WO2024123749A1

WO2024123749A1 - Antiviral compounds and methods of making and use thereof

Info

Publication number: WO2024123749A1
Application number: PCT/US2023/082465
Authority: WO
Inventors: Jie Luo; Jeff Ranish
Original assignee: Institute For Systems Biology
Priority date: 2022-12-05
Filing date: 2023-12-05
Publication date: 2024-06-13
Also published as: WO2024123749A9

Abstract

Described are analogues of 3'-ketoriboside having antiviral properties and optionally low toxicity. Generally, these compounds contain a 3'-ketoribose, a lower alkyl attached to the 2'-position of the 3'-ketoribose, a nucleobase or analogue thereof attached to the 1'-position of the 3'-ketoribose, and a prodrug side chain attached to the 5'-oxygen of the 3'-ketoribose. The overall structure of these compounds provides stability, viral RNA chain elongation inhibitory property, and hydrogen bond acceptor for recognition by various enzymes for these compounds. Pharmaceutical formulations suitable for the delivery of the compounds to a subject in need thereof are disclosed. The pharmaceutical formulation can be administered by oral administration, parenteral administration, inhalation, and/or mucosal administration. Methods for preventing or treating a viral infection in a subject are also disclosed.

Description

ANTIVIRAL COMPOUNDS AND METHODS OF MAKING AND USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. Provisional Application No. 63/386,069 filed December 5, 2022, the content of which is incorporated herein by reference for all purpose in its entirety.

REFERENCE TO SEQUENCE LISTING

The Sequence Listing submitted as an xml file named “ISB_136_PCT_ST26.xml”, created December 5, 2023, and having a size of 4,933 bytes is hereby incorporated by reference pursuant to 37 C.F.R. 1.834(c)(1).

FIELD OF THE INVENTION

The disclosed invention is generally in the field of antiviral compounds and methods of making and use thereof.

BACKGROUND OF THE INVENTION

In the past two decades, several large pandemics with global health problems have been caused by RNA viruses, such as SARS-CoV in 2003, HINT influenza virus in 2009, Ebola virus in 2014, Zika virus in 2016 and SARS-CoV2 since 2019. With increasing population and globalization, pandemics caused by viruses, including RNA viruses, will be inevitable and frequent. However, there are no effective treatments for most infections caused by RNA viruses, especially at the early stage(s) of the outbreaks. Curbing disease development at this stage can drastically influence spread dynamics and thus benefit the general public. While large efforts are underway to develop vaccines for prevention of infections and drugs for treatment of affected patients, the slow pace and uncertainty of efficacy of the former, and the rapid development of resistance of the latter establish a need for continuous stream of new effective antiviral drugs. Despite efforts of developing antibody or recombinant protein-based approaches that block viral entry into cells, the traditional small-molecule approach remains a preferred option because of established pharmacological principle, namely, ease of distribution and relative low cost in deployment.

The antiviral nucleoside/nucleotide analogs and protease inhibitors are promising approaches to block viral replication. Take COVID-19 treatment for example, Remdesivir is a prodrug of an adenosine nucleotide analogue that inhibits viral RNA chain elongation by its 1 ’-cyano bulky group. Remdesivir is a non-obligate chain terminator, which allows the viral RNA-dependent RNA polymerase to incorporate three more nucleotides before stalling (Kokic et al. (2021) Nat Commun 72(1 ):279; and Lo et al. (2017) Sei Rep 7:43395). Remdesivir is applied to patients through intravenous injection. Molnupiravir is an oral prodrug of N4-hydroxycytidine (NHC) which induces mutations during viral replication by mismatch-pairing with adenine, resulting in loss-of-function mutations for the viral proteins through accumulated changes (Sheahan et al. (2020) Sei Transl Med 72(541). Paxlovid (copackaged oral medication of nirmatrelvir/ritonavir) is a protease inhibitor that blocks viral protein processing and maturation (Yang et al. (2022) J Med Chem 65(13) : 8686- 8698). The 2’, 3 ’-dideoxynucleosides, such as Zalcitabine (2’,3’-dideoxycytidine, ddC), Lamivudine (2’,3’-dideoxy-3’thiacytidine, 3TC), Didanosine (2’3’- dideoxyinosine, ddl) and Zidovudine (3 ’-azidothymidine, AZT) are examples of reverse-transcriptase inhibitors (RTIs) widely used for antiretroviral therapies (Holec et al. (2017) Curr HIV Res 75(6):411-421). These dideoxynucleosides are obligate chain terminators that block D A chain elongation during retroviral replication. Once incorporated as monophosphates into the viral nucleic acid, they immediately block the progression of the polymerase as a result of their lack of a reactive 3'-hydroxyl (3'-OH) group. However, the 3 ’ -deoxyribonucleosides and 3’-O-methyl-ribonucleosides have proved largely ineffective at inhibiting viral RNA chain elongation in vivo (Eyer et al. (2018) Antivir Chem Chemother 26:2040206618761299).

There remains a need to develop compounds that possess antiviral properties. Therefore, it is an object of the present invention to provide compounds that possess antiviral properties.

It is a further object of the present invention to provide methods of using such compounds.

SUMMARY OF THE INVENTION

Antiviral compounds and methods of making and using thereof are described. The compounds disclosed herein contain a 3 ’-ketoribose, a lower alkyl (i.e., Ci-Ce alkyl) attached to the 2’ -position of the 3 ’-ketoribose, a nucleobase or analogue thereof attached to the T -position of the 3'-ketoribose via a glycosidic bond, and a prodrug side chain attached to the 5 ’-oxygen of the 3 ’-ketoribose.

The overall structure of the compounds provides stability, viral RNA chain elongation inhibitory property, and hydrogen bond acceptor for recognition by various enzymes for these compounds. For example, the compound has ex vivo: (a) a half effective concentration EC50 of 20uM or less as measured by hepatitis C (HCV) replicon analysis relative to 100% inhibition of HCV by 1.0 pM danoprevir; and/or (b) a half cytotoxicity concentration CC50 of 500 pM or greater as measured by Cell Counting Kit-8 (CCK8) live cell counting assay in 100% fresh media.

In some forms, the compound disclosed herein can have the structure of Formula I:

Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein: (i) R1 can be a prodrug side chain; (ii) R2 can be a nucleobase or an analogue thereof; and (iii) R3 can be a C1-C6 unsubstituted alkyl.

In some forms, the compound can have the structure of Formula II:

Formula II or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein R1 and R2 can be as defined above for Formula I.

In some forms, R1 can be hydrogen, a carbonyl (e.g., an ester or a thioester), a phosphonyl (e.g., a phosphoester or a phosphoramidate), a thiophosphonyl, a sulfinyl, a sulfonyl, or a sulfamoyl. In some forms, R1 can be hydrogen, -C(=O)R⁴, -C(=O)OR⁴, - C(=O)NR⁴R⁵, -C(=O)SR⁴, -S(O)R⁴, -S(O)₂R⁴, -S(O)(OR⁴), -S(O)₂(OR⁴), - S(O)₂(NR⁴R⁵),-P(O)(OR⁴)(OR⁵), -P(O)(OR⁴)(NR⁵), -P(S)(OR⁴)(OR⁵), or P(S)(OR⁴)(NR⁵), wherein each R⁴ or R^s is independently H, an unsubstituted (C1-C8) alkyl, a substituted (C1-C8) alkyl, an unsubstituted (C2-C8) alkenyl, a substituted (C2- C8) alkenyl, an unsubstituted (C2-C8) alkynyl, or a substituted (C2-C8) alkynyl, and wherein each substituent (when present) is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a carbonyl, an alkoxy, a halogen, a hydroxyl, a phenoxy, a thiol, an alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a carboxyl, an amino, an amido, an oxo, a silyl, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, or a phosphonyl. In some forms, R1 can be hydrogen, 2-methyl-propinyl, or ProTide phosphoramidate.

In some forms, R2 can be adenine, cytidine, guanine, uridine, thymidine, pseudouridine, hypoxanthine, xanthine, 6-methyl-adenine, 5-methylcytidine, 7- deazaadenine, 7-deazaguanine, 4-aza-7,9-dideazaadenine, 5-fluorourdine, 5- bromouridine, 5-N-hydroxycytidine, or N4-hydroxycytidine. In some forms, R2 can be adenine, cytosine, guanine, thymine, uridine, pseudouridine, hypoxanthine, xanthine, 7- deazaadenine, 4-aza-7,9-dideazaadeonine, or 7-deazaguanine. In some forms, R2 can be adenine or an adenine analogue. In some forms, R2 can be adenine, 4-aza-7,9- dideazaadenine, or 7-deazaadenine. Typically, a carbon atom or nitrogen atom of the pyrimidine or purine moiety of R2 forms a C-C or N-C linkage with the carbon to which R2 is attached.

In some forms, the compound has the structure of:

MKA

Pharmaceutical formulations suitable for the delivery of the compounds and their preparation are disclosed. Generally, the pharmaceutical formulation contains one or more of the compounds and a suitable pharmaceutically acceptable excipient. The compounds in the pharmaceutical formulations are in an effective amount for preventing or treating a viral infection in a subject in need thereof. The pharmaceutical formulation may further contain one or more additional active agents, such as one or more additional antiviral agents and/or one or more anti-inflammatory agents.

Methods of making the compounds disclosed herein include (i) oxidizing a riboside to form a raw product comprising the compound; and (ii) purifying the raw product to produce a purified product, wherein the compound in the purified product has a purity suitable for use in food or medicine. For example, the purity of the compound in the purified product is at least about 50% as determined by high performance liquid chromatography.

In some forms, the riboside being oxidized in step (i) can have the structure of Formula la to form the compound of Formula I:

Formula la wherein: (i) R1 is a prodrug side chain; (ii) R2 is a nucleobase or analogue thereof; and (iii) R3 is a C1-C6 unsubstituted alkyl.

The oxidation reaction in step (i) can be performed using any suitable reactions known in the art, such as Dess-Martin oxidation. The purification in step (ii) can be performed using any suitable purification technique known in the art, such as reverse phase chromatographic separation or vacuum concentration, or a combination thereof.

Methods of using the compounds are disclosed. The compounds are administered to a cell, to prevent or treat a viral infection in the cell. The cell can be in vitro or in vivo, for example, in a subject in need thereof. The cell is typically a cell of a mammal, such as a human. In some forms, the cell is infected by an RNA virus, such as a virus of Flaviviridae, Orthomyxoviridae, Filoviridae, Coronaviridae, or Paramyxoviridae family. The treatment effect can be indicated by the improvement or relief of one or more symptoms associated with the viral infection. For example, the treatment effect can be indicated by the improvement or relief of one or more symptoms associated with the viral infection in a subject that is infected by an RNA virus.

