Thionucleosides as antiviral agents

Abstract

Disclosed herein are compounds, compositions, and methods for managing vial and other microbial infections. In certain embodiments, this disclosure relates to methods of treating or preventing a viral infection, such as RSV, COVID, and HIV, by administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient.

Description

[0001] THIONUCLEOSIDES AS ANTIVIRAL AGENTS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63 / 668,101 filed July 5, 2024. The entirety of this application is hereby incorporated by reference for all purposes. FIELD Compounds, compositions, and methods for treating or preventing viral infections such as Pneumoviridae infections, RSV, Coronaviridae infections, COVID, Noroviridae infection, Lentiviridae infections, HIV, and other viral infections are disclosed. More specifically, disclosed are certain nucleoside and nucleotide analogs, pharmaceutically acceptable salts, and derivatives thereof, and uses thereof in the treatment of viral and other microbial infections. BACKGROUND Human respiratory syncytial virus (RSV) causes acute lower respiratory infections. It is a major cause of hospital visits for premature babies and newborns. RSV infections also pose a threat for the elderly and immune compromised. Palivizumab is a humanized chimeric antibody that binds the RSV fusion protein (RSV F) that is clinically approved for prevention of serious lower respiratory tract disease caused by RSV in certain high-risk infants. Palivizumab has limited efficacy and sometimes causes allergic reactions. Thus, there is a need to identify additional therapies. Vaccines are typically killed (inactivated) or weakened (attenuated) versions of a live viral strain. Kim et al. report that administration of a formalin-inactivated RSV vaccine was not sufficiently effective and primed for enhanced disease. Am J Epidemiol 89, 422-434 (1969). Attenuated RSV vaccine candidates face significant safety hurdles, and the development of pediatric RSV live-attenuated vaccine (LAV) strains that are sufficiently attenuated and immunogenic have been elusive. See Collins et al. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res, 2011,162, 80-99. Reist et al. report the synthesis of 4-thio-D- and -L-ribofuranose and the corresponding adenine nucleosides. J. Am. Chem. Soc.1964, 86, 24, 5658–5663. Draanen et al. report antiviral activity of 2'-deoxy-4'-thio purine nucleosides. J Med Chem, 1996, 39(2):538-42. Mitra et al. report compounds as inhibitors of M protein and F protein function of human respiratory syncytial virus. In Silico Pharmacol, 2023, 12(1):5. Foolad et al. report the use of oral and aerosolized ribavirin for the treatment of RSV infections in hematopoietic cell transplant recipients. Clinical Infectious Diseases, 2019, 68(10): 1641–1649. Sourimant et al. report orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase. Sci Adv, 2022, 8(25):eabo2236. References cited herein are not an admission of prior art. SUMMARY Disclosed herein are compounds, compositions, and methods for managing viral and other microbial infections. In certain embodiments, this disclosure relates to methods of treating or preventing a viral infection, such as RSV, COVID, or HIV by administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, methods involve administering a therapeutically or prophylactically effective amount of at least one compound described herein to a subject or human patient in need thereof, e.g., an amount sufficient to reduce the biological activity of, Pneumoviridae, Lentiviridae, Coronaviridae, Noroviridae, or other viral infections including, but not limited to RSV, COVID, and HIV. In certain embodiments, the subject does not have but is at risk of developing an RSV infection. In certain embodiments, the subject is a human patient, a pregnant mother, infant, child, adult, or newborn less than 1 years old. In certain embodiments, the disclosure relates to methods of using potent, selective antiviral agents to target Pneumoviridae, Lentiviridae, Coronaviridae, Noroviridae, and other viral infections and thus eliminate and / or treat infection in patients infected by these viruses. In one aspect, the compounds used include one or more of the specific nucleoside inhibitors described herein. In certain embodiments, this disclosure relates to pharmaceutical compositions including one or more of the compounds described herein. In certain embodiments, the pharmaceutical composition comprises a purine analog or pyrimidine analog as reported herein, in combination with a pharmaceutically acceptable carrier or excipient. In certain embodiments, the compositions can be used to treat a human patient infected with a Pneumoviridae, Lentiviridae, Coronaviridae, Noroviridae, or other viral infections, to prevent one of these infections, and / or to reduce the biological activity of one of these viruses. In certain embodiments, the compositions can include a combination of one or more of the compounds described herein, optionally with other antiviral compounds or biological agents, including anti-viral agents and biological agents. In certain embodiments, this disclosure relates to processes for preparing the specific nucleoside compounds described herein which entail contacting a starting material with a reagent under conditions providing synthetic product as reported herein. In certain embodiments, it is contemplated that the compounds described herein are deuterated, i.e., one or more of the hydrogens are substituted with deuterium. Where the compounds are nucleosides, deuterium can be present in one or more positions on the sugar moiety of the compounds, the base portion of the compounds, and / or at any position. In some embodiments, ester prodrugs were prepared and were tested to determine whether improved distribution would be obtained when given orally, e.g., providing improved plasma and whole blood distribution. It is contemplated that triphosphate derivatives may be trapped in the gut. Thus, ester prodrugs were prepared to improve the oral bioavailability. In some embodiments, ester prodrugs were prepared to allow more drug, when given orally, to reach the plasma and not be trapped in the gut as a triphosphate, i.e., ester prodrugs were prepared to improve the oral bioavailability of drugs. The present disclosure will be better understood with reference to the following Detailed Description. DETAILED DESCRIPTION Described herein are compounds with inhibitory activity against viruses in cell-based assays. In certain embodiments, this disclosure contemplates use the compounds to treat or prevent a Pneumoviridae, Lentiviridae, Coronaviridae, Noroviridae, or other viral infection in a subject, or reduce the biological activity of the virus. The subject can be a mammal, and in particular, a human, infected with a virus or other microbe. In certain embodiments, this disclosure relates to pharmaceutical formulations including one or more compounds described herein, in combination with a pharmaceutically acceptable carrier or excipient. In one embodiment, the formulations include at least one compound described herein and at least one further therapeutic agent. The present disclosure will be better understood with reference to the following definitions: Definitions As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration / oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing a oxygen atom with a sulfur atom, replacing an amino group with a hydroxyl group, replacing a nitrogen with a protonated carbon (CH) in an aromatic ring, replacing a bridging amino group (-NH-) with an oxy group (-O-), replacing a bridging amino group (-NH-) with an thio group (-S-), or vice versa. In certain embodiments, a derivative is an alkyl group substituted with a carbocyclyl, e.g., a propyl or butyl group substituted with corresponding a cyclopropyl or cyclobutyl group. The derivative may be a prodrug. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry textbooks, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference. In certain embodiments, a derivative is a compound disclosed herein substituted with a substituent. The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, thio, amine, alkyl, alkoxy, alkylamine, dialkyl amine, alkylthio, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -Narks(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, -NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. The term, "subject" refers to any animal, preferably a human patient, livestock, horse, cow, pig, chicken, turkey, mouse, rodent, monkey, dog, cat, or other domestic pet. In certain embodiments, the subject is a human patient, a pregnant mother, infant, child, adult, or newborn less than 1 years old. Veterinary applications are contemplated by the present disclosure (such as for use in treating chimpanzees). As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced. As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and / or delays disease progression. The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. As used herein, the term "combination with" when used to describe administration of an agent with an additional treatment means such that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof, such that multiple agents are bioavailable at some overlapping time. The term "nucleoside" refers to a non-aromatic five membered ring substituted, e.g., tetrahydrothiophen-2-yl or tetrahydrofuran-2-yl substituted in the 5 position, with a nucleobase or heterocyclic derivative thereof. The five membered ring and / or nucleobase may be further substituted or derivatized. Examples of nucleosides with modified adenosine or guanosine include, but are not limited to, hypoxanthine, xanthine, and 7-methylguanine. Examples of nucleosides with modified cytidine, thymidine, or uridine include 5,6-dihydrouracil, 5- methylcytosine, and 5-hydroxymethylcytosine. The term nucleoside also includes ribonucleosides, and representative ribonucleosides are disclosed, for example, in the Journal of Medicinal Chemistry, 43(23), 4516-4525 (2000), Antimicrobial Agents and Chemotherapy, 45(5), 1539-1546 (2001), and PCT WO 2000 / 069876. The terms "nucleobase" or “base” refer to any variety of nitrogen containing monocyclic or bicyclic heterocycles. Nucleobases typically have at least one optionally substituted amino group connected to the ring(s), or a carbonyl / hydroxyl group within the ring(s), or an optionally substituted amide connected to the ring(s). Typically having two to four nitrogen atoms in the ring(s). Examples of a nucleobase include adenine, guanine, cytosine, uracil, thymine, inosine, and heterocycles of the following structures: , , , es. Contemplated isobases include 2'-deoxy-5-methylisocytidine (iC) and 2'-deoxy-isoguanosine (iG). Examples of nucleobases include pyrimidine bases and derivatives thereof include cytosine, uracil, 5-fluorocytosine, 5-fluorouracil, 5-chlorocytosine, 5-chlorouracil, 5- bromocytosine, 5-bromouracil, 5-iodocytosine, 5-iodouracil, 5-methylcytosine, 5- ethylcytosine, 5-methyluracil (thymine), 5-ethyluracil, 5-fluoromethylcytosine, 5-fluorouracil, 5-trifluorocytosine, 5-trifluorouracil, 5-vinyluracil, 5-bromovinyluracil, 5-chlorovinyluracil, 5- ethynylcytosine, 5-ethynyluracil, 5-propynyluracil, pyrimidin-2-one, 4- hydroxyaminopyrimidin-2-one, 4-aminoxypyrimidin-2-one, 4-methoxypyrimidin-2-one, 4- acetoxypyrimidin-2-one, 4-fluoropyrimidin-2-one, and 5-fluoropyrimidin-2-one. Examples of nucleobases include purine bases and derivatives thereof include purine, 6-aminopurine (adenine), 6-hydroxypurine, 6-fluoropurine, 6-chloropurine, 6- methylaminopurine, 6-dimethylaminopurine, 6-trifluoromethylaminopurine, 6- benzoylaminopurine, 6-acethylaminopurine, 6-hydroxyaminopurine, 6-aminoxypurine, 6- methoxypurine, 6-acetoxypurine, 6-benzoyloxypurine, 6-methylpurine, 6-ethylpurine, 6- trifluoromethylpurine, 6-phenylpurine, 6-mercaputopurine, 6-methylmercaputopurine, 6- aminopurine-1-oxide, 6-hydroxypurine-l-oxide, 2-amino-6-hydroxypurine (guanine), 2,6- diaminopurine, 2-amino-6-chloropurine, 2-amino-6-iodepurine, 2-aminopurine, 2-amino-6- mercaptopurine, 2-amino-6-methylmercaptopurine , 2-amino-6-hydroxyaminopurine, 2- amino-6-methoxypurine, 2-amino-6-benzoyloxypurine, 2-amino-6-acetoxypurine, 2-amino-6- methylpurine, 2-amino-6-cyclopropylaminomethylpurine, 2-amino-6-phenylpurine, 2-amino- 8-bromopurine, 6-cyanopurine, 6-amino-2-chloropurine (2-chloroadenine) , 6-amino-2- fluoropurine (2-fluoroadenine), 6-amino-3-deazapurine, 6-amino-8-azapurine, 2-amino-6- hydroxy-8-azapurine, 6-amino-7-deazapurine, 6-amino-l-deazapurine, and 6-amino-2- azapurine. The term “independently” is used herein to indicate that the variable, which is independently applied, varies independently from application to application. Thus, in a compound such as