0-Ci _-6 alkyl;

-;

is a four- or five-membered ring selected from among radicals c,

d, e, f, g, and h, represented by the following structures

c d e f g h where * represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -0- or -CH ₂ - c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are each hydrogen; and

7a) m is 0, is a double-bond and R and R are independently selected from among

i) hydrogen,

ii) -NH ₂ ,

iii) -NH(Ci_ ₆ alkyl),

iv) -NH(C _2-7 acyl),

iv) -NH-C(0)-0-Ci _-6 alkyl,

v) - cycloheteroalkyl,

vi) -0(Ci _-6 alkyl),

vii) -0(C _2-7 acyl),

viii) -0(Ci _-6 alkyleneoxyacyl),

ix) -0-C(0)-0-Ci _-6 alkyl,

x) -S(C _1-6 alkyl), and

xi) -OC _1-3 alkaryl,

7b) m is 1, is a single-bond and

bl) R ¹⁶ is selected from among

i) =0,

ii) =NH, and

iii) =N(C _1-6 alkyl), and

b2) R ¹⁷ is selected from among

i) -NH ₂ ,

ii) -NH(C _1-6 alkyl),

iii) -NH(C _2-7 acyl), iv) -NH-C(0)-0-C _1-6 alkyl, and

v) - cycloheteroalkyl,

membered ring comprises a single or a double bond and i) W ¹ is O, S, N, or CR ¹⁴ ,

ii) W ² is N or CR ¹⁵ ,

iii) W ³ is C or N, and

iv) W ⁴ is C or N, and

where R ¹⁴ and R ¹⁵ , if present, are independently selected from among i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH ₂ ,

iv) C,_ ₆ alkyl,

vii) vinyl, and

viii) ethynyl.

A fourth aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3

wherein

1) R ¹ is selected from among

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P(0)(0(CH ₂ )i- ₃ OC(0)0(C ₁ . ₆ alkyl)) ₂ ,

d) -P(0)(0(CH ₂ ),_ ₃ OC(0)(C ₁ _ ₆ alkyl)) ₂ ,

e) -P(0)(0(CH ₂ ) ₁ _ ₃ SC(0)(C ₁ . ₆ alkyl)) ₂ ,

f) -P(0)(0(CH ₂ )i _-3 OCH ₂ (aryl)) ₂ ,

g) -P(0)(0(CH ₂ ) _)-3 SCH ₂ (aryl)) ₂ ,

h) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^lc ),

wherein

R ^Ia is

i) hydrogen or

iv) aryl,

R ^lb is

i) hydrogen or

ii) Ci _-6 alkyl, and

R ^lc is

i) hydrogen

ii) Ci _-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) Ci _-3 alkaryl,

i) -P*(0)(NH(alkaryl)(0(CH ₂ ) _1-3 SC(0)(alkyl)),

j) a l,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide,

1) -P*(0)(OR ^lc )~ _> when Y is -0~, where R ^lc is defined above, m) -P(0)(OH)-0-P(0)(OH) ₂ , n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ , o) an C _2-7 acyl,

p) an aminoacyl,

q) a C^-alkylene-oxy-Ca^acyl, and

r) a -C(0)-0-C _1-6 alkyl;

2) R ² is hydrogen;

3) R ³ is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C ₂ . acyl), and

d) -O(aminoacyl);

-;

is a four- or five-membered ring selected from among radicals c,

d, e, and f represented by the following structures c d e f where * represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -O- or -CH ₂ - c) R ⁴ , R ⁵ , R ⁸ , and R ⁹ are each hydrogen; and

16 17

7a) m is 0, is a double-bond and R and R are independently selected from among

i) hydrogen,

ii) -NH ₂ ,

iii) -NH(C _1-6 alkyl),

iv) -NH(C _2-7 acyl),

iv) -NH-C(0)-0-Ci_ ₆ alkyl,

v) - cycloheteroalkyl,

vi) -0(C,_ ₆ alkyl),

vii) -0(C _2-7 acyl),

viii) -0(Ci_ ₆ alkyleneoxyacyl),

ix) -0-C(0)-0-Ci _-6 alkyl,

x) -S(C _1-6 alkyl), and

xi) -OCi _-3 alkaryl,

7b) m is 1 , is a single-bond and

bl) R ¹⁶ is selected from among

i) =0,

ii) =NH, and

iii) =N(C _1-6 alkyl), and

b2) R ¹⁷ is selected from among

i) -NH ₂ ,

ii) -NH(C _1-6 alkyl),

iii) -NH(C _2-7 acyl), iv) -NH-C(0)-0-C _1-6 alkyl, and

v) - cycloheteroalkyl,

7c) independent of the value of m, each bonding pair, W ¹ — W ² , W

^„ C, C^W ⁴ , W ⁴ ^ •W , and W— W , contained in the five- membered ring comprises a single or a double bond and