In some forms of the method, the pharmaceutical formulation can be administered by oral administration, parenteral administration (such as by intravenous injection or infusion), inhalation, mucosal administration, topical or a combination thereof. The administration step can occur one or more times. Typically, following a single administration step or all of the administration steps, an effective amount of the compounds is administered for a given end use, such as to ameliorate one or more symptoms associated with the viral infection. Optionally, the disclosed method further includes administering one or more additional active agent, such as one or more antiviral agents and/or one or more anti-inflammatory agents, to the subject prior to, during, and/or subsequent to the administration of the compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a representative mass spectrometry spectrum of 2’-methyl-3’- ketoriboadenosine.

Figures 2A-2D are graphs showing hepatitis C (HCV) replicon analysis and % cell viability in the presence of Remdesivir (FIG. 2A), N4-hydroxy cytidine (FIG. 2B), 3 ’-deoxy cytidine (FIG. 2C), and 2’ -methyl-3’ -ketoriboadenosine (FIG. 2D).

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

It is to be understood that the disclosed compounds, compositions, and methods are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular forms and embodiments only and is not intended to be limiting.

“Substituted,” as used herein, refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a halogen, a hydroxyl, an alkoxy, a phenoxy, an aroxy, a silyl, a thiol, an alkylthio, a substituted alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a substituted or unsubstituted carbonyl, a carboxyl, an amino, an amido, an oxo, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, an amino acid. Such a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a halogen, a hydroxyl, an alkoxy, a phenoxy, an aroxy, a silyl, a thiol, an alkylthio, a substituted alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a substituted or unsubstituted carbonyl, a carboxyl, an amino, an amido, an oxo, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, and an amino acid can be further substituted.

Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e. , a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

“Alkyl,” as used herein, refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl, and cycloalkyl (alicyclic). In some forms, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 15 or fewer, or 10 or fewer. Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Likewise, a cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms, 3-20 carbon atoms, or 3-10 carbon atoms in their ring structure, and have 5, 6 or 7 carbons in the ring structure. Cycloalkyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkyl rings”). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, etc. "Substituted alkyl” refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen (such as fluorine, chlorine, bromine, or iodine), hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), aryl, alkoxyl, aralkyl, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, an aromatic or heteroaromatic moiety. -NRR’ , wherein R and R’ are independently hydrogen, alkyl, or aryl, and wherein the nitrogen atom is optionally quaternized; -SR, wherein R is a phosphonyl, a sulfinyl, a silyl a hydrogen, an alkyl, or an aryl; -CN; -NO2; -COOH; carboxylate; -COR, -COOR, or -C0N(R)2, wherein R is hydrogen, alkyl, or aryl; imino, silyl, ether, haloalkyl (such as -CF3, -CH2-CF3, -CCh); -CN; -NCOCOCH2CH2; -NCOCOCHCH; and -NCS; and combinations thereof.

It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, aralkyl, azido, imino, amido, phosphonium, phosphanyl, phosphoryl (including phosphonate and phosphinate), oxo, sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), haloalkyls, -CN and the like. Cycloalkyls can be substituted in the same manner.

Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

“Heteroalkyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkyl radicals, or combinations thereof, containing at least one heteroatom on the carbon backbone. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkyl group” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus. The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond. Alkenyl groups include straight-chain alkenyl groups, branched-chain alkenyl, and cycloalkenyl. A cycloalkenyl is a non-aromatic carbon-based ring composed of at least three carbon atoms and at least one carbon-carbon double bond, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in their ring structure, and have 5, 6 or 7 carbons and at least one carbon-carbon double bond in the ring structure. Cycloalkenyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkenyl rings”) and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C’D) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present, or it may be explicitly indicated by the bond symbol C. The term "alkenyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkenyls" and "substituted alkenyls,” the latter of which refers to alkenyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term “alkenyl” also includes “heteroalkenyl.”

The term “substituted alkenyl” refers to alkenyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

“Heteroalkenyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkenyl radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkenyl group” is a cycloalkenyl group where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.

The term “alkynyl group” as used herein is a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups include straight-chain alkynyl groups, branched-chain alkynyl, and cycloalkynyl. A cycloalkynyl is a non-aromatic carbon-based ring composed of at least three carbon atoms and at least one carbon-carbon triple bond, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond in their ring structure, and have 5, 6 or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkynyl rings”) and contain at least one carbon-carbon triple bond. Asymmetric structures such as (AB)C=C(C”D) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkyne is present, or it may be explicitly indicated by the bond symbol C. The term "alkynyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkynyls" and "substituted alkynyls,” the latter of which refers to alkynyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term “alkynyl” also includes “heteroalkynyl.”

The term “substituted alkynyl” refers to alkynyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. “Heteroalkynyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkynyl radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkynyl group” is a cycloalkynyl group where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.

“Aryl,” as used herein, refers to C5-C26-membered aromatic or fused aromatic ring systems. Examples of aromatic groups are benzene, naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, etc.

The term “substituted aryl” refers to an aryl group, wherein one or more hydrogen atoms on one or more aromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, - CCh), -CN, aryl, heteroaryl, and combinations thereof.

“Heterocycle” and “heterocyclyl” are used interchangeably, and refer to a cyclic radical attached via a ring carbon or nitrogen atom of a non-aromatic monocyclic or polycyclic ring containing 3-30 ring atoms, 3-20 ring atoms, 3-10 ring atoms, or 5-6 ring atoms, where each ring contains carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, C1-C10 alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Heterocyclyl are distinguished from heteroaryl by definition. Heterocycles can be a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, etc, such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-/?]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H- 1,2,5-thiadiazinyl. Heterocyclic groups can optionally be substituted with one or more substituents as defined above for alkyl and aryl.

The term “heteroaryl” refers to Cs-C v.-membered aromatic or fused aromatic ring systems, in which one or more carbon atoms on one or more aromatic ring structures have been substituted with a heteroatom. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. Examples of heteroaryl groups pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzo thiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined below for “substituted heteroaryl.”

The term “substituted heteroaryl” refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, - CCI3), -CN, aryl, heteroaryl, and combinations thereof.

The term “polyaryl” refers to a chemical moiety that includes two or more fused aryl groups. When two or more fused heteroaryl groups are involved, the chemical moiety can be referred to as a “polyheteroaryl.”

The term “substituted polyaryl” refers to a polyaryl in which one or more of the aryls are substituted, with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. When a polyheteroaryl is involved, the chemical moiety can be referred to as a “substituted polyheteroaryl.”

The term “cyclic ring” or “cyclic group” refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (such as those formed from single or fused ring systems), such as a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, or a substituted or unsubstituted heterocyclyl, that have from three to 30 carbon atoms, as geometric constraints permit. The substituted cycloalkyls, cycloalkenyls, cycloalkynyls, and heterocyclyls are substituted as defined above for the alkyls, alkenyls, alkynyls, and heterocyclyls, respectively.

The term “aralkyl” as used herein is an aryl group or a heteroaryl group having an alkyl, alkynyl, or alkenyl group as defined above attached to the aromatic group, such as an aryl, a heteroaryl, a polyaryl, or a polyheteroaryl. An example of an aralkyl group is a benzyl group.

The terms “alkoxyl” or “alkoxy,” “aroxy” or “aryloxy,” generally describe compounds represented by the formula -OR^V, wherein R^v includes, but is not limited to, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted alkylheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, and an amino. Exemplary alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. A “lower alkoxy” group is an alkoxy group containing from one to six carbon atoms. An “ether” is two functional groups covalently linked by an oxygen as defined below. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-arakyl, -O-aryl, -O-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclyl, etc.

The term “substituted alkoxy” refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, oxo, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term “ether” as used herein is represented by the formula A²OA¹, where A² and A¹ can be, independently, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, a substituted or unsubstituted carbonyl, an alkoxy, an amido, or an amino, described above.

The term “polyether” as used herein is represented by the formula:

where A³ can be, independently, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a phosphonium, a phosphanyl, a substituted or unsubstituted carbonyl, an alkoxy, an amido, or an amino, described above; g can be a positive integer from 1 to 30.

The term “phenoxy” is art recognized and refers to a compound of the formula -OR^V wherein R^v is CeHs (i.e., -O-G.Hs). One of skill in the art recognizes that a phenoxy is a species of the aroxy genus.

The term “substituted phenoxy” refers to a phenoxy group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The terms “aroxy” and “aryloxy,” as used interchangeably herein, are represented by -O-aryl or -O-heteroaryl, wherein aryl and heteroaryl are as defined herein.

The terms “substituted aroxy” and “substituted aryloxy,” as used interchangeably herein, represent -O-aryl or -O-heteroaryl, having one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl, as defined herein. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. The term "amino" as used herein includes the group

R^x - E- NH₂ -E-NH

’ (primary amino), *» (secondary amino),

R^X R^x

R^XI (tertiary amino), and R^XI (quaternary amino), wherein, E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R^x, R^X1, and R^X11 each independently represent a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)_m-R’” ; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. The term “quaternary amino” also includes the groups where the nitrogen, R^x, R^X1, and R^xn with the N⁺ to which they are attached complete a heterocyclyl or heteroaryl having from 3 to 14 atoms in the ring structure. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1 ,2-diyl). The terms “amide” or “amido” are used interchangeably, refer to both “unsubstituted amido” and “substituted amido” and are represented by the general formula:

wherein, E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted poly aryl, a substituted or unsubstituted polyheteroaryl, or a substituted or unsubstituted heterocyclyl, wherein independently of E, R and R’ each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)_m-R”’, or R and R’ taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. In some forms, when E is oxygen, a carbamate is formed. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl). “Carbonyl,” as used herein, is art-recognized and includes such moieties as can be represented by the general formula:

wherein X is a bond, or represents an oxygen or a sulfur, and R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH2)_m-R”, or a pharmaceutical acceptable salt; E” is absent, or E” is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl; R’ represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH2)_m-R” ; R” represents a hydroxyl group, a substituted orunsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E” groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl). Where X is oxygen and R is defined as above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a “carboxylic acid.” Where X is oxygen and R’ is hydrogen, the formula represents a “formate.” Where X is oxygen and R or R’ is not hydrogen, the formula represents an "ester.” In general, where the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a “thiocarbonyl” group. Where X is sulfur and R or R’ is not hydrogen, the formula represents a “thioester.” Where X is sulfur and R is hydrogen, the formula represents a “thiocarboxylic acid.” Where X is sulfur and R’ is hydrogen, the formula represents a “thioformate.” Where X is a bond and R is not hydrogen, the above formula represents a “ketone.” Where X is a bond and R is hydrogen, the above formula represents an “aldehyde.”