R”XYR,” wherein R” is “independently carbon or nitrogen,” both R” can be carbon, both R” can be nitrogen, or one R” can be carbon and the other R” nitrogen. As used herein, the term “enantiomerically pure” refers to a compound composition that comprises at least approximately 95%, and, preferably, approximately 97%, 98%, 99% or 100% of a single enantiomer of that compound. As used herein, the terms “substantially free of” or “substantially in the absence of” refer to a compound composition that includes at least 85 to 90% by weight, preferably 95% to 98 % by weight, and, even more preferably, 99% to 100% by weight, of the designated compound from other chemical impurities, enantiomers, or diastereomers. In a preferred embodiment, the compounds described herein are substantially free of enantiomers or diastereomers. In as such, the compounds can be designated as having greater than 80%, 85%, 90%, 95%, 97, 98, or 99% enantiomeric excess or diastereomeric excess. Similarly, the term “isolated” refers to a compound composition that includes at least 50% by weight, preferably 85% to 90% or 95% to 98% by weight, and, even more preferably, 99% to 100% by weight, of the compound, the remainder comprising other chemical species, enantiomers or diastereomers. The term “fatty alcohol” as used herein refers to straight-chain primary alcohols with between 4 and 26 carbons in the chain, preferably between 8 and 26 carbons in the chain, and most preferably, between 10 and 22 carbons in the chain. The precise chain length varies with the source. Representative fatty alcohols include lauryl, stearyl, and oleyl alcohols. Fatty alcohols usually have an even number of carbon atoms and a single alcohol group (-OH) attached to the terminal carbon. Some are unsaturated and some are branched. Fatty alcohols are often referred to generically by the number of carbon atoms in the molecule, such as "a C12 alcohol", that is an alcohol having 12 carbons, for example dodecanol. The term “protected” or “protecting group” as used herein and unless otherwise defined refer to a chemical group that is added to an oxygen, nitrogen, sulfur, or phosphorus atom to prevent its further reaction or for other purposes, i.e., chemical moieties that are introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis, and are described, for example, in Greene et al., Protective Groups in Organic Synthesis, supra. Examples include, but are not limited to, alkyl, alkoxy, polyalkoxy groups, acyl groups, acetyl, propionyl, mesyl (methanesulfonyl), heterocycles such as succinimide, maleimide, and phthalimide that are optionally substituted, 4-methoxy-2,3,6-trimethylphenyl)sulfonyl (Mtr), 2,2,5,7,8- pentamethyl-chroman-6-sulphonyl (Pmc), tosyl (Tos), mesitylenesulfonyl (Mts), 4,4'- dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), tripheylmethyl (Trt), 9- fluorenylmethyloxycarbonyl (fmoc), tert-butyl (tBu), benzyl (Bzl), t-butoxymethyl ether (Bum), (2,4-dinitrophenol) Dnp, benzyloxymethyl (Bom), benzyloxycarbonyl (Z), 2-chloro- benzyloxycarbonyl (CIZ), t-butyloxycarbonyl (Boc), formyl (CHO), 2- bromobenzyloxycarbonyl (BrZ), trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, trityl, and substituted trityl. The protecting group can be substituted with any moiety that does not adversely affect the reaction, including but not limited, those described for alkyl and aryl. The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight, branched, primary, secondary, or tertiary hydrocarbons. It is contemplated that an alkyl can be optionally substituted with a carbocyclyl such as cyclopropyl, cyclopentyl, or cyclohexyl or other substituent as reported herein. The alkyl group can be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3and CH2CF3. In the text, whenever the term “C” (alkyl range) is used, the term independently includes each member of that class as if specifically and separately set out. The term “alkyl” includes C1-22alkyl moieties, and the term “lower alkyl” includes C1-6alkyl moieties. It is understood to those of ordinary skill in the art that the relevant alkyl radical is named by replacing the suffix “-ane” with the suffix “-yl.” The term “alkenyl” refers to an unsaturated, hydrocarbon radical, linear, or branched, in so much as it contains one or more double bonds. The alkenyl group disclosed herein can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to those described for substituents on alkyl moieties. Non-limiting examples of alkenyl groups include ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl. The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds. The alkynyl group can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to those described above for alkyl moieties. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2- yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2- yl, and hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals. The term “aryl” refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused. Aryl includes polycyclic ring systems containing aromatic and non-aromatic rings, as long as one of the rings is aromatic. Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl. The aryl group can be optionally substituted with substituents as described above for alkyl moieties. Additional examples of aryl substituents include heteroarylamino, N-aryl- N-alkylamino, N-heteroarylamino-N-alkylamino, arylamino, arylalkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, hydroxyarylalkyl, hydoxyheteroarylalkyl, haloalkoxyalkyl, aryl, arylalkyl, aryloxy, arylalkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. The term “alkylaryl” refer to an aryl group (radical) with an alkyl substituent. The term “arylalkyl” refer to an alkyl group (radical) with an aryl substituent. The term “halo,” as used herein, includes chloro, bromo, iodo, and fluoro. The term “acyl” refers to an alkylcarbonyl or arylcarbonyl in which the non-carbonyl moiety of the group is selected from the group consisting of straight, branched, or cyclic alkyl or lower alkyl, arylalkyl, benzyl (benzoyl), aryl (aroyl), wherein the acyl group is optionally substituted with halogen (F, Cl, Br, or I), alkyl (including but not limited to C1, C2, C3, and C4) or alkoxy (including but not limited to C1, C2, C3, and C4), such as alkoxyalkyl, methoxymethyl, aryloxy, such as phenoxymethyl, sulfonate esters such as alkyl or arylalkyl sulphonyl including but not limited to methanesulfonyl, mono, di or triphosphate ester, trityl or monomethoxytrityl, benzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) or diphenylmethylsilyl. The term “lower acyl” refers to an acyl group in which the non-carbonyl moiety is lower alkyl. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals having alkyl moieties, such as methoxy radical. The “alkoxy” radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. The term “alkylamino” denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical. The term “arylalkylamino” refers to arylalkyl radicals attached to an amino radical. The term arylalkylamino denotes “monoarylalkylamino” and “diarylalkylamino” containing one or two arylalkyl radicals, respectively, attached to an amino radical. The term “heteroatom,” as used herein, refers to oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. The term “heterocyclic,” and “heterocyclyl,” refer to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, phosphorus, boron, silicon, or sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like. Further, a second ring may share the same carbon or different carbons to form a spiro ring, condensed ring, or bridged ring. Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" or “cycloalkyl” groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like. "Heterocarbocycles" or heterocarbocyclyl" or “cycloheteroalkyl” groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, boron, and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to an aromatic that includes at least one nitrogen, oxygen, phosphorus, silicon, boron, or sulfur in the aromatic ring. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent. Nonlimiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5- azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alkylpurines, N6-benzylpurine, N6-halopurine, N6- vinypurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, thymine, cytosine, 6- azapyrimidine, 2-mercaptopyrmidine, uracil, N5- alkylpyrimidines, N5-benzylpyrimidines, N5- halopyrimidines, N5-vinylpyrimidine, N5-acetylenic pyrimidine, N5-acyl pyrimidine, N5- hydroxyalkyl purine, and N6-thioalkyl purine, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, and dialkylamino. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired. The term “peptide” refers to a natural or synthetic compound containing two to one thousand amino acids linked by the carboxyl group of one amino acid to the amino group of another. The term “pharmaceutically acceptable salt or prodrug” is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester) compound which, upon administration to a patient, natural metabolic processes of the subject provide the compound in vivo. Pharmaceutically-acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the subject to form the compound described herein. Typical examples of prodrugs include compounds that have biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. The prodrug forms of the compounds described herein can possess antiviral activity, can be metabolized to form a compound that exhibits such activity, or both. Stereoisomerism and Polymorphism The compounds described herein can have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present disclosure. Compounds described herein having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can exhibit polymorphism. The present disclosure encompasses racemic, optically-active, polymorphic, stereoisomeric, diastereomeric forms, or mixtures of a compound described herein, which possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution. One can either purify the respective compound, then derivatize the compound to form the compounds described herein, or purify the compound themselves. Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. Examples of methods to obtain optically active materials include at least the following. i)physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii)simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii)enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv)enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v)chemical asymmetric synthesis: a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi)diastereomer separations: a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii)first- and second-order asymmetric transformations: a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii)kinetic resolutions: this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix)enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x)chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC). The stationary phase can be made of chiral material, or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi)chiral gas chromatography: a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii)extraction with chiral solvents: a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii)transport across chiral membranes: a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including but not limited to simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available. Salt or Prodrug Formulations In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α- ketoglutarate and α-glycerophosphate. Suitable inorganic salts can also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts. For certain transdermal applications, it can be preferred to use fatty acid salts of the compounds described herein. The fatty acid salts can help penetrate the stratum corneum. Examples of suitable salts include salts of the compounds with stearic acid, oleic acid, lineoleic acid, palmitic acid, caprylic acid, and capric acid. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. In those cases where a compound includes multiple amine groups, the salts can be formed with any number of the amine groups. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made. A prodrug is a pharmacological substance that is administered in an inactive (or significantly less active) form and subsequently metabolized in vivo to an active metabolite. Getting more drug to the desired target at a lower dose is often the rationale behind the use of a prodrug and is generally attributed to better absorption, distribution, metabolism, and / or excretion (ADME) properties. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor. Additionally, the use of a prodrug strategy can increase the selectivity of the drug for its intended target thus reducing the potential for off target effects. Compounds, Compositions, and Methods of Treatment In certain embodiments, this disclosure relates to methods of treating or preventing a viral or other microbial infection comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, this disclosure relates to compounds, compositions and methods of treating or preventing a Pneumoviridae infection, Lentiviridae infection, Coronaviridae infection, Noroviridae viral infection or other viral or microbial infection as reported herein comprising administering a treatment or preventative amount of a compound of Formula (A) to a subject in need thereof: or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is H, deuterium, CN; R2is H, deuterium, F; R2’ is OH, F, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, anN,N-disubstituted D-amino acid , an optionally substituted-O-C(O)-R’, an optionally substituted -O-C(O)SR', an optionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’, provided that when R2 is F, R2’ is not OH, R’ is PEG (polyethylene glycol), aryl, heteroaryl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, or C3-7cycloalkyl, wherein optional substituents are selected from the group consisting of halo, C 1 - 12haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido, carboxyl derivatives, alkylamino, di-C 1 -12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine,sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R11 and R11’ are, independently, H, deuterium, C1-20 alkyl, C1-20 alkene, C1-20 alkyne,the carbon chain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein thesubstituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl;or R 11 and R11’ are independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl,-CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R11’and the NR12form a 2- pyrrolidinyl ring, wherein R11or R12’and the 2-pyrrolidinyl ring are optionally substituted withone or more, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy,amino, amido, carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R12 and R12’ are, independently, H, C1-20 alkyl, C1-20 alkene, C1-20 alkyne;R3is H; R3’ is OH, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N- disubstituted D-amino acid este , an optionally substituted -O-C(O)-R’, an optionally substituted -O-C(O) ally substituted -O-C(O)SR', an optionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’, R4 is H, deuterium, F, C1-5alkyl, C1-5alkene, C1-5alkyne, N3, CH2-halogen;R5is and R5’are, independently, H, deuterium, CH3, CH2F, CHF2, or CF3, wherein,when R5is Me, the carbon to which it is attached may be wholly or partially R or S or anymixture thereof, or R5and R5’can combine to form a C3-7cycloalkyl ring; R6is H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acidester, an N-substituted D-amino acid , an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino ester, (acyloxybenzyl)ether, optionally substituted bis-acyloxybenzyl)ester, optionally substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)SR', an optionally substituted -C(S)SR’, PEG ester, PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a lipid ester, a lipid carbonate (in which a lipid is an optionally substituted C12- 22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22alkoxy), O-P(O)R8R8’, or a mono-, di-, or triphosphate, wherein, when chirality exists at the phosphorous center, it may be wholly or partially Rpor Spor any mixture thereof, R8and R8’are independently selected from the group consisting of:(a) OR15where R15selected from the group consisting of H ,, Li, Na, K, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted optionally substituted -C(NR’)OR’, optionally substituted -C(NR’)SR’, optionally substituted -C(NR’)N(R’)2, optionally substituted -C(O)N(R’)2, C1-4(alkyl)aryl, benzyl, C1-6 haloalkyl, C2-3(alkyl)OC1-20alkyl, C2-3(alkyl)OC2-20alkene, C2-3(alkyl)OC2-20alkyne, CH2-O-C(O)C1-20alkyl, CH2-O-C(O)C2-20alkene, CH2-O-C(O)C2-20alkyne, CH2-O- C(O)-O-C1-20alkyl, CH2-O-C(O)-O-C2-20alkene, CH2-O-C(O)-O-C2-20alkyne, aryl, andheteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionally substitutedwith zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16and (CH2)0-6 CON(R16)2;where R16is independently H, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, the carbon chain derived from a fatty alcohol or C1-20alkyl substituted with a C1-6alkyl, C1-6alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, C1-5alkene,C1-5alkyne, C3-7cycloalkyl or C1-5alkyl substituted with a C1-6 alkyl, alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; andR17 R17A (b) the ester of a D- or L-amino , wherein R17Ais H or C1-2alkyl; R17 and R18 are, independently, H, 20alkene, C1-20alkyne, the carbonchain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; or R17is selected from H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; Base is selected from the group consisting of: X1and X1’are independently CH, C- deuterium, C-(C1-6)alkyl, C-(C2-6)alkenyl, C-(C2- 6)alkynyl, C-(C3-7)cycloalkyl, C-(C1-6) haloalkyl, C-(C1-6)hydroxyalkyl, C-OR9’, C- NR10R10’, C-halo, C-CN, -C-C(O)-NR10R10’or N, X2and X2’are independently H, deuterium, halo, -(C1-3)alkyl, -(C1-3)fluoroalkyl, OR9’or NR10R10’; R9’is H, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3-7)cycloalkyl, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, an (acyloxybenzyl)ester, an (acyloxybenzyl)ether, an optionally substituted bis- acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12-alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a PEG ester, a PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O- C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid ester, or a lipid carbonate; wherein a lipid is an optionally substituted C12-22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22 alkoxy), R10and R10’are independently H, OH, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3-7)cycloalkyl, an L-amino acid amide, a D-amino acid amide, (acyloxybenzyl)amide, (acyloxybenzyl)amine, optionally substituted (acyloxybenzyl)esters, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12alkyl, an optionally substituted C2-12 alkenyl, an optionally substituted C2-12 alkynyl, an optionally substituted C3-6 cycloalkyl, PEG amide, PEG carbamate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid amide, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, or a lipid carbamate, wherein a lipid is an optionally substituted C12-22alkyl, an optionally substituted C12-22alkenyl, an optionally substituted C12-22alkynyl or an optionally substituted C12-22alkoxy), with the proviso that R10and R10’cannot both be OH. In certain embodiments, this disclosure relates to compounds, compositions and methods of treating or preventing a Pneumoviridae infection, Lentiviridae infection, Coronaviridae infection, Noroviridae infection, or other viral or microbial infection as reported herein comprising administering a treatment or preventative amount of a compound of Formula (B) to a subject in need of treatment or prevention thereof:

[0002] or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3, R4, R5and R5’are as defined in Formula A, A is O or S, and D is selected from the group consisting of: (a) OR15where R15is selected from the group consisting of H, substituted orunsubstituted CH2-O-C(O)C1-20alkyl, substituted or unsubstituted CH2-O-C(O)C2-20alkene, substituted or unsubstituted CH2-O-C(O)C2-20alkyne, substituted or unsubstituted CH2-O-C(O)- O-C1-20alkyl, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkene, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkyne, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, substituted or unsubstituted C3-6cycloalkyl, C1-4(alkyl)aryl, benzyl, C1-6 haloalkyl, C2-3(alkyl)OC1-20alkyl,aryl, and heteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionallysubstituted with zero to three substituents independently selected from the group consisting of(CH2)0-6CO2R16and (CH2)0-6 CON(R16)2;R17 R17A O N (b) the ester of a D- or L-amino acid H OR18, wherien R17Ais H or C1-2alkyl; R17 and R18 are independently H, C1-20 alkyl, the carbon chain from a natural aminoacid or an unnatural amino acid, the carbon chain derived from a fatty alcohol or C1-20 alkyloptionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; or R 17 is independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl,-CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid, or boronic ester; and where R30is selected from the group consisting of substituted or unsubstituted C3-6 cycloalkyl, substituted or or unsubstituted (C2-10)alkyne, C1-4(alkyl)aryl, aryl, heteroaryl, and C1-6 haloalkyl. In certain embodiments, this disclosure relates to compounds, compositions and methods of treating or preventing a Pneumoviridae infection, Lentiviridae infection, Coronaviridae infection, Noroviridae infection or other viral or microbial infection as reported herein comprising administering a treatment or preventative amount of a compound of Formula (C) to a subject in need of treatment or prevention thereof: or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3and R3’are as defined in Formula A, R4’ is selected from the group consisting of H , deuterium, CN, substituted orunsubstituted (C1-8)alkyl, substituted or unsubstituted (C2-8)alkenyl, substituted or unsubstituted (C2-8)alkynyl, substituted or unsubstituted (C1-8) haloalkyl; R6’ is selected from the group consisting of - P(O)R8R8’, or a mono-, di-, ortriphosphate, wherein, when chirality exists at the phosphorous center, it may be wholly orpartially Rpor Spor any mixture thereof andR8and R8’are as defined in Formula A. In certain embodiments, the compound has the following formula D: Formula D ester, salt, prodrug or deuterated form thereof; wherein the base is a nitrogen containing heterocyclyl optionally substituted with one or more, the same or different, R21; wherein R1is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R2’is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R3’is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R6is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; or R6and R3’and the attached atoms form a heterocyclic ring optionally substituted with one or more, the same or different, R21; R21is C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R21is optionally substituted with one or more, the same or different, R22; and R22is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert- butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, the compound has the following formula D or E: ester, salt, prodrug or deuterated form thereof; wherein R1is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R2’is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R3’is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R6is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; or R6and R3’and the attached atoms form a heterocyclic ring optionally substituted with one or more, the same or different, R21; R21is C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R21is optionally substituted with one or more, the same or different, R22; and R22is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert- butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, the compound has the following formula F or G: ester, salt, prodrug or deuterated form thereof; wherein R2’is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R3’is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R6is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; or R6and R3’and the attached atoms form a heterocyclic ring optionally substituted with one or more, the same or different, R21; R21is C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R21is optionally substituted with one or more, the same or different, R22; and R22is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert- butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, the compound has the following formula H or I: ester, salt, prodrug or deuterated form thereof; wherein R3’is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; wherein R6is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; or R6and R3’and the attached atoms form a heterocyclic ring optionally substituted with one or more, the same or different, R21; R21is C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R21is optionally substituted with one or more, the same or different, R22; and R22is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert- butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, the compound has the following formula J, K, or L: ester, or wherein R6is selected from hydrogen, C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein each R6is optionally substituted with one or more, the same or different, R21; R21is C1-10alkyl, C2-10alkenyl or C2-10alkynyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, phosphate, phosphonate, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl, wherein