i) W ¹ is O, S, N, or CR ¹⁴ ,

ii) W ² is N or CR ¹⁵ ,

iii) W ³ is C or N, and

iv) W ⁴ is C or N, and

where R— and R ¹⁵ , if present, are independently selected from i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH ₂ ,

iv) Ci. ₆ alkyl,

vii) vinyl, and

viii) ethynyl.

A fifth aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3-1

1-3-1

wherein

1) R ¹ is selected from among:

a) hydrogen,

b) -P(0)(OH) ₂ ,

c) -P*(0)(OR ^la )(NHCHR ^lb C(0)OR ^IC ),

wherein

R ^la is

i) hydrogen or

ii) aryl,

R ^lb is

i) hydrogen or

ii) Q^alkyl, and

R ^lc is

i) hydrogen ii) C _1-6 alkyl,

iii) C _3-6 cycloalkyl, or

iv) Ci _-3 alkaryl,

d) a l ,3,2-dioxaphosphinane-2-oxide,

e) a 4H-benzo[d][l,3,2]dioxaphosphinine-2-oxide, f) -P*(0)(OR ^lG )~, when Y is -0~, where R ^lc is defined above, g) -P(0)(OH)-0-P(0)(OH) ₂ ,

h) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

i) a C _2-7 acyl, and

j) an aminoacyl; and

is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C _2-7 acyl), and

-O(aminoacyl); and

where * represents the point of attachment to the 2'-carbon; and

4a) m is 0, is a double-bond

4al) R ¹⁶ is selected from among

i) -NH ₂ ,

ii) -NH(d_ ₆ alkyl),

iii) -NH(C _2-7 acyl),

iv) -cycloalkylamino,

v) -0(Ci _-6 alkyl),

vi) -0(C _2-7 acyl),

vii) -0(Cj_ ₆ alkyleneoxyacyl), and viii) -0-C(0)-0-C _1-6 alkyl,

ix) -S(Ci _-6 alkyl), and

x) -OC i _-3 alkaryl, and

4a2) R ¹⁷ is selected from among

i) hydrogen,

ii) -NH ₂ , and

iii) -NH(C _1-6 alkyl), or

4b) m is 1, is a single-bond

4bl) R ¹⁶ is =0; and

4b2) R ¹⁷ is selected from among

i) -NH ₂ and

ii) -NH(Ci _-6 alkyl).

A sixth aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3-1

wherein

1) R ¹ is selected from among: a) hydrogen,

b) -P(0)(OH) _2>

c) -P*(0)(OR ^Ia )(NHCHR ^lb C(0)OR ^IC ),

wherein

R ^la is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphthyl,

R ^Ib is

i) hydrogen or

ii) Ci- ₆ alkyl, and

R ^lc is

i) hydrogen

ii) C _!-6 alkyl,

iii) C ₃ _ ₆ cycloalkyl, or

iv) Ci _-3 alkaryl,

d) -P*(0)(OR ^lc )~, when Y is -0~, where R ^lc is defined above, e) -P(0)(OH)-0-P(0)(OH) ₂ ,

f) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH) ₂ ,

g) a C _2-7 acyl, and

h) an aminoacyl; and

2) Y is selected from among

a) -OH,

b) -0~, when R ¹ is -P(0)(OR ^lc )~, where R ^lc is defined above, c) -0(C _2-7 acyl), and

-O(aminoacyl); and

where * represents the point of attachment to the 2'-carbon; and

4a) m is 0, is a double-bond

4al) R ¹⁶ is selected from among

i) -NH ₂ ,

ii) -NH(C _1-6 alkyl),

iii) -NH(C _2-7 acyl),

iv) -cycloalkyl amino,

v) -0(C _1-6 alkyl),

vi) -0(C _2-7 acyl),

vii) -0(C _1- alkyleneoxyacyl), and

viii) -0-C(0)-0-C _1-6 alkyl,

ix) -S(C _1-6 alkyl), and

x) -OCi _-3 alkaryl, and

4a2) R ¹⁷ is selected from among

i) hydrogen,