The term “phosphanyl” is represented by the formula

wherein, E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, R^V1 and R™ each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)_m-R”’, or R^V1 and R™ taken together with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane - 1,2-diyl).

The term “phosphonium” is represented by the formula

wherein, E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, R^V1, R™, and R^vni each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)_m-R’”, or R^V1, R™, and R^vm taken together with the P⁺ atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1 ,2-diyl).

The term “phosphonyl” is represented by the formula

wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, oxygen, alkoxy, aroxy, or substituted alkoxy or substituted aroxy, wherein, independently of E, R^V1 and R™ are independently a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)_m-R’”, or R^V1 and R^v“ taken together with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R”’ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1 ,2-diyl).

The term “phosphoryl” defines a phosphonyl in which E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and independently of E, R^V1 and R™ are independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the phosphoryl cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. When E, R^V1 and R™ are substituted, the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl).

The term “thiophosphonyl” is represented by the formula

wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, oxygen, alkoxy, aroxy, or substituted alkoxy or substituted aroxy, wherein, independently of E, R^V1 and R™ are independently a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)_m-R’”, or R^V1 and R^vu taken together with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1 ,2-diyl).

The term “sulfinyl” is represented by the formula

wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, wherein independently of E, R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a silyl, a thiol, an amido, an amino, or -(CH2)m-R”’, or E and R taken together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl).

The term “sulfonyl” is represented by the formula

wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, wherein independently of E, R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH2)m-R”’, or E and R taken together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1 ,2-diyl).

The term “sulfonic acid” refers to a sulfonyl, as defined above, wherein R is hydroxyl, and E is absent, or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl).

The term “sulfate” refers to a sulfonyl, as defined above, wherein E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the sulfate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1 ,2-diyl).

The term “sulfonate” refers to a sulfonyl, as defined above, wherein E is oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, -(CFEjm-R”’, R’” represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, an amido, an amino, or a polycycle; and m is zero or an integer ranging from 1 to 8. When E is oxygen, sulfonate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1 ,2-diyl).

The term “sulfamoyl” refers to a sulfonamide or sulfonamide represented by the formula

wherein E is absent, or E is substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted cycloalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, R and R’ each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH₂) m- R’”, or R and R’ taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl).

The term “silyl group” as used herein is represented by the formula -SiRR’R,” where R, R’, and R” can be, independently, a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a thiol, an amido, an amino, an alkoxy, or an oxo, described above. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy], carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

The terms “thiol” are used interchangeably and are represented by -SR, where R can be a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, an amido, an amino, an alkoxy, an oxo, a phosphonyl, a sulfinyl, or a silyl, described above. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

The disclosed compounds and substituent groups, can, independently, possess two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be substituted with a hydroxy] group, an alkoxy group, etc. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (/.<?., attached) to the second group. For example, with the phrase “an alkyl group comprising an ester group,” the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

The compounds and substituents can be substituted, independently, with the substituents described above in the definition of “substituted.”

The numerical ranges disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of subranges encompassed therein. For example, in a given range carbon range of C3-C9, the range also discloses C3, C4, C5, Cf>, CT, CS, and C9, as well as any subrange between these numbers (for example, C4 -Ce), and any possible combination of ranges possible between these values. In yet another example, a given temperature range may be from about 25 °C to 30 °C, where the range also discloses temperatures that can be selected independently from about 25, 26, 27, 28, 29, and 30 °C, as well as any range between these numbers (for example, 26 to 28 °C), and any possible combination of ranges between these values.

Use of the term "about" is intended to describe values either above or below the stated value, which the term “about” modifies, to be within a range of approximately +/- 10%. When the term "about" is used before a range of numbers (i.e., about 1-5) or before a series of numbers i.e., about 1, 2, 3, 4, etc.) it is intended to modify both ends of the range of numbers and/or each of the numbers recited in the entire series, unless specified otherwise.

The disclosed compounds and substituent groups, can, independently, possess two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (/.<?., attached) to the second group. For example, with the phrase “an alkyl group comprising an ester group,” the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

The compounds and substituents can be substituted with, independently, with the substituents described above in the definition of “substituted.” IL Compositions

Analogues of 3’ -ketoriboside (also referred to herein as “compounds”) having antiviral properties and optionally low toxicity have been developed. These compounds have broad antiviral properties. For example, the compounds disclosed herein show ex vivo: (a) a half effective concentration EC50 of 20 uM or less as measured by hepatitis C (HCV) replicon analysis relative to 100% inhibition of HCV by 1.0 uM danoprevir; and/or (b) a half cytotoxicity concentration CC50 of 500 uM or greater as measured by Cell Counting Kit-8 (CCK8) live cell counting assay in 100% fresh media. Therefore, they should be suitable for use in the prophylaxis and/or treatment of multiple classes of viruses, such as for use as pan-anti RNA virus compounds for the treatment of RNA viral infection.

The compounds disclosed herein contain a 3’-ketoribose, a lower alkyl (i.e., Ci- Ce alkyl) attached to the 2 ’-position of the 3’-ketoribose, a nucleobase or analogue thereof attached to the 1 ’-position of the 3'-ketoribose via a glycosidic bond, and a prodrug side chain attached to the 5 ’-oxygen of the 3'-ketoribose. The overall structure provides stability, viral RNA chain elongation inhibitory property, and hydrogen bond acceptor for recognition by various enzymes for these compounds (discussed below).

The compounds disclosed herein are stable and can be stored in physiological solutions. For example, the disclosed compounds are stored in IX PBS at 4 °C or -20 °C for up to two months without significant activity loss (i.e., the change of EC50 value against a cell line under the same test conditions is less than 10%). Without being bound to any theories, it is believed that the stability of the 3'-ketoribose can be attributed to the due in large part to a lower alkyl group at the 2’ position, such as a 2’- methyl group. Further, the disclosed compounds can efficiently block viral RNA replication with little cytotoxicity to host cells. Without being bound to any theories, it is believed that the disclosed compounds exhibit an RNA chain elongation termination mechanism: obligate chain termination via 3 ’-ketone in combination with host cell transport and kinase recognition via 2’ -hydroxyl and 3 ’-ketone. For example, the compounds disclosed herein can serve as obligate RNA chain terminators as the 3’- ketone group will block formation of the 3’ to 5’ phosphodiester bond once incorporated into the elongating virus RNA chain.

Additionally, the disclosed compounds preserve the 3 ’-oxygen as a hydroxyl group, which can readily serve as a hydrogen bond acceptor for recognition by various enzymes, such as concentrative nucleoside transporters (CNTs) and nucleoside kinases, for example, adenosine kinase, inosine-guanosine kinase, and uridine-cytidine kinase. Meanwhile, no groups that can affect the enzymatic activities of polymerases and kinases are introduced.

Pharmaceutical compositions and formulations containing the compounds or prodrugs of the compounds are also disclosed.

A. Compounds

The disclosed compounds can have the structure of Formula I’ :

or a pharmaceutically acceptable salt thereof, wherein: (i) R1 can be a prodrug side chain; (ii) R2 can be a nucleobase or analogue thereof; and (iii) R3 can be a C1-C6 unsubstituted alkyl (including linear, branched, or cyclic alkyls, such as methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tertbutyl), pentyl, hexyl, etc.).

In some forms, the disclosed compounds can have the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Rl, R2, and R3 can be as defined above for Formula I’ .

As illustrated by Formulae I’ and I, the nucleobase or analogue thereof (R2) is attached to the 2'-alkyl-3'-ketoribose via a glycosidic bond; and the prodrug side chain (Rl) is attached to the 5’-oxygen of the 2'-alkyl-3’-ketoribose.

In some forms, the disclosed compounds can have the structure of Formula IF:

or a pharmaceutically acceptable salt thereof, wherein Rl and R2 can be as defined above for Formula I’.

In some forms, the disclosed compounds can have the structure of Formula II:

Formula II or a pharmaceutically acceptable salt thereof, wherein Rl and R2 can be as defined above for Formula I’ .

As illustrated in Formulae IF and II, the nucleobase or analogue thereof (R2) is attached to the 2'-methyl-3'-ketoribose via a glycosidic bond; and the prodrug side chain (Rl) is attached to the 5’-oxygen of the 2'-methyl-3'-ketoribose.

In some forms of Formulae I’, I, IF, and II, Rl is a prodrug side chain. The term “prodrug side chain” refers to a chemical functional group of a prodrug compound capable of being metabolized so as to convert the prodrug compound into a pharmacologically active metabolite. For example, the Rl group of the compounds disclosed herein can be metabolized into a triphosphate, which is capable of being incorporated into an RNA chain. For example, non-phosphorylated ribonucleosides (e.g., a compound in which Rl is a hydrogen and thus a prodrug side chain) are generally converted by cellular kinases into a triphosphate form (e.g., in which Rl is a triphosphate and thus the compound is converted into a pharmacologically active metabolite) before incorporation into an elongating RNA chain with diphosphate release. Once incorporated, the disclosed compounds can act as a chain terminator and stop the virus from replicating because the compounds lack the 3 ’-hydroxyl needed for attachment of the next incoming ribonucleotide triphosphate.

In some forms of Formulae I’, I, II’, and II, R¹ can be hydrogen, a carbonyl (e.g., an ester or a thioester), a phosphonyl (e.g., a phosphoester or a phosphoramidate), a thiophosphonyl, a sulfinyl, a sulfonyl, or a sulfamoyl.

In some forms of Formulae I’, I, IF, and II, R1 can be hydrogen, -C(=O)R⁴, - C(=O)OR⁴, -C(=O)NR⁴R⁵, -C(=O)SR⁴, -S(O)R⁴, -S(O)?R⁴, -S(O)(OR⁴), -S(Oh(OR⁴), - S(O)₂(NR⁴R⁵),-P(O)(OR⁴)(OR⁵), -P(O)(OR⁴)(NR⁵), -P(S)(OR⁴)(OR⁵), or P(S)(OR⁴)(NR⁵), wherein each R⁴ or R^s is independently H, H, an unsubstituted (Cl- C8) alkyl, a substituted (C1-C8) alkyl, an unsubstituted (C2-C8) alkenyl, a substituted (C2-C8) alkenyl, an unsubstituted (C2-C8) alkynyl, or a substituted (C2-C8) alkynyl, and wherein each substituent (when present) can be independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a carbonyl, an alkoxy, a halogen, a hydroxyl, a phenoxy, a thiol, an alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a carboxyl, an amino, an amido, an oxo, a silyl, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, or a phosphonyl.