R21is optionally substituted with one or more, the same or different, R22; and R22is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert- butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, phosphate, phosphonate, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, this disclosure relates to compounds, compositions and methods of treating or preventing a Pneumoviridae infection, lentiviral infection, coronaviral infection, noroviral viral infection or other viral or microbial infection as reported herein comprising administering a treatment or preventative amount of one of the following optionally substituted compounds or derivatives thereof. In certain embodiments, the compound is 9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrothiophene- 3,4-diol, a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is - 9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl)methyl isobutyrate, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , purin-9-yl)-5-((isobutyryloxy)methyl)tetrahydrothiophene- 3,4-diyl bis(2-methylpropanoate), or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , -5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrothiophen-2-yl) methoxy)(phenoxy)phosphoryl)-L-alaninate or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , (2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , purin-9-yl)-7-hydroxy-2-isopropoxytetrahydro-4H- thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxide or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , 9H-purin-9-yl)-7-hydroxy-2-oxidotetrahydro- 4H-thieno[3,2-d][1,3,2]dioxaphosphinin-2-yl)alaninate or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is yl)-2-(2-(tert-butyldisulfaneyl)phenethoxy)- 7-hydroxytetrahydro-4H-thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxide or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , [2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrothiophene-2-carbonitrile, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl isobutyrate or a pharmaceutically acceptable salt or prodrug, derivative, thereof. In certain embodiments, the compound is , [2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((isobutyryloxy)methyl)tetrahydrothiophene-3,4-diyl bis(2-methylpropanoate), or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl L-valinate, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , [2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , [2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , -3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(fluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-methylpyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compound is , dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide or a pharmaceutically acceptable salt, derivative, or prodrug thereof. In certain embodiments, the compounds can be present in the β-D or β-L configuration. In certain embodiments, the compound is co-administered with one or more additional active compounds. In certain embodiments, methods involve administering a therapeutically or prophylactically-effective amount of at least one compound as described herein to treat, cure or prevent an infection by, or an amount sufficient to reduce the biological activity of, a viral or microbial infection. Subjects, including but not limited to humans infected with a virus or other microbe or a gene fragment thereof, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, transdermally, subcutaneously, or topically, in liquid or solid form. In certain embodiments, a subject is human patient infected with a virus or other microbe or a gene fragment thereof, that can be treated by administering to the patient an effective amount of an active compound as disclosed herein or prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, transdermally, subcutaneously, or topically, in liquid or solid form. In certain embodiments, the subject is pregnant woman, a premature baby, newborn, infant, child, adult, elderly, or immune compromised. In certain embodiments, the subject is a human subject is 2, 12, or 16 years old or older. In certain embodiments, the subject is a human subject 2, 12, or 15 years old or less than 2, 12, or 16 years old. In certain embodiments, the subject is a human subject 55 or 65 years old or older. In certain embodiments, the subject is an infant, e.g., from one month to two years of age. In certain embodiments, the subject is a child, e.g., from one two to twelve years of age. In certain embodiments, the subject is an adolescent, e.g., from twelve to sixteen years of age. In certain embodiments, the subject is a human subject sixteen years of age or older. In certain embodiments, the subject is immune compromised due to the need to maintain an immune suppressive drug(s) therapy, e.g., the subject is or diagnoses with DiGeorge syndrome, Wiskott-Aldrich syndrome, Bruton’s agammaglobulinemia, the subject is receiving (being administered) chemotherapy or radiation due to being diagnosed with cancer, the subject is receiving corticosteroids due to a diagnosis of rheumatoid arthritis, lupus, vasculitis, or the subject is a solid organ recipient to prevent rejection of the transplanted organ. Combination or Alternation Therapy In one embodiment, the compounds described herein can be employed together with at least one other active agent, which can be an antiviral, antibiotic, and / or anti-inflammatory agent. Contemplated antiviral agents include derivatives of naturally occurring nucleotides. Examples of antiviral agents include abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, atazanavir, atripla, baloxavir marboxil, bictegravir, boceprevir, bulevirtide, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, doravirine, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfinavir, nevirapine, nexavir, nitazoxanide, norvir, oseltamivir, penciclovir, peramivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, remdesivir, ribavirin, rilpivirine, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, taribavirin, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir disoproxil fumarate, tipranavir, trifluridine, trizivir, tromantadine, truvada, umifenovir, vidarabine, valaciclovir, valganciclovir, vicriviroc, vidarabine, zalcitabine, zanamivir, zidovudine, or combinations thereof. In certain embodiments, if the subject to be treated is diagnosed with or at risk of an RSV infection the other active agent can be palivizumab, palivizumab, nirsevimab and / or aerosolized or non-aerosolized ribavirin or can be administered in combination with an RSV vaccine. In certain embodiments, if the subject to be treated is diagnosed with or at risk of an HIV infection the other active agent can be administered in combination with a multi-drug anti- retroviral therapy (ART). In certain embodiments, the multi-drug anti-retroviral therapy comprises a nucleoside reverse transcriptase inhibitor (NRTI), abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, zidovudine, and / or a non-nucleoside reverse transcriptase inhibitor (NNRTI), doravirine, efavirenz, etravirine, nevirapine, rilpivirine, protease inhibitor (PI), atazanavir, darunavir, fosamprenavir, ritonavir, tipranavir, fusion inhibitor, enfuvirtide, CCR5 antagonist, maraviroc, capsid Inhibitor, lenacapavir, attachment inhibitor, fostemsavir, post-attachment inhibitor, ibalizumab-uiyk, and / or an integrase strand transfer inhibitor (INSTI), cabotegravir, dolutegravir, raltegravir, or combinations thereof. In certain embodiments, if the subject to be treated is diagnosed with or at risk of an HIV infection, the other active agent can be administered in combination with a multi-drug anti- retroviral therapy (ART) wherein the combination is abacavir and lamivudine; or abacavir, dolutegravir, and lamivudine; or abacavir, lamivudine, and zidovudine; or atazanavir and cobicistat; or bictegravir, emtricitabine, and tenofovir alafenamide; or cabotegravir and rilpivirine; or darunavir and cobicistat; or darunavir, cobicistat, emtricitabine, and tenofovir alafenamide; or dolutegravir and lamivudine; or dolutegravir and rilpivirine; or doravirine, lamivudine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, lamivudine, and tenofovir disoproxil fumarate; or elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide; or elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; or emtricitabine, rilpivirine, and tenofovir alafenamide; or emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or emtricitabine and tenofovir alafenamide; or emtricitabine and tenofovir disoproxil fumarate; or lamivudine and tenofovir disoproxil fumarate; or lamivudine and zidovudine; or lopinavir and ritonavir. In certain embodiments, methods include treating or preventing a coronaviral infection such as severe acute respiratory syndrome associated coronavirus (SARS-CoV-1) and SARS- CoV-2 (also referred to as COVID-19), MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, or HCoV-HKU1, an endemic human coronavirus, epidemic coronavirus, or pandemic coronavirus. In certain embodiments, the subject is more than 55, 65, or 75 years old or diagnosed with a severe acute infection requiring intensive care. In certain embodiments, the compound is co-administered with one or more additional active compounds such as remdesivir, chloroquine, hydroxychloroquine, azithromycin, ivermectin, lopinavir, ritonavir, nitazoxanide, molnupiravir, nirmatrelvir and ritonavir, or combinations thereof. In certain embodiments, compounds disclosed used in methods disclosed herein and administered to a subject at risk of developing pneumonia (a bacterial infection) and / or sepsis. Thus, compounds disclosed herein may be administered in combination with antibiotic agent and / or anti-inflammatory agent. An “antibiotic” refers to molecules that are recognized to aid in the treatment of a bacteria. Examples include agents such as sulfanilamide, sulfamethizole, sulfamethoxazole, sulfapyridine, trimethoprim, pyrimethamine, nalidixic acids, norfloxacin, ciprofloxacin, cinoxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, penicillins (amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, hetacillin, oxacillin, mezlocillin, penicillin G, penicillin V, piperacillin), cephalosporins (cefacetrile, cefadroxil, cefalexin, cefalonium, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefonicid, ceforanide, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefoxitin, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefotiam, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefepime), carbapenems (imipenem, ertapenem, meropenem) monobactams (aztreonam) oxytetracycline, chlortetracycline, clomocycline, demeclocycline, tetracycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, chloramphenicol, amikacin, gentamicin, framycetin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, telithromycin, colistin, bacitracin, tyrothricin, furazolidone, metronidazole, tinidazole, isoniazid, pyrazinamide, ethionamide, nystatin, amphotericin-B, hamycin, miconazole, clotrimazole, ketoconazole, fluconazole, lincomycin, clindamycin, spectinomycin, fosfomycin, loracarbef, polymyxin B, polymyxin B Sulfate, ramoplanin, teicoplanin, vancomycin, nitrofurantoin or combinations thereof. An “anti-inflammatory” refers to molecules that are recognized to aid in the reduction in immune responses. Examples include agents such as aceclofenac, acemetacin, acetyl- salicylic acid, 5-aminoacetyl salicylic acid, alclofenac, amfenac, bendazac, benoxaprofen, bermoprofen, 5-bromo salicylic acid acetate, butibufen, caffeic acid, carprofen, cinmetacin, clidanac, clopirac, sodium diclofenac, diflunisal, 3,4-dihydroxybenzoic acid, etodolac, felbinac, fenbufen, fendosal, fenoprofen, fentiazac, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, 1-hydroxynaphthoic acid, ibuprofen, indomethacin, indoprofen, isoxepac, ketoprofen, ketorolac, loxoprofen, meclofenamic acid, mefenamic acid, 3,4- methylenedioxycinnamic acid, montelukast, mycophenolic acid, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, pirprofen, pranoprofen, sulindac, suprofen, tiaprofenic acid, tinoridine acid, tolfenamic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen, zomepirac, or combinations thereof. Pharmaceutical Compositions In certain embodiments, this disclosure relates to pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient. Subjects, including but not limited to humans, infected with a Pneumoviridae virus, or the other viruses or microbes described, herein can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. While it is possible that, for use in therapy, a therapeutically effective amount of a compound disclosed herein may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation. Accordingly, the disclosure further provides a pharmaceutical composition comprising a compound disclosed herein. Pharmaceutical compositions typically comprise an effective amount of a compound(s) and a suitable pharmaceutical acceptable carrier. The preparations can be prepared in a manner known per se, which usually involves mixing the compounds according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pill, tablet, or capsule or the composition is an aqueous buffer, e.g., a pH between 6 and 8. In certain embodiments, the pharmaceutically acceptable excipient is selected from a filler, glidant, binder, disintegrant, lubricant, and saccharide. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier(s), diluent(s) and / or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the disclosure there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound disclosed herein with one or more pharmaceutically acceptable carriers, diluents and / or excipients. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). In certain embodiments, the pharmaceutical composition is in the form of in the form of a pill, capsule, tablet, particles, powder, lotion, or gel. In certain embodiments, the pharmaceutical composition is in the form of a neutral pH buffered solution optionally comprising isotonic saline or a pharmaceutically acceptable mono or polysaccharide. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient for uses reported herein. In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, particles, powder, lotion, or gel. In certain embodiments, the pharmaceutical composition is in the form of a neutral pH buffered solution optionally comprising isotonic saline or a pharmaceutically acceptable monosaccharide or polysaccharide. In certain embodiments, the excipient is a sterilized aqueous solution. In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof. In certain embodiments, a preferred dose of the compound will be in the range of between about 0.01 and about 10 mg / kg, more generally, between about 0.1 and 5 mg / kg, and, preferably, between about 0.5 and about 2 mg / kg of body weight of the recipient per day, until the patient has recovered. In some cases, a compound may be administered at a dosage of up to 10 μM, which might be considered a relatively high dose if administered for an extended period of time, but which can be acceptable when administered for the duration of an infection with one or more of the viruses described herein, which is typically on the order of several days to several weeks. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art. The compound is conveniently administered in unit any suitable dosage form, including but not limited to one containing 7 to 600 mg, preferably 70 to 600 mg of active ingredient per unit dosage form. An oral dosage of 5-400 mg is usually convenient. The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once or can be divided into a number of smaller doses to be administered at varying intervals of time. A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup can contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti- inflammatory agents or other antiviral compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). In some embodiments, the compositions are present in the form of transdermal formulations. The transdermal formulations can be single-phase matrices that include a backing layer, an active substance-containing self-adhesive matrix, and a protective film to be removed prior to use. More complicated embodiments contain multiple-layer matrices that may also contain non-adhesive layers and control membranes. If a polyacrylate adhesive is used, it can be crosslinked with multivalent metal ions such as zinc, calcium, aluminum, or titanium ions, such as aluminum acetylacetonate and titanium acetylacetonate. When silicone adhesives are used, they are typically polydimethylsiloxanes. However, other organic residues such as, for example, ethyl groups or phenyl groups may in principle be present instead of the methyl groups. Representative acrylate-based polymer adhesives include acrylic acid, acrylamide, hexylacrylate, 2-ethylhexylacrylate, hydroxyethylacrylate, octylacrylate, butylacrylate, methylacrylate, glycidylacrylate, methacrylic acid, methacrylamide, hexylmethacrylate, 2- ethylhexylmethacrylate, octylmethacrylate, methylmethacrylate, glycidylmethacrylate, vinylacetate, vinylpyrrolidone, and combinations thereof. The adhesive must have a suitable dissolving capacity for the active substance, and the active substance most be able to move within the matrix and be able to cross through the contact surface to the skin. Those of skill in the art can readily formulate a transdermal formulation with appropriate transdermal transport of the active substance. Certain pharmaceutically acceptable salts tend to be more preferred for use in transdermal formulations because they can help the active substance pass the barrier of the stratum corneum. Examples include fatty acid salts, such as stearic acid and oleic acid salts. Oleate and stearate salts are relatively lipophilic and can even act as a permeation enhancer in the skin. Permeation enhancers can also be used. Representative permeation enhancers include fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol or its fatty acid esters, N-methylpyrrolidone, terpenes such as limonene, alpha-pinene, alpha- terpineol, carvone, carveol, limonene oxide, pinene oxide, and 1,8-eucalyptol. The patches can generally be prepared by dissolving or suspending the active agent in ethanol or in another suitable organic solvent, then adding the adhesive solution with stirring. Additional auxiliary substances can be added either to the adhesive solution, the active substance solution or to the active substance-containing adhesive solution. The solution can then be coated onto a suitable sheet, the solvents removed, a backing layer laminated onto the matrix layer, and patches punched out of the total laminate. The compounds described herein can also be administered in the form of micron sized particles or nanoparticulate compositions. In one embodiment, controlled release nanoparticulate formulations comprise a nanoparticulate active agent to be administered and a rate-controlling polymer which prolongs the release of the agent following administration. In this embodiment, the compositions can release the active agent, following administration, for a time period ranging from about 2 to about 24 hours or up to 30 days or longer. Representative controlled release formulations including a nanoparticulate form of the active agent are described, for example, in U.S. Patent No.8,293,277. Nanoparticulate compositions can comprise particles of the active agents described herein, having a non-crosslinked surface stabilizer adsorbed onto, or associated with, their surface. The average diameter of nanoparticles is typically less than about 800 nm, more typically less than about 600 nm, still more typically less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm. In one aspect of this embodiment, at least 50% of the particles of active agent have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques. A variety of surface stabilizers can be used to prevent the particles from clumping or aggregating. Representative surface stabilizers are selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p- isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide, n-decyl -D-glucopyranoside, n-decyl-D-maltopyranoside, n-dodecyl-D-glucopyranoside, n-dodecyl-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-D-thioglucoside, n- hexyl-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-D-glucopyranoside, and octyl-D-thioglucopyranoside. Lysozymes can also be used as surface stabilizers for nanoparticulate compositions. Certain nanoparticles such as poly(lactic-co-glycolic acid) (PLGA)-nanoparticles are known to target the liver when given by intravenous (IV) or subcutaneously (SQ). Representative polymers that may be incorporated into formulations include chitosan, polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetal diethylamino acetate, poly(alkylmethacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters. Liposomes are spherical vesicles which include a phospholipid bilayer. A variety of lipids can be utilized, allowing for a degree of control in degradation level. One of more of these formulations can be used to deliver the active agents described herein to the macrophages, across the blood brain barrier, and other locations as appropriate. In certain embodiments, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. For example, enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially. Liposomal suspensions (including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (incorporated by reference). For example, liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. Examples The terms used in describing the embodiments described herein are commonly used and known to those skilled in the art. As used herein, the following abbreviations have the indicated meanings: DMSO: dimethylsulfoxide EtOAc: ethyl acetate H: hour Liq.liquid M: molar MeOH: Methanol Min: minute rt or RT: room temperature TBAF: Tetrabutylammonium fluoride THF: tetrahydrofuran General Methods for Preparing Active Compounds Methods for the facile preparation of active compounds are known in the art and result from the selective combination known methods. The compounds disclosed herein can be prepared as described in detail below, or by other methods known to those skilled in the art. It will be understood by one of ordinary skill in the art that variations of detail can be made without departing from the spirit and in no way limiting the scope of the present disclosure. For some compounds, the syntheses described herein are exemplary and can be used as a starting point to prepare additional compounds of the formulas described herein. These compounds can be prepared in various ways, including those synthetic schemes shown and described herein. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims. The various reaction schemes are summarized below. Scheme 1 is a synthetic approach to nucleosides 3. Scheme 2 is an enzymatic approach to the synthesis of compound 8. In the schemes described herein, if a nucleoside base includes functional groups that might interfere with or be decomposed or otherwise converted during the reaction steps, such functional groups can be protected using suitable protecting groups that can be removed. Protected functional groups, if any, can be deprotected later on. to nucleosides 3. Compounds of general formula 3 can be prepared from nucleosides 1 by selective protection of the 2’,3’ hydroxyl groups, with for instance, acetone in presence of H2SO4, followed by coupling with a protected amino acid in present of a coupling agent, such as EDC, or with an acid chloride, a carbonate chloride or a chloromethylester derivative in presence of a base such as Et3N or NaH followed by appropriate deprotection. Scheme 2. Enzymatic approach to the synthesis of compound 8. Compounds of general formula 8 can also be made by adapting the chemistry described in ACS Omega 2021, 6, 15, 10396–10402 and in Scheme 2. Compounds of general Formula A and B can also be prepared by adapting the chemistry described in: J. Am. Chem. Soc.2000, 122, 30, 7233–7243; J. Med. Chem.2006, 49, 5, 1624– 1634; Nucleosides, Nucleotides & Nucleic Acids (2001), 20(4-7), 743-746; European Journal of Organic Chemistry (1999), (3), 691-696; Journal of Organic Chemistry (1971), 36(1), 108- 10; Nucleosides & Nucleotides (1992), 11(8), 1467-79; Journal of Medicinal Chemistry (1975), 18(8), 784-7; Tetrahedron Letters (2006), 47(4), 591-594. Compounds of general Formula C and F can also be prepared by adapting the chemistry described in: Bioorganic & Medicinal Chemistry (2007), 15(16), 5519-5528; Chemistry & Biology (Oxford, United Kingdom) (2013), 20(3), 416-423; Nucleosides, Nucleotides & Nucleic Acids (2007), 26(6-7), 573-577; WO2004096286 A2; US20110288053 A1. Compounds of general Formula D and E can also be prepared by adapting the chemistry described in: WO2021 / 159044 A1; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1991), (1), 43-8; Bioorganic Chemistry (2015), 58, 18-25; Tetrahedron Letters (1985), 26(37), 4467-70; Journal of Medicinal Chemistry (2006), 49(22), 6614-6620; Collection of Czechoslovak Chemical Communications (1969), 34(12), 3755-68; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1973), (7), 665-9; Organic & Biomolecular Chemistry (2011), 9(3), 676-678; Monophosphate prodrugs of general Formula A-L can also be prepared by adapting the chemistry described in: Chem Rev.2014;114(18):9154-9218. Incorporation of Deuterium: Single or multiple replacement of hydrogen with deuterium (carbon-hydrogen bonds to carbon-deuterium bond) at site(s) of metabolism in the sugar portion of a nucleoside antiviral agent