When R⁴ and/or R⁵ are/is substituted or unsubstituted alkyl(s), the alkyl(s) can be a linear alkyl, a branched alkyl, or a cyclic alkyl (either monocyclic or polycyclic). The terms “cyclic alkyl” and “cycloalkyl” are used interchangeably herein. Exemplary alkyl include a linear Ci-Cs alkyl, a branched C i-Cs alkyl, a cyclic C3-C8 alkyl, a linear Ci-Ce alkyl, a branched C4-C6 alkyl, a cyclic C3-C6 alkyl, a linear C1-C4 alkyl, a cyclic C4-C8 alkyl, a cyclic C3-C4 alkyl, such as a linear Ci-Cs, C1-C7, Ci-Ce, C1-C5, C1-C4, C1-C3, or C1-C2 alkyl group, a branched C₃-C₈, C3-C7, C₃-C₆, C3-C5, or C3-C4 alkyl group, or a cyclic C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 alkyl group. The cyclic alkyl can be a monocyclic or polycyclic alkyl, such as a C4-C8, C4-C7, C4-C6, or C4-C5 monocyclic or polycyclic alkyl group.

When R⁴ and/or R^s are/is substituted or unsubstituted alkenyl(s), the alkenyl(s) can be a linear alkenyl, a branched alkenyl, or a cyclic alkenyl (either monocyclic or polycyclic). The terms “cyclic alkenyl” and “cycloalkenyl” are used interchangeably herein. Exemplary alkenyl include a linear C2-C8 alkenyl, a branched C4-C8 alkenyl, a cyclic Cr-Cs alkenyl, a linear C2-C6 alkenyl, a branched C4-C6 alkenyl, a cyclic C3-C6 alkenyl, a linear C2-C4 alkenyl, a cyclic C3-C4 alkenyl, a cyclic C4-C8 alkenyl, such as a linear C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkenyl group, a branched C3-C8, C3-C7, C₃-C₆, C3-C5, C3-C4 alkenyl group, or a cyclic C₃-C₈, C3-C7, C₃-C₆, C3-C5, C3-C4 alkenyl group. The cyclic alkenyl can be a monocyclic or polycyclic alkenyl, such as a C4-C8, C4-C7, C4-C6, or C4-C5 monocylcic or polycyclic alkenyl group.

When R⁴ and/or R⁵ are/is substituted or unsubstituted alkynyl(s), the alkynyl(s) can be a linear alkynyl, a branched alkynyl, or a cyclic alkynyl (either monocyclic or polycyclic). The terms “cyclic alkynyl” and “cycloalkynyl” are used interchangeably herein. Exemplary alkynyl include a linear C2-C8 alkynyl, a branched C4-C8 alkynyl, a cyclic C3-C8 alkynyl, a linear C2-C6 alkynyl, a branched C4-C6 alkynyl, a cyclic C3-C6 alkynyl, a linear C2-C4 alkynyl, a branched C4-C8 alkynyl, a cyclic C3-C4 alkynyl, such as a linear C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkynyl group, a branched C₃-C₈, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl group, or a cyclic C₃-C₈, C3-C7, C₃-C₆, C3-C5, C3-C4 alkynyl group. The cyclic alkynyl can be a monocyclic or polycyclic alkynyl, such as a C4-C8, C4-C7, C4-C6, or C4-C5 monocyclic or polycyclic alkynyl group.

It is understood that any of the exemplary alkyl, alkenyl, and alkynyl groups can be heteroalkyl, heteroalkenyl, and heteroalkynyl, respectively.

In some forms, the substituents (when present in any one of Formulae I’, I, II’, and II) can be independently a substituted or unsubstituted C1-C8 alkyl (such as methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tertbutyl), pentyl, hexyl, and any of those described above for R⁴ and R⁵), a substituted or unsubstituted C1-C8 alkenyl (such as any of those described above for R⁴ and R⁵), a substituted or unsubstituted C1-C8 alkynyl (such as any of those described above for R⁴ and R⁵), a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl (such as an unsubstituted phenyl), a substituted or unsubstituted heteroaryl, a substituted or unsubstituted poly aryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted alkylaryl (e.g. benzyl), a carbonyl (e.g. carboxyl, ester, etc.), an alkoxy (e.g. methoxy, ethoxy, aryloxy, benzoether, etc.), a halide, a hydroxyl, or a haloalkyl, or a combination thereof. In some forms of Formulae I’, I, II’, and II, R1 can be hydrogen, 2-methyl- propinyl, or ProTide phosphoramidate (Mehellou et al., J. Med. Chem. 61:2211-2226 (2018)).

Generally, R2 of Formulae I’, I, II’, and II can be adenine, cytidine, guanine, uridine, and thymidine, and analogues thereof. Examples of nucleobase analogues for R2 include, but are not limited to, naturally occurring analogues such as pseudouridine, hypoxanthine, xanthine, 6-methyl-adenine, and 5-methylcytidine, as well as synthetic analogues including, but not limited to, 7-deazaadenine, 7-deazaguanine, 4-aza-7,9- dideazaadenine, 5-fluorourdine, 5-bromouridine, 5-N-hydroxycytidine, N4- hydroxycytidine. In a specific embodiment, R² is a C-N or C-C linked pyrimidine or purine nucleobase or analogue thereof selected from adenine, cytosine, guanine, thymine, uridine, pseudouridine, hypoxanthine, xanthine, 7-deazaadenine, 7- deazaguanine. Additional examples of nucleobase analogues for R2 are described in, for example, Lucas, J. F., & Rius, M. J. C. (Eds.) (2019) Enzymatic and Chemical Synthesis of Nucleic Acid Derivatives, John Wiley & Sons; Yates et al. (2019) Antiviral Res 762:5-21 ; Seley-Radtke et al. (2018) Antiviral Chemistry and Chemotherapy 26: 1- 12; Seley-Radtke et al. (2018) Antiviral Research 754:66-86; Maslova et al. (2022) Molecular Biology 56(3):469-473; and Eyer et al. (2018) Antiviral Chemistry & Chemotherapy 26:2040206618761299.

In some forms of Formulae I’, I, II’, and II, R2 can be adenine, cytidine, guanine, uridine, thymidine, pseudouridine, hypoxanthine, xanthine, 6-methyl-adenine, 5-methylcytidine, 7-deazaadenine, 7-deazaguanine, 4-aza-7,9-dideazaadenine, 5- fluorourdine, 5-bromouridine, 5-N-hydroxycytidine, or N4-hydroxycytidine. In some forms of Formula I and Formula II, R2 can be adenine, cytosine, guanine, thymine, uridine, pseudouridine, hypoxanthine, xanthine, 7-deazaadenine, 4-aza-7,9- dideazaadenine, or 7-deazaguanine. For example, R2 of Formula I and Formula II can be adenine, 4-aza-7,9-dideazaadenine, or 7-deazaadenine.

Typically, R2 of Formulae I’, I, II’, and II can be attached to the carbon atom of the 3’-ketoribose via a carbon atom or a nitrogen atom of the pyrimidine or purine moiety of R2 at any suitable position. Accordingly, the carbon or nitrogen atom of the pyrimidine or purine moiety of R2 forms a C-C or N-C linkage with the carbon to which R2 is attached. In some forms, a carbon atom of the pyrimidine moiety of R2 forms a C-C linkage with the carbon to which R2 is attached. In some forms, a carbon atom of the purine moiety of R2 forms a C-C linkage with the carbon to which R2 is attached. In some forms, a nitrogen atom of the pyrimidine moiety of R2 forms an N-C linkage with the carbon to which R2 is attached. In some forms, a nitrogen atom of the purine moiety of R2 forms an N-C linkage with the carbon to which R2 is attached.

In some forms, the compound is a 2’ -methyl-3’ -ketoadenosine, wherein R¹ of Formulae II’ and II is a prodrug side chain (such as any one of those described above), and R² is adenine or an adenine analogue (such as 4-aza-7,9-dideazaadenine or 7- deazaadenine). In some forms, the compound is a 2’ -methyl-3 ’-ketoadenosine compound of Formulae II’ and II or a pharmaceutically acceptable salt thereof, wherein: (a) R¹ is 2-methyl-propionyl, and R² is adenine; (b) R¹ is 2-methyl-propionyl, and R² is 4-aza-7,9-dideazaadenine; (c) R¹ is hydrogen, and R² is 4-aza-7,9- dideazaadnine; (d) R¹ is methyl-propionyl, and R² is 7-deazaadenine; (e) R¹ is hydrogen, and R² is 7-deazaadenine; or (f) R¹ is hydrogen, and R² is adenine.

In some forms, the compound can have the structure of Formula III’ :

or a pharmaceutical salt thereof.

In some forms, the compound can have the structure of Formula III:

Formula III or a prodrug thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound of Formula III is also referred to herein as ISB-MKA or MKA. The compounds (such as the compounds of Formulae I’, II’, and III’) may contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. These may be pure (single) stereoisomers or mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. The compounds may be capable of existing as geometric isomers. Accordingly, it is to be understood that the disclosed compounds include pure geometric isomers or mixtures of geometric isomers.

The compounds may be neutral or may be one or more pharmaceutically acceptable salts, crystalline forms, non-crystalline forms, hydrates, or solvates, or a combination thereof. References to the compounds may refer to the neutral molecule, and/or those additional forms thereof collectively and individually from the context. Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof.

Suitable acid addition salts of the compounds are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts of the compounds are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases of the compounds may also be formed, for example, hemisulphate and hemicalcium salts.

B. Pharmaceutical Formulations

Pharmaceutical compositions (also referred herein as “pharmaceutical formulations”) including unit dosage forms suitable for the delivery of the conjugates (including their pharmaceutically acceptable salts) and their preparation are disclosed. Suitable pharmaceutical formulations can be determined by the skilled artisan depending on the route of administration and the desired dosage (e.g., Remington’s Pharmaceutical Sciences, (23rd ed., Academic Press, 2020). Formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered compounds.

Generally, the pharmaceutical formulation contains one or more of the compounds described herein and a pharmaceutically acceptable excipient/carrier. The term “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” are used interchangeably herein to describe any ingredient in the formulation other than the compounds described herein, such as any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Typically, the pharmaceutically acceptable excipients/carriers are molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human, and are compatible with the compounds and any additional active agents.

The pharmaceutical formulations can include an effective amount of one or more of the compounds described herein, their stereoisomers, and/or their pharmaceutically acceptable salts (together referred to as the “compounds”), for administration in a subject in need thereof, to prevent or treat a viral infection in a subject in need thereof. It is to be understood that combinations and/or mixtures of the compounds may be included in the pharmaceutical composition or formulation.