will slow down the rate of metabolism. This can provide a relatively longer half-life, and slower clearance from the body. The slow metabolism of a therapeutic nucleoside is expected to add extra advantage to a therapeutic candidate, while other physical or biochemical properties are not affected. Intracellular hydrolysis or deuterium exchanges my result in liberation of deuterium oxide (D2O). Methods for incorporating deuterium into amino acids, phenol, sugars, and bases, are well known to those of skill in the art. Representative methods are disclosed in U.S. Patent No.9,045,521. A variety of enzymatic and chemical methods have been developed for deuterium incorporation at both the sugar and nucleoside stages to provide high levels of deuterium incorporation (D / H ratio). The enzymatic method of deuterium exchange generally has low levels of incorporation. Enzymatic incorporation has further complications due to cumbersome isolation techniques which are required for isolation of deuterated mononucleotide blocks. Schmidt et al., Ann. Chem. 1974, 1856; Schmidt et al., Chem. Ber., 1968, 101, 590, describes synthesis of 5',5'-2H2-adenosine which was prepared from 2',3'-O- isopropylideneadenosine-5'-carboxylic acid or from methyl-2,3-isopropylidene-beta-D- ribofuranosiduronic acid, Dupre, M. and Gaudemer, A., Tetrahedron Lett. 1978, 2783.. Kintanar, et al., Am. Chem. Soc.1998, 110, 6367 reported that diastereoisomeric mixtures of 5'-deuterioadenosine and 5'(R / S)-deuterated thymidine can be obtained with reduction of the appropriate 5'-aldehydes using sodium borodeuteride or lithium aluminum deuteride (98 atom %2H incorporation). Berger et al., Nucleoside & Nucleotides 1987, 6, 395 described the conversion of the 5'- aldehyde derivative of 2'deoxyguanosine to 5' or 4'-deuterio-2'-deoxyguanosine by heating the aldehyde in2H2O / pyridine mixture (1:1) followed by reduction of the aldehyde with NaBD4. Ajmera et al., Labelled Compd. 1986, 23, 963 described procedures to obtain 4'- deuterium labeled uridine and thymidine (98 atom %2H). Sinhababu, et al., J. Am. Chem. Soc. 1985, 107, 7628) demonstrated deuterium incorporation at the C3' (97 atom %2H) of adenosine during sugar synthesis upon stereoselective reduction of 1,2:5,6-di-O-isopropylidene-β-D- hexofuranos-3-ulose to 1,2:5,6-di-O-isopropylidene-3-deuterio-β-D-ribohexofuranose using sodium borodeuteride and subsequently proceeding further to the nucleoside synthesis. Robins, et al., Org. Chem.1990, 55, 410 report the synthesis of more than 95% atom2H incorporation at C3' of adenosine with virtually complete stereoselectivity upon reduction of the 2'-O-tert-butyldimethylsilyl(TBDMS) 3-ketonucleoside by sodium borodeuteride in acetic acid. David, S. and Eustache, J., Carbohyd. Res.1971, 16, 46 and David, S. and Eustache, J., Carbohyd. Res. 1971, 20, 319 described syntheses of 2'-deoxy-2'(S)-deuterio-uridine and cytidine. The synthesis was carried out by the use of 1-methyl-2-deoxy-2'-(S)-deuterio ribofuranoside. Radatus, et al., J. Am. Chem. Soc. 1971, 93, 3086 described chemical procedures for synthesizing 2'-monodeuterated (R or S)-2'-deoxycytidines. These structures were synthesized from selective 2-monodeuterated-2-deoxy-D-riboses, which were obtained upon stereospecific reduction of a 2,3-dehydro-hexopyranose with lithium aluminum deuteride and oxidation of the resulting glycal. Wong et al. J. Am. Chem. Soc. 1978, 100, 3548 reported obtaining deoxy-1-deuterio- D-erythro-pentose, 2-deoxy-2(S)-deuterio-D-erythro-pentose and 2-deoxy-1,2(S)-dideuterio- D-erythro-pentose from D-arabinose by a reaction sequence involving the formation and LiAlD4 reduction of ketene dithioacetal derivatives. Pathak et al. J., Tetrahedron 1986, 42, 5427) reported stereospecific synthesis of all eight 2' or 2'-deuterio-2'-deoxynucleosides by reductive opening of appropriate methyl 2,3-anhydro- beta-D-ribo or beta-D-lyxofuranosides with LiAlD4. Wu et al. J. Tetrahedron 1987, 43, 2355 described the synthesis of all 2',2''-dideuterio-2'-deoxynucleosides, for both deoxy and ribonucleosides, starting with oxidation of C2' of sugar and subsequent reduction with NaBD4or LiAlD4 followed by deoxygenation by tributyltin deuteride. Roy et al. J. Am. Chem. Soc. 1986, 108, 1675, reported 2',2'-dideuterio-2'-deoxyguanosine and thymidine can be prepared from 2-deoxyribose 5-phosphate using 2-deoxyribose 5-phosphate aldolase enzyme in2H2O achieving some 90 atom % deuteration. Similarly, the synthesis of 4',5',5'-2H3-guanosine can be carried out. Therefore, each position of the sugar residue can be selectively labeled. A useful alternative method of stereospecific deuteration was developed to synthesize polydeuterated sugars. This method employed exchange of hydrogen with deuterium at the hydroxyl bearing carbon (i.e. methylene and methine protons of hydroxyl bearing carbon) using deuterated Raney nickel catalyst in2H2O. Various techniques are available to synthesize fully deuterated deoxy and ribonucleosides. Thus, in one method, exchange reaction of deuterated Raney nickel-2H2O with sugars, a number of deuterated nucleosides specifically labeled at 2’, 3' and 4' positions were prepared. The procedure consisted of deuteration at 2’, 3’ and 4’ positions of methyl beta-D- arabinopyranoside by Raney nickel-2H2O exchange reaction followed by reductive elimination of ‘2-hydroxyl group by tributyltin deuteride to give methyl beta-D-2’,2',3’,4’-2H4-2- deoxyribopyranoside, which was converted to methyl beta-D-2’,2',3’,4’-2H4-2’- deoxyribofuranoside and glycosylated to give various 2’,2',3’,4’-2H4-nucleosides (> 97 atom %2H incorporation for H3' & H4'. The synthesis of deuterated phenols is described, for example, in Hoyer, H. (1950), Synthese des pan-deutero-o-nitro-phenols. Chem. Ber., 83: 131–136. This chemistry can be adapted to prepare substituted phenols with deuterium labels. Deuterated phenols, and substituted analogs thereof, can be used, for example, to prepare phenoxy groups in phosphoramidate prodrugs. The synthesis of deuterated amino acids is described, for example, in Matthews et al., Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 497, Issue 1, 29 March 1977, Pages 1–13. These and similar techniques can be used to prepare deuterated amino acids, which can be used to prepare phosphoramidate prodrugs of the nucleosides described herein. One method for synthesizing a deuterated analog of the compounds described herein involves synthesizing a deuterated ribofuranoside with a 1’-CN substitution; and attaching a nucleobase to the deuterated ribofuranoside to form a deuterated nucleoside. A prodrug, such as a phosphoramidate prodrug, can be formed by modifying the 5’-OH group on the nucleoside. Where a deuterated phenol and / or deuterated amino acid is used, one can prepare a deuterated phosphoramidate prodrug. Another method involves synthesizing a ribofuranoside with 1’-CN substitution, and attaching a deuterated nucleobase to form a deuterated nucleoside. This method can optionally be performed using a deuterated furanoside to provide additional deuteration. As with the method described above, the nucleoside can be converted into a prodrug form, which prodrug form can optionally include additional deuteration. A third method involves synthesizing a ribofuranoside with 1’-CN substitution, attaching a nucleobase to form a nucleoside, and converting the nucleoside to a phosphoramidate prodrug using one or both of a deuterated amino acid or phenol analog in the phosphoramidate synthesis. Accordingly, using the techniques described above, one can provide one or more deuterium atoms in the sugar, base, and / or prodrug portion of the nucleoside compounds described herein. Methods for making compounds Specific representative compounds described herein were prepared as per the following examples and reaction sequences; the examples and the diagrams depicting the reaction sequences are offered by way of illustration, to aid in the understanding of the disclosure and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. The present compounds can also be used as intermediates in subsequent examples to produce additional compounds described herein. No attempt has necessarily been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and / or reagents. Unless noted otherwise, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. Melting points (mp) were determined on an Electrothermal digit melting point apparatus and are uncorrected.1H and13C NMR spectra were taken on a spectrometer at room temperature and reported in ppm downfield from internal tetramethylsilane. Deuterium exchange, decoupling experiments or 2D-COSY were performed to confirm proton assignments. Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet), br (broad), bs (broad singlet), m (multiplet). All J- values are in Hz. Experimental Synthesis of compounds 4 and 7

[0003] 3,4-diyl dibenzoate (3) To a stirred solution of compound 1 (1.20 g, 2.31 mmol, 1.0 eq) and 6-chloro-9H-purine 2 (536 mg, 3.47 mmol, 1.5 eq) in anhydrous PhMe (60 ml) was added N,O- bis(trimethylsilyl)acetamide (1.72 ml, 6.93 mmol, 3.0 eq) at r.t. The reaction mixture was refluxed for 30 minutes and then cooled down to 0oC before addition of TMSOTf (1.67 ml, 9.22 mmol, 4.0 eq). The resulting mixture was refluxed for 24 h until completion of the reaction as monitored by TLC. The reaction was quenched with a saturated solution of NaHCO3, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4. After concentration under reduced pressure, the residue was purified by flash chromatography (Hexane / EtOAc) to give compound 3 (454 mg, 32%) as a light yellowish foam.1H NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 8.44 (s, 1H), 8.13-7.88 (m, 6H), 7.62-7.36 (m, 9H), 6.51 (d, J = 4.0 Hz, 2H), 6.26 (t, J = 4.0 Hz, 1H), 5.01-4.96 (m, 1H), 4.85-4.81 (m, 1H), 4.28-4.24 (m, 1H). (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrothiophene-3,4- diol (4) Compound 3 (450 mg) was dissolved in a saturated solution of NH3in isopropanol and the reaction was stirred at 100oC for 24 h in a sealed tube. A saturated solution of NH3in MeOH was then added and the reaction at 100oC for 4 h in a sealed tube. The solvent was removed in vacuo and the residue was purified by flash chromatography (DCM: MeOH = 4 / 1) to give 4 (RS-4118, 85 mg, 41% yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.14 (s, 1H), 7.28 (s, 2H), 5.85 (d, J = 6.7 Hz, 1H), 5.55 (d, J = 6.2 Hz, 1H), 5.33 (d, J = 4.5 Hz, 1H), 5.22 (t, J = 5.4 Hz, 1H), 4.69-4.65 (m, 1H), 4.20 (d, J = 3.4 Hz, 1H), 3.83 -3.77 (m, 1H), 3.65-3.60 (m, 1H), 3.17 (d, J = 5.3 Hz, 1H). ((3aS,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrothieno[3,4-d] [1,3] dioxol-4-yl) methanol (5) To a solution of 4 (20 mg, 0.07 mmol) in anhydrous acetone (3 mL) and 2,2- dimethoxypropane (1 mL) was added p-toluenesulfonic acid monohydrate (30 mg). After stirring for 24 h at r.t, the mixture was quenched with a saturated solution of NaHCO3. The solvent was removed in vacuo and the residue was purified by flash chromatography (0−20% MeOH / DCM) to give 5 (16 mg, 70%) as a colorless foam.1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.16 (s, 1H), 7.33 (s, 2H), 6.07 (d, J = 2.5 Hz, 1H), 5.38 (dd, J = 2.5 Hz, J = 5.4 Hz, 1H), 5.33 (d, J = 4.4 Hz, 1H), 5.03 (d, J = 5.4 Hz, 1H), 3.68-3.59 (m, 3H), 1.53 (s, 3H), 1.29 (s, 3H). Isopropyl ((S)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy tetrahydro thio phen-2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate (7, RS-4127) To a mixture of dry compound 5 (13 mg, 0.04 mmol) in dry DMF (1.8 mL) was added tert-butylmagnesium chloride (160 µL, 0.16 mmol, 1 M in THF, 4 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then warmed to 25 °C, and stirred for an additional 15 min. A solution of isopropyl (S)-(perfluorophenoxy) -(phenoxy) phosphoryl)-L-alaninate (22 mg, 0.048 mmol) in THF (0.2 mL) was added dropwise to the white suspension at 0 °C. After 24 h at r.t, the clear solution was quenched by addition of 0.5 M NH4Cl (2 mL) at 0 °C. The mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (1 mL), brine (1 mL), dried over MgSO4, and concentrated under reduced pressure. The crude compound 6 was dissolved in 90% HCOOH (5 mL) and stirred for 24 h at r.t. The solvent was removed under vacuo and the residue was neutralized with a saturated NaHCO3solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over Na2SO4. The crude residue was purified by flash chromatography (0−1% MeOH / DCM) to give 7 (5.1 mg, 23%).1H NMR (400 MHz, MeOH- d4) δ 8.44 (s, 1H), 8.23 (s, 1H), 7.41-7.38 (m, 2H), 7.31-7.29 (m, 2H), 7.24-7.20 (m, 1H), 6.01 (d, J = 8.0 Hz, 1H), 4.99-4.90 (m, 2H), 4.77-4.75 (m, 1H), 4.58-4.53 (m, 1H), 4.42-4.35 (m, 2H), 3.97-3.93 (m, 1H), 3.72-3.69 (m, 1H), 1.37(d, J = 7.1 Hz, 3H), 1.23 (dd, J = 6.4 Hz, J = 7.2 Hz, 6H).31P NMR (162 MHz, MeOD-d4) δ 3.46.