In some forms, the pharmaceutical composition or formulation can further contain one or more active agents in addition to the compounds, such as one or more additional antiviral agents and/or one or more anti-inflammatory agents.

Any one or more of the compounds provided herein can be expressly included or expressly excluded from the pharmaceutical compositions, dosage units, and/or methods of use or treatment disclosed herein.

1. Oral Formulations

The compounds can be administered orally. Oral administration may involve swallowing so that the conjugate enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the conjugate enters the bloodstream directly from the mouth.

Formulations suitable for oral administration of the compounds disclosed herein include solid formulations such as tablets, capsules containing particulates, liquids, powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomes, films, ovules, sprays and liquid formulations. In some forms, the conjugates can be associated with a suitable carrier, such as particles or micelles, e.g. polymeric particles or micelles, lipid particles, and dendrimers. In these forms, the compounds can be encapsulated in, covalently bond to, and/or complexed with the particles. These particles containing the conjugates can be used for increasing the solubility of the compounds disclosed herein. Examples of materials suitable for forming the particles (nanoparticles and/or microparticles) containing the disclosed compounds include, but are not limited to, poly(alkylene glycol) or a copolymer thereof, such as poly(ethylene glycol) (“PEG”) and copolymers thereof, phospholipids, and polyamidoamine (“PAMAM”) or derivatives thereof (e.g. hydroxyl PAMAM). These particles containing the disclosed compounds may be further formulated into tablets, capsules, powders, etc.

Liquid formulations containing the disclosed compounds include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically contain a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds may also be used in fast dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

For tablet or capsule dosage forms, depending on dose, the compounds may make up from 1 weight % to 80 weight % of the dosage form or from 5 weight % to 60 weight % of the dosage form. In addition to the conjugates described herein, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will contain from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (as, for example, the monohydrate, spray-dried monohydrate or anhydrous form), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets or capsules may also optionally contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may contain from 0.2 weight % to 5 weight % of the tablet, and glidants may contain from 0.2 weight % to 1 weight % of the tablet.

Tablets or capsules also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally contain from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

Other possible ingredients include glidants (e.g. Talc or colloidal anhydrous silica at about 0.1 weight% to about 3 weight %), antioxidants, colorants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% of one or more of the conjugates described herein, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet or capsule blends may be compressed directly or by roller to form tablets. Tablet or capsule blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may contain one or more layers and may be coated or uncoated; it may even be encapsulated.

Solid formulations of the compounds for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.

2. Parenteral Formulations

The compounds can also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. Parenteral formulations containing the disclosed compounds are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents or the association of the conjugates with particles, such as those described above. For example, formulations for parenteral administration of the compounds can contain a suitable carrier that can increase the solubility of the conjugates disclosed herein. For example, the compounds disclosed herein can be encapsulated in, covalently bond to, or complexed with polymeric nanoparticles, microparticles, or micelles, such as nanoparticles, microparticles, or micelles formed by a poly(lactic-co-glycolic acid), poly (lactic-co-gly colic acid)- poly(ethylene glycol), poly(lactic acid)-poly(ethylene oxide), poly(caprolactone)- poly (ethylene glycol), or a copolymer thereof.

Formulations of the compounds for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Thus, the compounds may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active agents. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

3. Pulmonary and Mucosal Formulations

The compounds can be formulated for pulmonary or mucosal administration. The administration can include delivery of the composition to the lungs, nasal, oral (sublingual, buccal), vaginal, or rectal mucosa.

For example, the compounds can also be administered intranasally or by oral inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as water, ethanol-water mixture, 1 , 1 , 1 ,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal or oral inhalation use, the powder may contain a bioadhesive agent, for example, chitosan or cyclodextrin. The term aerosol as used herein refers to any preparation of a fine mist of particles, which can be in solution or a suspension, whether or not it is produced using a propellant. Aerosols can be produced using standard techniques, such as ultrasonication or high-pressure treatment.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of one or more of the conjugates including, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the compound is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the conjugates described herein, a suitable powder base such as lactose or starch and a performance modifier such as 1 -leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

A suitable solution formulation containing the disclosed compounds for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20 mg of one or more of the conjugates described herein per actuation and the actuation volume may vary from 1 pl to 100 pl. A typical formulation may contain one or more of the compounds described herein, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration of the compounds may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release formulations.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the conjugates are typically arranged to administer a metered dose or "puff". The overall daily dose will be administered in a single dose or, more usually, as divided doses throughout the day.

In some forms, the compounds described herein can be formulated for pulmonary delivery, such as intranasal administration or oral inhalation. Carriers for pulmonary formulations containing the compounds can be divided into those for dry powder formulations and for administration as solutions. Aerosols for the delivery of therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the formulation can be formulated into an aqueous solution, e.g., water or isotonic saline, buffered or un-buffered, or as an aqueous suspension, for intranasal administration as drops or as a spray. Such aqueous solutions or suspensions may be isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. One skilled in the art can readily determine a suitable saline content and pH for an innocuous aqueous solution for nasal and/or upper respiratory administration.

In some forms, the aqueous solution is water, physiologically acceptable aqueous solutions containing salts and/or buffers, such as phosphate buffered saline (PBS), or any other aqueous solution acceptable for administration to an animal or human. Such solutions are well known to a person skilled in the art and include, but are not limited to, distilled water, de-ionized water, pure or ultrapure water, saline, phosphate-buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

In some forms, solvents that are low toxicity organic (i.e. nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol may be used for the formulations. The solvent is selected based on its ability to readily aerosolize the formulation. The solvent should not detrimentally react with the conjugates. An appropriate solvent should be used that dissolves the conjugates or forms a suspension of the conjugates. The solvent should be sufficiently volatile to enable formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as freons, can be added as desired to increase the volatility of the solution or suspension.

In some forms, the pharmaceutical compositions may contain minor amounts of polymers, surfactants, or other excipients well known to those of the art. In this context, “minor amounts” means no excipients are present that might affect or mediate uptake of the conjugates by cells and that the excipients that are present in amount that do not adversely affect uptake of conjugates by cells. In some forms, the compounds described herein may be associated with particles, such as those described above. For example, formulations for pulmonary or mucosal administration can contain a suitable carrier that can increase the solubility of the compounds disclosed herein. For example, the compounds disclosed herein can be encapsulated in, covalently bond to, or complexed with polymeric nanoparticles, microparticles, or micelles, such as nanoparticles, microparticles, or micelles formed by a poly(alkylene glycol) or a copolymer thereof.

Dry lipid powders can be directly dispersed in ethanol because of their hydrophobic character. For lipids stored in organic solvents such as chloroform, the desired quantity of solution is placed in a vial, and the chloroform is evaporated under a stream of nitrogen to form a dry thin film on the surface of a glass vial. The film swells easily when reconstituted with ethanol. To fully disperse the lipid molecules in the organic solvent, the suspension is sonicated. Nonaqueous suspensions of lipids can also be prepared in absolute ethanol using a reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA).

4. Topical Formulations

The compounds can be administered directly to the external surface of the skin or the mucous membranes (including the surface membranes of the nose, lungs and mouth), such that the compounds cross the external surface of the skin or mucous membrane and enters the underlying tissues.

Formulations for topical administration of the disclosed compounds generally contain a dermatologically acceptable carrier that is suitable for application to the skin, has good aesthetic properties, is compatible with the active agents and any other components, and will not cause any untoward safety or toxicity concerns.

The carrier can be in a wide variety of forms. For example, emulsion carriers, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil- in- water-in- silicone emulsions, are useful herein. These emulsions can cover a broad range of viscosities, e.g., from about 100 cps to about 200,000 cps. These emulsions can also be delivered in the form of sprays using either mechanical pump containers or pressurized aerosol containers using conventional propellants. These carriers can also be delivered in the form of a mousse or a transdermal patch. Other suitable topical carriers include anhydrous liquid solvents such as oils, alcohols, and silicones (e.g., mineral oil, ethanol isopropanol, dimethicone, cyclomethicone, and the like); aqueous-based single phase liquid solvents (e.g., hydro-alcoholic solvent systems, such as a mixture of ethanol and/or isopropanol and water); and thickened versions of these anhydrous and aqueous-based single phase solvents (e.g. where the viscosity of the solvent has been increased to form a solid or semi-solid by the addition of appropriate gums, resins, waxes, polymers, salts, and the like). Examples of topical carrier systems useful in the present formulations are described in the following four references all of which are incorporated herein by reference in their entirety: “Sun Products Formulary” Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); “Sun Products Formulary,” Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Pat. No. 5,605,894 to Blank et al., and U.S. Pat. No. 5,681,852 to Bissett.

Formulations for topical administration of the compounds may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Thus, the compounds may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres. 5. Additional Active Agent(s)

In some forms, the pharmaceutical composition or pharmaceutical formulation can include one or more additional active agents, such as one or more additional antiviral agents and/or one or more anti-inflammatory agents. Antiviral and antiinflammatory agents that can be included in the pharmaceutical compositions or formulations are known, for example, see Erik De Clercq, Medmicro, Chapter 52 (2000); and the WebMD, “Anti-inflammatory Drugs,” web site webmd.com/arthritis/anti-inflammatory-drugs; Barnes, Nature, 402(6760): 31-38 (1999); and Rainsford, Inflammation in the pathogenesis of chronic diseases 3:27 (2007).

Exemplary antiviral drugs that can be included in the pharmaceutical composition or pharmaceutical formulation include, but are not limited to, chloroquine, darunavir, galidesivir, interferon beta, lopinavir, ritonavir, remdesivir, tribavirin, favipiravir, and triazavirin, and combinations thereof.

Exemplary anti-inflammatory drugs that can be included in the pharmaceutical composition or pharmaceutical formulation include, but are not limited to, ibuprofen, naproxen sodium, aspirin, naproxen sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, naproxen, esomeprazole, diclofenac, diflunisal, etodolac, ketorolac tromethamine, katoprofen, meclofenamate, nabumetone, salsalate, tolmetin, and steroids, such as corticosteroids (e.g. hydrocortisone, cortisone, ethamethasoneb, prednisone, prednisolone, triamcinolone, methylprednisolone, and dexamethasone) and mineralocorticoids (e.g. fludrocortisone), and a combination thereof.

6. Effective Amount

Effective amounts of the compounds contained in the pharmaceutical composition or pharmaceutical formulation depend on many factors, including the indication being treated, the route of administration, co-administration of other therapeutic compositions, and the overall condition of the patient. For example, depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays as well as the pharmacokinetic data obtainable through animal or human clinical trials. In some forms, the total amount of the one or more compounds in the pharmaceutical formulation (in unit dosage form) can be from 0.001 mg to 1500 mg, from 0.01 mg to 1500 mg, from 0.1 mg to 1500 mg, from 1 mg to 1500 mg, from 10 mg to 1500 mg, from 20 mg to 1500 mg, from 0.01 mg to 1000 mg, from 0.1 mg to 1000 mg, from 1 mg to 1000 mg, from 10 mg to 1000 mg, from 20 mg to 1000 mg, from 0.01 mg to 700 mg, from 0.1 mg to 700 mg, from 1 mg to 700 mg, from 10 mg to 700 mg, from 20 mg to 700 mg, from 50 mg to 700 mg, from 0.01 mg to 500 mg, from 0.1 mg to 500 mg, from 1 mg to 500 mg, from 10 mg to 500 mg, from 20 mg to 500 mg, from 50 mg to 500 mg, from 0.01 mg to 100 mg, or from 0.1 mg to 100 mg.

In some forms, the total amount of the one or more compounds in the pharmaceutical formulation (in unit dosage form) is in a range from 1 mg to 1000 mg. For example, the total amount of the one or more compounds in a pill dosage form is from about 50 mg to about 400 mg, or from about 100 mg to about 300 mg (such as by considering the sheer volume restrictions on what a human can swallow). For example, the total amount of the one or more compounds in an IV dosage form is from about 10 mg to about 500 mg (e.g., provided by reconstitution of 10-500 mg of the compounds in solid form in sterile water or saline).

In some forms, the total amount of the one or more compounds in the pharmaceutical formulation can be at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, in a range from about 0.01 wt% to about 50 wt%, from about 0.05 wt% to about 50 wt%, from about 0. 1 wt% to about 50 wt%, from about 0.01 wt% to about 40 wt%, from about 0.05 wt% to about 40 wt%, from about 0.1 wt% to about 40 wt%, from about 0.01 wt% to about 30 wt%, from about 0.05 wt% to about 30 wt%, from about 0.1 wt% to about 30 wt%, from 0.01 wt% to 20 wt%, from about 0.05 wt% to about 20 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 15 wt%, from about 0.2 wt% to about 20 wt%, from about 0.1 wt% to about 10 wt%, from about 0.5 wt% to about 20 wt%, from about 0.5 wt% to about 15 wt%, from about 0.5 wt% to about 10 wt%, from about 0.5 wt% to about 5 wt%, from about 0.1 wt% to about 5 wt%, or from about 0. 1 wt% to about 1 wt%. The term “total amount of the one or more compounds in the pharmaceutical formulation” refers to the sum of the weight of the one or more compounds relative to the total weight of the pharmaceutical formulation.

Optionally, the total amount of the one or more compounds in the pharmaceutical formulation is effective to prevent or treat a viral infection in a subject in need thereof, such as to ameliorate one or more symptoms associated with an RNA viral infection.

III. Methods of Making and Reagents Thereof

The compounds described herein can be synthesized using methods known in the art of organic chemical synthesis. Generally, the method of producing the compound includes: (i) oxidizing a riboside to form a raw product comprising the compound; and (ii) purifying the raw product to produce a purified product.

The riboside being oxidized in step (i) can have the structure of Formula I’ a:

or a pharmaceutical salt thereof, wherein: (i) R1 can be a prodrug side chain, such as any of those described above; (ii) R2 can be a nucleobase or analogue thereof, such as any of those described above for Formulae F, I, II’, and II; and (hi) R3 can be a C1-C6 unsubstituted alkyl.

In some forms, the riboside being oxidized in step (i) can have the structure of

Formula la:

Formula la or a pharmaceutical salt thereof, wherein: (i) R1 can be a prodrug side chain, such as any of those described above; (ii) R2 can be a nucleobase or analogue thereof, such as any of those described above for Formulae I’, I, II’, and II; and (iii) R3 can be a C1-C6 unsubstituted alkyl. In some forms, the riboside being oxidized in step (i) can have the structure of

Formula II’ a:

or a pharmaceutical salt thereof, wherein: (i) R1 can be a prodrug side chain, such as any of those described above; and (ii) R2 can be a nucleobase or analogue thereof, such as any of those described above for Formulae F, I, IF, and II.

In some forms, the riboside being oxidized in step (i) can have the structure of Formula Ila:

Formula Ila or a pharmaceutical salt thereof, wherein: (i) R1 can be a prodrug side chain, such as any of those described above; and (ii) R2 can be a nucleobase or analogue thereof, such as any of those described above for Formulae F, I, IF, and II.

In some forms, the riboside being oxidized in step (i) can have the structure of Formula III’ a:

or a pharmaceutical salt thereof. In some forms, the riboside being oxidized in step (i) can have the structure of

Formula Illa:

or a pharmaceutical salt thereof.

The riboside being oxidized in step (i) (such as the riboside of Formulae I’ a, IF a, and III’ a) may contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. These may be pure (single) stereoisomers or mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. The riboside may be capable of existing as geometric isomers. Accordingly, it is to be understood that the riboside being oxidized in step (i) include pure geometric isomers or mixtures of geometric isomers.

The oxidation reaction in step (i) (i.e., oxidizing the riboside) for converting secondary alcohols to ketones can be performed using reactions known in the art. Examples of known reactions suitable for oxidizing the riboside in step (i) include, but are not limited to, Corey-Kim Oxidation, Dess-Martin Oxidation, Oppenauer Oxidation, and Swern Oxidation. Typically, selective and mild oxidation conditions are preferably used to convert the 3 ’-hydroxyl group to the 3 ’-ketone or aldehyde for nucleosides in step (i), such as by using Dess-Martin Oxidation. The Des-Martin Oxidation is selective, relatively mild, and readily performed in a solvent such as dichloromethane, chloroform, dimethyl formamide, dimethyl sulfoxide, or various combinations (e.g., 12-1-5 -periodinane (i.e., Dess-Martin Periodinane or DMP), DMSO/DCC, CrO₃/pyridine/Ac₂O, DMSO/oxalyl chloride, and DMSO/Ac₂O reagents). For example, the Dess-Martin Oxidation reaction can be carried out at room temperature, and is usually complete within minutes to hours such as overnight, and the raw product can be easily separated from the iodo-compound byproduct after basic work-up (see, e.g. , Robins et al. (1997) Tetrahedron 53(2):447-456; https://www.organic-chemistry.org/namedreactions/dess-martin-oxidation.shtm; Dess et al. (1983) J. Org. Chem. 48 (22): 4155-4156; and Meyer et al. (1994) J. Org. Chem. 59 (24): 7549-7552).

The raw product produced in step (i) is purified in step (ii) to produce a purified product that contains the disclosed compounds. The purification in step (ii) can be performed using methods known in the art, such as by using reverse phase chromatographic separation and/or vacuum concentration. For example, purification in step (ii) is performed by using reverse phase chromatographic separation to isolate the target fraction(s) and optionally vacuum concentration of the target fraction(s). Optionally, salt removal or exchange can be carried out in step (ii) if needed by standard techniques. Optionally, the concentrates produced by vacuum concentration can be further worked up by, for example, dissolving in phosphate buffered saline (PBS), DMSO, or other solvates for testing or additional processing.

Typically, the compound in the purified product has a purity suitable for a given end use, for example, technical or laboratory grade for general research settings up to a grade that meets or exceeds pharmaceutical grade (e.g., United States Pharmacopeia (USP) grade) for food or medicinal use. As can be appreciated, purity reflects the presence of the desired species (i.e., the compounds disclosed herein) and the presence of byproducts, residual chemicals, or macromolecule contaminants that occur during production and purification processes.

For example, the purity of the compound in the purified product is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, or at least 99%). Methods for determining the purity of the compound in the purified product are known, such as analytical test (for example High Performance Liquid Chromatography (HPLC), sensitive colorimetric assays and the like) and biology assays (for example assay with enzymatic or cell based assays to complement analytical tests). For example, the compound purity in the purified product is readily assessed by HPLC optionally coupled with mass spectrometry (MS) detection, and in particular by Reverse Phase (RP) HPLC and optionally coupled with linear ion trap mass spectrometry (LIT-MS). For example, the purity of the compound in the purified product is at least about 50% as determined by high performance liquid chromatography .

The purified product obtained in step (ii) can be stored or formulated in various formats and dosage forms, including, but not limited to, as a pharmaceutically acceptable salt or solvate thereof. The concentration and activity of the compounds in the purified product can be determined by standard techniques. For example, functional performance of the compounds in the purified product can be assessed for a biological activity, and usually a minimum activity. For example, the exemplary 2’-methyl-3’- ketoadenosine compound MKA reconstituted in PBS solution at a concentration of lOOmM and purity of about 50% or greater exhibits ex vivo: (a) half effective concentration EC50 of 20uM or less as measured by hepatitis C (HCV) replicon analysis relative to 100% inhibition of HCV by 1.0 uM danoprevir; and/or (b) half cytotoxicity concentration CC50 of 500 uM or greater as measured by Cell Counting Kit-8 (CCK8) live cell counting assay in 100% fresh media.

More specific reagents, reaction conditions, products formed, and purifications are described in the Examples.

IV. Methods of Using

The compounds described herein have antiviral properties. It is believed that these compounds can terminate elongation of nucleic acid chains, and thus can be potent virus chain elongation inhibitors, such as potent RNA virus chain elongation inhibitors. For example, the compounds exhibit activity against RNA-dependent RNA polymerase of the RNA virus (viral RdRp) and terminates viral RdRp-mediated RNA chain elongation. Accordingly, the compounds disclosed herein are particularly suitable for use in preventing or treating a variety of viral infections, in particular infections caused by RNA virus. For example, the compounds disclosed herein are used for preventing or treating a viral infection in a cell, where the cell can be in vitro or in vivo (such as in a human in need thereof).

It will be appreciated the disclosed methods can be methods of treatment of the symptoms and conditions associated with viral infections. “Treatment” refers to the medical management of a target, such as a cell or a patient, with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

A. Preventing or Treating Viral Infections

Generally, the method for preventing or treating a viral infection in a cell includes administering to the cell one or more the disclosed compounds or a pharmaceutical formulation containing one or more of the compounds disclosed herein. The cell can be in vitro or in vivo.

For example, the method disclosed herein is for preventing or treating a viral infection in a cell in vitro, which includes administering to the cell one or more the disclosed compounds or a pharmaceutical formulation containing one or more of the compounds disclosed herein.

For example, the method disclosed herein is for preventing or treating a viral infection in a subject in need thereof (i.e., treating cells in vivo, where the cells are in the subject, such as a human or other mammal), which includes administering to the subject a pharmaceutical formulation containing one or more of the compounds disclosed herein.