[0004] Synthesis of compounds 11 and 12 (2R,3R,4S,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5-((benzoyloxy)methyl) tetrahydro thiophene-3,4-diyl dibenzoate (9) To a stirred solution of compound 1 (250 mg, 0.48 mmol, 1.0 eq) and 6-chloro-9H- purin-2-amine 8 (122 mg, 0.72 mmol, 1.5 eq) in anhydrous PhMe (8 ml) was added N,O- bis(trimethylsilyl)acetamide (348 µL, 1.44 mmol, 3.0 eq) at r.t. The reaction mixture was refluxed for 30 minutes before addition of TMSOTf (348 µL, 1.44 mmol, 3.0 eq) at 0oC. The reaction was then refluxed for 24 h until completion as monitored by TLC. The reaction was quenched with a saturated solution of NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over Na2SO4. The volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography (DCM: EtOAc= 2:1) to give compound 9 (85 mg, 28%) as a yellowish foam.1H NMR (400 MHz, MeOH-d4) δ 8.31 (s, 1H), 8.05-8.00 (m, 3H), 7.88 (d, J = 8.0 Hz, 2H), 7.63-7.54 (m, 3H), 7.46-7.36 (m, 5H), 6.59-6.56 (m, 1H), 6.53 (d, J = 4.0 Hz, 1H), 6.42 (t, J = 4.0 Hz, 1H), 5.18-5.13 (m, 1H), 4.85-4.80 (m, 1H), 4.66 (s, 1H), 4.29-4.25 (m, 1H), 4.11 (dd, J = 8.0 Hz, J = 12.0 Hz, 1H). (2R,3R,4S,5R)-2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-((benzoyloxy) methyl) tetrahydrothiophene-3,4-diyl dibenzoate (10) Compound 9 (50 mg) was dissolved in HCOOH (5 mL) and refluxed at 105oC for 24 h. The solvent was removed in vacuo. The residue was neutralized with a saturated NaHCO3solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash chromatography (DCM: MeOH =10:1) to give 10 (39 mg, 81 % yield) as a colorless solid.1H NMR (400 MHz, MeOH-d4) δ 8.01-7.96 (m, 4H), 7.86 (d, J = 4.0 Hz, 2H), 7.60-7.50 (m, 4H), 7.42-7.33 (m, 6H), 6.46 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.3 (s, 1H), 5.10-5.05 (m, 1H), 4.81-4.77 (m, 1H), 4.24 (d, J = 4.0 Hz, 1H). 2-amino-9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrothiophen-2-yl)- 1,9-dihydro-6H-purin-6-one (12) Compound 10 (20 mg) was dissolved in a saturated solution of NH3in MeOH (10 mL) and the reaction mixture was stirred at r.t for 24 h. The solvent was removed in vacuo and the residue purified by flash chromatography (DCM: MeOH = 4:1) to give 12 (8 mg, 84% yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.04 (s, 1H), 6.51 (s, 2H), 5.66 (d, J = 6.9 Hz, 1H), 5.49 (d, J = 4.7 Hz, 1H), 5.31 (s, 1H), 5.18-5.15 (m, 1H), 4.48 (s, 1H), 4.16 (s, 1H), 3.75-3.71 (m, 1H), 3.61-3.55 (m, 1H), 3.28-3.24 (m, 1H). (2R,3R,4S,5R)-2-(2,6-diamino-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrothiophene- 3,4-diol (11) Compound 9 (30 mg) was dissolved in a saturated solution of NH3in isopropanol (20 mL) and stirred at 100oC for 24 h in a sealed tube. A solution of saturated NH3 in MeOH was then added and the reaction was stirred at 100oC for 4 h in a sealed tube. The solvent was removed in vacuo and the residue purified by flash chromatography (DCM: MeOH = 4:1) to give 11 (7.2 mg, 51 % yield) as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 6.72 (s, 2H), 6.81(s, 2H), 5.70 (d, J = 8.0 Hz, 1H), 5.47 (d, J = 4.0 Hz, 1H), 5.28 (d, J = 4.0 Hz, 1H), 5.20 (t, J = 4.0 Hz, 1H), 4.54-4.50 (m, 1H), 4.18 (t, J = 4.0 Hz, 1H), 3.78-3.73 (m, 1H), 3.62-3.59 (m, 1H), 3.27-3.25 (m, 1H). Synthesis of compounds 14 and 15. (2R,3R,4S,5R)-2-(6-amino-2-fluoro-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrothiophene-3,4-diol (14): A mixture of 2-fluoro-9H-purin-6-amine (530 mg, 2.08 mmol) and BSA (2.54 mL, 6.2 mmol) in 5 mL of acetonitrile was heated at 80oC for 30 min until a clear solution was obtained. To this solution was added TMSOTf (0.628 mL, 3.46 mmol) and compound 1 (900 mg, 1.73 mmol) in 2 mL of acetonitrile. The mixture was stirred at 80oC for 3 hours and then cooled to room temperature. The mixture was diluted with 200 mL of ethyl acetate, washed with saturated NaHCO3and water. The organic layer was dried under vacuum and the residue was purified by flash chromatography (hexane to hexane / ethyl acetate =1:2) to give crude compound 13 (0.517 g). Crude 13 was stirred overnight in a saturated solution NH3 in methanol (15 mL) containing a few drops of a saturated solution NH3in water. The mixture was stirred overnight. The precipitate was collected and washed with ethyl acetate and 1 mL of methanol to give pure compound 14 (58 mg)1H NMR (DMSO): ^ 8.44 (1H, s), 7.8 (1H, bs), 5.73 (1H, d, J = 8.0 Hz), 5.58 (1H, d, J = 4.0 Hz), 5.35 (1H, d, J = 4.0 Hz), 5.18 (1H, t, J = 4.0 Hz), 4.61 (1H, m), 4.19 (1H, m), 3.78 (1H, m), 3.62 (1H, m).19F (DMSO): ^ -52.04.13C NMR (DMSO): ^ 158.2, 158.0, 151.5(d), 140.8, 117.9, 77.3, 73.5, 63.6, 61.8, 53.8. isopropyl ((S)-(((2R,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-dihydroxytetra hydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (15): Compound 3 (54 mg, 0.18 mmol) in 3 mL of DMF and 2 mL of THF was cooled to 0oC.tBuMgCl (0.54 mL, 0.54mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. To the mixture was added isopropyl (S)-(perfluorophenoxy) -(phenoxy) phosphoryl)-L-alaninate (97.4 mg, 0.21 mmol)and the mixture was stirred for 2 hours. The mixture was poured into cold 30 mL of a saturated solution of ammonium chloride and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash chromatography (DCM to DCM / MeOH = 10:1) to give compound XX (14 mg).1H NMR (CD3OD): ^ 8.36 (1H, s), 7.2-7.4 (5H, m), 5.89 (1H, d, J = 8 Hz), 4.5-5.0 (3H, m, overlapped with H2O), 4.4 (1H, m), 4.35 (1H, t, J = 4.0 Hz), 3.95 (1H, m), 3.7 (1H, m).1.38 (3H, d, J = 8.0 Hz), 1.23 (3H, d, J = 8.0 Hz), 1.22 (3H, d, J = 8.0 Hz).19F NMR (CD3OD): ^ -52.93.31P NMR (CD3OD) ^ 3.46.13C NMR (CD3OD): ^ 173.2, 160.1, 158.0 (d), 150.8, 140.5,129.5, 124.9, 120.1, 77.4, 73,5, 69.0, 67.2, 62.6, 50.3, 20.6, 19.2, 18.0.