The administration step of the disclosed method can occur one or more times. Typically, following a single administration or all of the administrations of the compound or pharmaceutical formulation, an effective amount of the compound is administered to the cell (in vitro or in vivo) for a given end use, such as to ameliorate one or more symptoms associated with the viral infection.

For example, following a single administration or all of the administrations of the compound or pharmaceutical formulation, an effective amount of the compound to prevent or treat a viral infection in a cell in vitro (as shown by the improvement and/or relief of one or more symptoms associated with the viral infection, e.g., by the inhibition of cell replication), is administered to the cell.

For example, following a single administration or all of the administrations of the pharmaceutical formulation, an effective amount of the compound to prevent or treat a viral infection in a subject in need thereof (i.e., treating cells in vivo), as shown by the improvement and/or relief of one or more symptoms associated with the viral infection in the subject, is administered to the subject.

Optionally, the disclosed method further includes administering one or more additional active agents to the cell or subject, such as one or more antiviral agents and/or one or more anti-inflammatory agents. Administration of the additional active agents may be performed prior to, during, and/or subsequent to the administration or each administration of the compounds or pharmaceutical formulation containing the disclosed compounds.

The cell being treated using the disclosed method can be a cell of a mammal, such as a human, a dog, a cat, a rat, a monkey, rabbits, guinea pigs, etc., that is in need of treatment.

In some forms, the cell or subject being treated using the disclosed method is infected by an RNA virus. The RNA virus infecting the subject can be a virus of a variety of families, such as Flaviviridae (e.g., hepatitis), Orthomyxoviridae (e.g., influenza), Filoviridae (e.g., Ebola), Coronaviridae (e.g., SARs), and Paramyxoviridae (e.g., parainfluenza).

1. Administration Routes

The pharmaceutical formulation containing one or more of the disclosed compounds can be administered to the subject by oral administration, parenteral administration (such as intramuscular administration, intravenous administration, intraperitoneal administration, or subcutaneous administration, or a combination thereof, e.g., intravenous injection or infusion), inhalation, mucosal administration (through mouth or nasal), or topical administration, or a combination thereof.

For example, the pharmaceutical formulation containing one or more of the disclosed compounds can be orally administered to a subject by a medical professional or the subject being treated (e.g., self-administration). The pharmaceutical formulation containing one or more of the disclosed compounds can be administered as tablets, capsules containing particulates, granules, powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, or liquids (e.g., solution or suspensions in aqueous or non-aqueous solvent).

Optionally, the pharmaceutical formulation containing one or more of the disclosed compounds can be administered to the subject by intravenous injection or intraperitoneal injection. The intravenous injection or intraperitoneal injection can be performed by a medical professional or the subject being treated (e.g., self-injection).

2. Effective Amount

For example, if the unit dosage form contains an effective amount of the compounds to prevent or treat the viral infection in the subject, as indicated by the improvement and/or relief of one or more symptoms associated with the viral infection in the subject, then the method only requires a single administration step. Alternatively, if the unit dosage form contains less than the needed effective amount of the compounds to prevent or treat the viral infection in the subject, then the method involves at least two steps of administering the pharmaceutical formulation, and optionally more than two steps of administering the pharmaceutical formulation to the subject until an effective amount of the compounds is administered to the subject to prevent or treat the viral infection, as indicated by the improvement and/or relief of one or more symptoms associated with the viral infection in the subject. When multiple administration steps are needed to administer an effective amount of the compounds to the subject, each administration step may involve administering the same dosage or different dosages of the pharmaceutical formulation to the patient; and the administration step may be repeated one or more times for a period of time. In some forms, the administration step is repeated once, twice, or three times, per day, for a time period of one day, three days, one week, two weeks, or one month. For example, the administration step is repeated every 4 hours, every 6 hours, every 12 hours, or every day, optionally for a time period from 1 day to 1 month, from 1 day to 2 weeks, from 1 day to 1 week, or from 1 day to 3 days.

In some forms, treatment regimens utilizing the compounds include administration of from about 0.1 mg to about 300 mg of the compounds per kilogram body weight of the recipient per day, achieved in multiple doses or in a single dose. In some embodiments, a suitable dose of the compounds may be in the range of 0.05 to 300 mg per kilogram body weight of the recipient, 0.05 to 200 mg per kilogram body weight of the recipient, 0.05 to 100 mg per kilogram body weight of the recipient, 0.1 to 300 mg per kilogram body weight of the recipient, 0.1 to 200 mg per kilogram body weight of the recipient, 0.1 to 100 mg per kilogram body weight of the recipient, 1 to 150 mg per kilogram body weight, 1 to 100 mg per kilogram body weight, 2 to 100 mg per kilogram body weight, 2 to 50 mg per kilogram body weight, 2 to 25 mg per kilogram body weight, 5 to 100 mg per kilogram body weight, 5 to 80 mg per kilogram body weight, 5 to 50 mg per kilogram body weight, 5 to 30 mg per kilogram body weight, 0.5 to 50 mg per kilogram body weight, or 5 to 20 mg per kilogram body weight, such as about 10 mg per kilogram body weight. Such a dose of compounds may be administered one time or multiple times in a day to achieve a suitable treatment regimen, such as from about 0.1 mg to about 300 mg of the conjugates per kilogram body weight of the recipient per day. For example, to achieve the treatment regimens as described above, the dosage of the compounds in the pharmaceutical formulation in step (i) is from about 0.1 mg to about 100 mg, from about 0.5 mg to about 50 mg, from about 1 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 2 mg to about 100 mg, from about 2 mg to about 50 mg, from about 2 mg to about 25 mg, or from about 5 mg to about 20 mg per kg of the subject.

The disclosed compounds, formulations, and methods can be further understood through the following numbered paragraphs.

Paragraph 1 . A compound having the structure of:

Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, wherein: (i) R1 is a prodrug side chain; (ii) R2 is a nucleobase or an analogue thereof; and (iii) R3 is a C1-C6 unsubstituted alkyl.

Paragraph 2. The compound of paragraph 1, wherein the compound has the structure of:

Formula II

Paragraph 3. The compound of paragraph 1 or paragraph 2, wherein R1 is hydrogen, a carbonyl (e.g., an ester or a thioester), a phosphonyl (e.g., a phosphoester or a phosphoramidate), a thiophosphonyl, a sulfinyl, a sulfonyl, or a sulfamoyl.

Paragraph 4. The compound of paragraph 3, wherein R1 is hydrogen, -

wherein each R⁴ or R⁵ is independently H, an unsubstituted (C1-C8) alkyl, a substituted (C1-C8) alkyl, an unsubstituted (C2-C8) alkenyl, a substituted (C2-C8) alkenyl, an unsubstituted (C2-C8) alkynyl, or a substituted (C2-C8) alkynyl, and wherein each substituent (when present) is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a carbonyl, an alkoxy, a halogen, a hydroxyl, a phenoxy, a thiol, an alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a carboxyl, an amino, an amido, an oxo, a silyl, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, or a phosphonyl.

Paragraph 5. The compound of any one of paragraphs 1-4, wherein R1 is hydrogen, 2-methyl-propinyl, or ProTide phosphoramidate.

Paragraph 6. The compound of any one of paragraphs 1-5, wherein R2 is adenine or an adenine analogue.

Paragraph 7. The compound of any one of paragraphs 1-6, wherein the compound has the structure of:

MKA

Paragraph 8. The compound of any one of paragraphs 1-7, wherein the compound has ex vivo: (a) a half effective concentration EC50 of 20uM or less as measured by hepatitis C (HCV) replicon analysis relative to 100% inhibition of HCV by 1.0 pM danoprevir; and/or (b) a half cytotoxicity concentration CC50 of 500 pM or greater as measured by Cell Counting Kit-8 (CCK8) live cell counting assay in 100% fresh media. Paragraph 9. A pharmaceutical formulation comprising:

(a) one or more compounds of any one of paragraphs 1-8 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof; and

(b) a pharmaceutically acceptable excipient.

Paragraph 10. The pharmaceutical formulation of paragraph 9, wherein the pharmaceutical formulation further comprises one or more active agents, and optionally wherein the one or more active agents are one or more antiviral agents and/or one or more anti-inflammatory agents.

Paragraph 11. A method of producing a 2’ -alky 1-3’ -ketoribose, comprising:

(i) oxidizing a riboside of Formula la to form a raw product comprising the compound,

Formula la wherein: (i) R1 is a prodrug side chain; (ii) R2 is a nucleobase or analogue thereof; and (iii) R3 is a C1-C6 unsubstituted alkyl; and

(ii) purifying the raw product to produce a purified product, wherein the compound in the purified product has a purity suitable for use in food or medicine.

Paragraph 12. The method of paragraph 1 1 , wherein the riboside being oxidized in step (i) has the structure of:

Formula Ila

Paragraph 13. The method of paragraph 11 or 12, wherein R1 is hydrogen, a carbonyl (e.g., an ester or a thioester), a phosphonyl (e.g., a phosphoester or a phosphoramidate), a thiophosphonyl, a sulfinyl, a sulfonyl, or a sulfamoyl.

Paragraph 14. The method of any one of paragraphs 11-13, wherein R1 is hydrogen, 2-methyl-propinyl, or ProTide phosphoramidate. Paragraph 15. The method of any one of paragraphs 11-14, wherein R2 is adenine or an adenine analogue.

Paragraph 16. The method of any one of paragraphs 11-15, wherein the riboside being oxidized in step (i) has the structure of:

Formula Illa

Paragraph 17. The method of any one of paragraphs 11-16, wherein the purity of the compound in the purified product is at least about 50% as determined by high performance liquid chromatography.

Paragraph 18. The method of any one of paragraphs 11-17, wherein the oxidation reaction of step (i) is performed using Dess-Martin oxidation.

Paragraph 19. The method of any one of paragraphs 11-18, wherein the purification of step (ii) is performed using reverse phase chromatographic separation or vacuum concentration, or a combination thereof.

Paragraph 20. A method for preventing or treating a viral infection in a cell in need thereof comprising

(i) administering to the cell one or more of the compounds of any one of paragraphs 1-8 or the pharmaceutical formulation of paragraph 9 or 10, wherein step (i) occurs one or more times.

Paragraph 21. The method of paragraph 20, wherein the cell is infected by an RNA virus.

Paragraph 22. The method of paragraph 21 , wherein the cell is in a subject infected by the RNA virus.

Paragraph 23. The method of paragraph 21 or 22, wherein the RNA virus is of a family selected from the group consisting of Flaviviridae, Orthomyxoviridae, Filoviridae, Coronaviridae, and Paramyxoviridae. Paragraph 24. The method of any one of paragraphs 20-23, wherein in step (i), the pharmaceutical formulation is administered by oral administration or intravenous administration.

Examples Example 1: Exemplary 3 ’-ketoriboside analogues inhibit HCV replication with little cytotoxicity

Materials and Methods

Synthesis of 2’ -methyl-3’ -ketoadenosine (MKA)

About 65 milligrams (mg) of 2’ -methyladenosine (2CMA, Cas # 15397-12-3, Carbosynth-BioSynth) was dissolved in 0.25M dimethylformamide (DMF)/dimethyl sulfoxide (DMSO) (1 : 1). An equal mole (~98mg) of Dess-Martin periodinane (DMP, CAS # 87413-09-0; Sigma) was added directly to the solution and vortex to dissolve the DMP. White precipitates of iodinane by-products were observed after overnight incubation at room temperature (RT, about 23° at latm). After spinning down the precipitates, the supernatant solution was diluted in 10X volume of 0.1% trifluoroacetic acid (TFA) in water and sat still for 30 min to allow more iodinane by-product precipitation. The precipitates were removed by centrifugation and the supernatant was loaded onto a fast protein liquid chromatography -re verse phase-C18 (FPLC-RP-C18) cartridge at 5 mL/min and eluted with a 70 min gradient from 0% to 30% acetonitrile (ACN). NGC chromatography system from Bio-Rad Laboratories (Hercules, CA) was used for reverse phase FPLC-C18 separation and FLASHPure, C18 30 um flash cartridges (40g) were purchased from BUCHI. Thermo-LTQ mass spectrometry was used to check the compositions of the eluted fractions (FIG. 1). The unreacted 2’-CMA MH+: 282.36 were eluted out early, followed by 2’- methyladenosine-5 ’ -acid, MH+: 296.18, and 2’ -C-methyladenosine-5 ’ -aldehyde hydrate, MH+: 298.27. The 2’- methyls’ -ketoadenosine, MH+: 280.26, were closely eluted out with the 5’ -aldehyde hydrate with slightly delay. The tube with the highest amount of 280.26 contents were dried by Speed-Vac and dissolved in IX phosphate buffered saline (PBS). The concentrations of the nucleosides were determined by NanoDrop uv 260 nm absorption using 2CMA as standard curve.

Synthesis of 2’ -methyl-3’ -ketoguanosine (MKG)

Dess-Martin periodinane oxidation of 2 ’-methylguanosine to produce 2’- methyl-3’ -ketoguanosine was carried out as described above for 2’-methyl-3’- ketoadenosine synthesis. Briefly, about 104 milligrams (mg) of 2’ -methylguanosine (2CMG, Cas # 374750-30-8, Carbosynth-BioSynth) was dissolved in 0.25M DMF/DMSO (1 :1). An equal mole (~148mg) of Dess-Martin periodinane (DMP, CAS # 87413-09-0; Sigma) was added directly to the solution and vortex to dissolve the DMP. White precipitates of iodinane by-products were observed after overnight incubation at RT. After spinning down the precipitates, the supernatant solution was diluted in 10X volume of 0. 1% TFA in water and sat still for 30 min to allow more iodinane by-product precipitation. The precipitates were removed by centrifugation and the supernatant was loaded onto a FPLC-RP-C18 cartridge at 5 mL/min and eluted with a 70 min gradient from 0% to 30% ACN. NGC chromatography system from Bio-Rad Laboratories (Hercules, CA) was used for reverse phase FPLC-C18 separation and FLASHPure, Cl 8 30 um flash cartridges (40g) were purchased from BUCHI. Thermo- LTQ mass spectrometry was used to check the compositions of the eluted fractions. The fractions with the highest amount of 296.26 contents were dried by Speed-Vac and dissolved in IX PBS. The concentrations of the nucleosides were determined by NanoDrop uv 260 nm absorption using 2CMG as standard curve.

Anti-viral activity and cytotoxicity testing

MKA and MKG compounds were tested for anti RNA virus activity using the hepatitis C virus (HCV) viral replicon replication in the human Huh7 cell line (ATCC: PTA-4583). The HCV replicon has all the viral structural proteins deleted and is maintained by its RNA-dependent RNA polymerase (RdRP) NS5B (Lohmann el al. (1999) Science 255(5424): 110-113). The cell line was maintained in DMEM with 10% FBS and Img/mL Geneticin (Gibco) for selection of the HCV replicon at 37 °C in a 5% CO2 incubator. For HCV inhibitory drug test, -8000 cells in 100 uL DMEM with 10% FBS were cultured 96 well plates for two days. Then the media were removed and replaced with lOOuL of the MKA and MKG test articles at various concentrations in the DMEM with 10% FBS media and cultured for 48 hours. After 2-days culture, the TaqMan Fast Advanced Cells-to-Ct Kits (A35377, ThermoFisher Scientific) were used for cell lysis, RT and qPCR following the manufacture’s protocols. 20uL lysis buffer was used for each well, and lOuL reactions were used for both RT and qPCR reaction. The ACTB (|)-actin) primer set in the TaqMan Cell-to-Ct control kit (ThermoFisher) was used for endogenous mRNA control. The primers for qPCR of HCV are: HCV- 131F: GGGAGAGCCATAGTGGTCTGC (SEQ ID NO: 1); HCV-231R: CCCAAATCTCCAGGCATTGA (SEQ ID NO:2); detection probe: 5’ 6-FAM- CGGAATTGCCAGGACGACCGG ) (SEQ ID NO:3). The wells with DMEM/10% FBS without MKA or MKG test articles were used as negative controls. The inhibition of 1.0 uM Danoprevir (ITMN-191, ApexBio), an effective HCV protease inhibitor, was set as 100% inhibition. For cytotoxicity test, -1500 to 1600 cells in lOOuL DMEM with 10% FBS were cultured in 96-well plates for 2 days and treated with different concentrations of drugs for 48 hours the same as the inhibition test. Then lOul of cell counting kit 8 (WST-8/CCK8, Abeam) was added to every lOOuL culture in each well and incubated at 37 °C for 3 to 6 hours and the absorption at 460 nm was measured for each well. Media without cells were used as negative control. Cells in the media without drug were used as 100% viability.

Results

MKA and MKG test articles were dissolved in IX PBS, sterile filtered by 0. 1 uM filters and stored in 4 °C or -20 °C for up to two months without significant activity changes. The hepatitis C (HCV) replicon analysis and % cell viability of CCK8 in the presence of MKA, MKG, and known compounds (i.e., Remdesivir, N4- hydroxycytidine, and 3 ’-deoxycytidine are shown in FIGs. 2A-2D. Consistent with the analytical data showing between about 1% to 10% purity in a trial synthesis, the MKG test article was found to exhibit a similarly low half effective concentration (EC50) of around lOOuM (data not shown). In contrast, the MKA test article was obtained in a trial synthesis at a purity of about 50% or greater and found to exhibit an EC50 around 20 uM and CC50 of about 800 uM or more (FIG. 2D). The selective index (SI = CC50/EC50) for MKA was around 40. Thus, MKA was found to be an effective HCV replication inhibitor with little cytotoxicity after only a relatively simple DMP oxidation synthesis and FPLC purification scheme.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Further, unless otherwise indicated, use of the expression “wt%” refers to “wt/wt%.”

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMS We claim:

1. A compound having the structure of:

2. The compound of claim 1, wherein the compound has the structure of:

Formula II

3. The compound of claim 1 or claim 2, wherein R1 is hydrogen, a carbonyl (e.g., an ester or a thioester), a phosphonyl (e.g., a phosphoester or a phosphoramidate), a thiophosphonyl, a sulfinyl, a sulfonyl, or a sulfamoyl.

4. The compound of any one of claims 1-3, wherein R1 is hydrogen, 2-methyl- propinyl, or ProTide phosphoramidate.

5. The compound of any one of claims 1-4, wherein R2 is adenine or an adenine analogue.

6. The compound of any one of claims 1-5, wherein the compound has the structure of:

MKA

7. The compound of any one of claims 1-6, wherein the compound has ex vivo: (a) a half effective concentration EC50 of 20uM or less as measured by hepatitis C (HCV) replicon analysis relative to 100% inhibition of HCV by 1.0 pM danoprevir; and/or (b) a half cytotoxicity concentration CC50 of 500 pM or greater as measured by Cell Counting Kit-8 (CCK8) live cell counting assay in 100% fresh media.

8. A pharmaceutical formulation comprising:

(a) one or more compounds of any one of claims 1-7 or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof; and

(b) a pharmaceutically acceptable excipient.

9. The pharmaceutical formulation of claim 8, wherein the pharmaceutical formulation further comprises one or more active agents, and optionally wherein the one or more active agents are one or more antiviral agents and/or one or more antiinflammatory agents.

10. A method of producing a 2’-alkyl-3’-ketoribose, comprising:

Formula la wherein: (i) Rd is a prodrug side chain; (ii) R2 is a nucleobase or analogue thereof; and (iii) R3 is a C1-C6 unsubstituted alkyl; and

11. The method of claim 10, wherein the riboside being oxidized in step (i) has the structure of:

Formula Ila

12. The method of claim 10 or 11, wherein R1 is hydrogen, a carbonyl (e.g., an ester or a thioester), a phosphonyl (e.g., a phosphoester or a phosphoramidate), a thiophosphonyl, a sulfinyl, a sulfonyl, or a sulfamoyl.

13. The method of any one of claims 10-12, wherein R1 is hydrogen, 2-methyl- propinyl, or ProTide phosphoramidate.

14. The method of any one of claims 10-13, wherein R2 is adenine or an adenine analogue.

15. The method of any one of claims 10-14, wherein the riboside being oxidized in step (i) has the structure of:

Formula Illa

16. The method of any one of claims 10-15, wherein the purity of the compound in the purified product is at least about 50% as determined by high performance liquid chromatography.

17. The method of any one of claims 10-16, wherein the oxidation reaction of step (i) is performed using Dess-Martin oxidation.

18. The method of any one of claims 10-17, wherein the purification of step (ii) is performed using reverse phase chromatographic separation or vacuum concentration, or a combination thereof.

19. A method for preventing or treating a viral infection in a cell in need thereof comprising

(i) administering to the cell one or more of the compounds of any one of claims 1 -7 or the pharmaceutical formulation of claim 8 or 9, wherein step (i) occurs one or more times.

20. The method of claim 19, wherein the cell is infected by an RNA virus.

21. The method of claim 20, wherein the cell is in a subject infected by the RNA virus.

22. The method of claim 20 or 21 , wherein the RNA virus is of a family selected from the group consisting of Flaviviridae, Orthomyxoviridae, Filoviridae, Coronaviridae, and Paramyxoviridae.