[0005] Synthesis of compound 21 and 23 IClICl-N N (3aR,6R,6aS)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrothieno[3,4- d][1,3]dioxol-4-ol (17) A solution of compound 1 (1.146 g, 2.415 mmol - RIBONUCLEIC ACIDs WITH 4'- THIO-MODIFIED NUCLEOTIDES AND RELATED METHODS WO2014152513A1) in 10 mL of acetic anhydride was heated at 130oC for 1 hour and then cooled to room temperature. The reaction mixture was poured into 50 mL of a saturated solution of NaHCO3 and extracted with 50 mL of ethyl acetate. The ethyl acetate layer was washed with a saturated solution of NaHCO3(50 mL x 2). The organic layer was dried over Na2SO4and evaporated under vacuum. To the residue was added 50 mL of a saturated solution of NH3 in methanol and the reaction was stirred for 2 hours. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (hexanes to hexanes / ethyl acetate = 5:1) to give compound 17 (0.926 g) as colorless liquid.1H NMR (CDCl3): ^ 7.7 (4H, m), 7.2-7.5 (6H, m), 5.28 (1H, d, J = 10.4Hz), 4.79 (2H, m), 4.35 (1H, d, J = 10.4 Hz), 3.89 (1H, dd, J = 10.8, 3.2 Hz), 3.74 (1H, dd, J = 10.8, 3.2 Hz).3.54 (1H, t, J = 3.2 Hz), 1.48 (3H, s), 1.30 (3H, s), 109 (9H, s). 7-((3aR,6R,6aS)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (18) To a solution of compound 17 (0.849 g, 1.91 mmol), 6-chloro-7-iodo-7-deazapurine (587 mg, 2.1 mmol) and PPh3 (1.002, 3.82 mmol) in THF (30 ml) at 0oC was added DIAD (0.76 mL, 3.82 mmol) dropwise. The mixture was stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the residue was purified by flash chromatography (hexanes to hexanes / ethyl acetate = 6:1) to give compound 18 (660 mg) as aa mixture of alpha / beta isomers (ratio 2.5:1). 7-((3aR,6R,6aS)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (19) To a solution of compound 18 (616 mg, 0.873 mmol) in 20 mL of THF at -78oC was addediPrMgCl LiCl (1.3 M in THF, 1.0 mL, 1.31 mmol) dropwise. The mixture was stirred for 30 min, theniPrOH (0.1 mL, 1.31 mmol) was added. The mixture was poured into 100 mL of a cold saturated solution of NH4Cl. The mixture was extracted with ethyl acetate (100 mL x 2). The organic layer was dried over Mg2SO4and the solvent removed under vacuum. The residue was used in the next step without purification. ((3aS,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)methanol (20): A solution of compound 19 in a saturated solution of NH3in MeOH (40 ml) was heated at 90oC in a steel bomb overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH=10:1) to give compound 20 (96 mg) along with its ^^isomer (24 mg).1H NMR (CD3OD): ^ 8.12 (1H, bs) 7.44 (1H, d, J = 4.0 Hz), 6.67 (1H, d, J = 4.0 Hz), 6.32 (1H, d, J = 4.0 Hz), 5.19 (1H, m), 5.0 (1H, m), 3.80 (1H, m), 3.72 (1H, m), 1.61 (3H, s), 1.34 (3H, s).13C NMR (CD3OD): ^ 157.4, 150.7, 149.4, 122.5, 112.2, 100.2, 88.6, 84.7, 66.0, 63.7, 55.0, 26.5, 24.2. ^ isomer:1H NMR (CD3OD): ^ 8.11 (1H, bs) 7.50 (1H, d, J = 4.0 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 4.0 Hz), 4.95 (2H, m), 3.84 (1H, dd, J = 12.0, 8.0 Hz), 3.77 (1H, dd, J = 12, 8.0 Hz), 3.52 (1H, t, J = 8.0 Hz), 1.49 (3H, s), 1.30 (3H, s).13C NMR (CD3OD): ^ 157.5, 150.8, 149.5, 125.1, 111.7, 102.8, 98.6, 85.3, 82.8, 64.2, 61.0, 53.9, 25.6, 24.9. (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrothiophene-3,4-diol (21): A solution of compound 20 (40 mg, 0.12 mmol) in 80% formic acid in water (1 mL) was stirred for 2h. The solvent was removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH=6:1) to give compound 21 (24 mg) as white solid.1H NMR (DMSO): ^ 8.05 (1H, s) 7.51 (1H, d, J = 4.0 Hz), 7.0 (2H, bs, NH2), 6.60 (1H, d, J = 4.0 Hz), 6.09 (1H, d, J = 4.0 Hz), 5.37 (1H, d, J = 6.4 Hz), 5.25 (1H, d, J = 4.8 Hz), 5.17 (1H, t, J = 5.6 Hz), 4.39 (1H, m), 4.15 (1H, m), 3.74 (1H, m), 3.59(1H, m), 3.27 (1H, m).13C NMR (DMSO): ^ 157.9, 152.1, 150.9, 122.2, 103.1, 100.3, 77.9, 73.9, 64.0, 61.6, 53.2. isopropyl ((S)-(((3aS,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (22): To a solution of compound 21 (35 mg, 0.11 mmol) in 4 mL of THF was addedtBuMgCl (0.3 mL, 0.3 mmol) at 0oC. The mixture was stirred for 30 min at 0oC before addition of isopropyl (S)-(perfluorophenoxy) -(phenoxy) phosphoryl)-L-alaninate (54 mg, 0.12 mmol). The mixture was stirred at room temperature for 1h, then poured into 20 mL of a cold saturated solution of NH4Cl. The mixture was extracted with ethyl acetate (20 mL x 2). The organic layer was dried over Mg2SO4 and the solvent was removed under vacuum. The residue was purified by flash chromatography (DCM to DCM / MeOH=10:1) to give compound 22 (38 mg).1H NMR (CD3OD): ^ 8.12 (1H, s), 7.2-7.4 (5H, m), 6.66 (1H, d, J = 4.0 Hz), 6.31 (1H, d, J = 4.0 Hz), 5.31 ( (1H, dd, J = 8.0, 4.0 Hz), 5.13 (1H, dd, J = 4.0, 4.0 Hz), 4.96 (1H, m), 4.39 (1H, m), 4.22 (1H, m), 3.91 (1H, m), 3.81 (1H, m).1.60 (3H, s), 1.35 (6H, s), 1.22 (3H, d, J = 3.2 Hz), 1.21 (3H, d, J = 3.6 Hz).31P NMR (CD3OD): ^ 3.33.13C NMR (CD3OD): ^ 173, 157.6, 151.1, 150.7, 149.4, 129.4, 124.8, 122.4, 120.1, 112.1, 103.5, 100.3, 88.6, 85.1, 68.7, 67.5, 66.8, 53.4, 50.3, 26.3, 24.0, 20.6, 19.1. isopropyl ((S)-(((2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (23): A solution of compound 22 (38 mg, 0.064 mmol) in 1 mL of 80% formic acid in water was stirred at room temperature for 1.5h. The volatiles were removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH = 10:1) to give compound 23 (31 mg).1H NMR (CD3OD): ^ 8.13 (1H, s), 7.53 (1H, d, J = 4.0 Hz), 7.2-7.4 (5H, m), 6.69 (1H, d, J = 8.0 Hz), 6.25 (1H, d, J = 8.0 Hz),), 5.0 (1H, m), 4.49 (1H, m), 4.37 (1H, m), 4.32 (1H, m), 3.96 (1H, m), 3.68 (1H, m)., 1.38 (3H, d, J = 8.0 Hz), 1.23 (3H, d, J = 4.0 Hz), 1.22 (3H, d, J = 8.0 Hz).31P NMR (CD3OD): ^ 3.38.13C NMR (CD3OD): ^ 173, 156.5, 150.8, 149.7, 149.3, 129.5, 124.8, 122.8, 120.0, 103.2, 100.2, 78.2, 73.7, 68.8, 67.4, 62.3, 50.3, 49.8, 20.6, 20.5, 19.2.

[0006] Synthesis of compound 26 (2R,3S,4R,5R)-2-((benzoyloxy)methyl)-5-hydroxytetrahydrothiophene-3,4-diyl dibenzoate (24): A solution of compound 1 (1.20 g, 2.38 mmol) and Hf(OTf)4(130 mg) in MeCN (50 mL) and water (2.0 mL) was stirred overnight at 65oC. After removal of the solvents under vacuum, the residue was diluted with 50 mL of ethyl acetate and washed with a saturated solution of NaHCO3and water. The organic layer was dried with Na2SO4and the solvent was removed under vacuum. The residue was purified by flash chromatography (Hexanes to hexanes / ethyl acetate =1:1) to give compound 24 (0.791 g). (Org. Biomol. Chem., 2022,20, 1401-1406) (2R,3S,4R)-2-((benzoyloxy)methyl)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrothiophene-3,4-diyl dibenzoate (25): To a solution of compound 24 (1.069 g, 2.24 mmol), PPh3(1.173 g, 4.48 mmol) and 6- chloro-7-fluoro-7-deazapurine (0.422g, 2.46 mmol) in 40 mL of THF at 0oC was added DIAD (0.88 mL, 4.48 mmol) dropwise. The mixture was stirred overnight at room temperature and the solvent was removed under vacuum. The residue was purified by flash chromatography (hexanes to hexanes / ethyl acetate=4:1) to give 350 mg of intermediate 25 as a mixture of isomers, as indicated by19F NMR. The mixture was used as is in the next step. (2R,3R,4S,5R)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrothiophene-3,4-diol (26): A solution of crude compound 25 in 30 mL of a saturated solution of NH3 in methanol was heated at 110oC overnight in steel bomb. After removal of the solvent under vacuum, the residue was purified by flash chromatography (DCM to DCM / MeOH =5:1) to give compound 26 (17 mg).1H NMR (CD3OD): ^ 8.05 (1H, s) 7.4 (1H, s), 6.24 (1H, dd, J = 8.0, 4.0 Hz), 4.45 (1H, m), 4.29 (1H, t, J = 4.0 Hz), 3.86 (1H, m), 3.59 (1H, m), 3.49 (1H, dd, J = 8.0, 4.0 Hz).19F NMR (CD3OD): ^ -169.0.13C NMR (CD3OD): ^^156.0, 152.0, 145.9 (d), 144.5, 142.1, 104.8(d), 93.2 (d), 78.7, 74.1, 63.1, 62.0, 52.5. Synthesis of compound 27 and 30

[0007] (2R,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrothiophene- 3,4-diyl dibenzoate (3): To a solution of compound 1 (404 mg, 0.8 mmol), 6-chloro purine (136 mg, 0.88 mmol) and DBU (0.36 mL, 2.4 mmol) in 10 mL of ACN was added TMSOTf (0.56 mL, 3.2 mmol) dropwise at 0oC. The mixture was stirred at 60oC for 2 h. After being cooled to room temperature, the mixture was poured into 50 mL of saturated NaHCO3and the mixture extracted with DCM (50 mL x 2). The volatiles were removed under vacuum and the residue was purified by flash chromatography (hexanes to hexanes / ethyl acetate=1:1) to give compound 3 (212 mg)1H NMR (CDCl3): ^ 8.72 (1H, s), 8.44 (1H, s), 8.15 (2H, d, J = 4.4 Hz), 8.04 (2H, d, J = 8.0 Hz), 7.9 (2H, d, J = 4.4 Hz), 7.3-7.6 (9H, m), 6.51 (2H, m), 6.26 (1H, t, J = 3.6 Hz), 4.99 (1H, dd, J=12.0, 6.4 Hz), 4.83 (1H, dd, J=12.0, 6.4 Hz), 4.27 (1H, m),13C NMR (CDCl3): ^^^^^^^^^^^^^^^^^^^^^^^152.2, 151.7, 151.6, 143.9, 133.92, 133.85, 133.6, 132.5, 129.88, 129.83, 129.2, 128.8, 128.7, 128.6, 128.2, 76.8, 74.6, 64.5, 61.5, 48.4. (2R,3R,4S,5R)-2-(6-hydroxy-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrothiophene-3,4- diol (27): A solution of compound 3 (212 mg, 0.345 mmol), mercaptoethanol (98 ^L, 1.38 mmol), sodium methoxide (50% in methanol, 0.3 ml, 1.04 mmol) in 8 mL of methanol was refluxed for 4 h under nitrogen. After cooling the reaction mixture to 0oC, the solution was acidified with acetic acid and diluted with water (20 mL). The precipitate was collected and washed with methanol to give compound 27 (110 mg) as white solid.1H NMR (DMSO-d6): ^ 8.44 (1H, s), 8.07 (1H, s), 5.82 (1H, d, J = 4.0 Hz), 5.62 (1H, bs), 5.39 (1H, bs), 5.20 (1H, bs), 4.58 (1H, m), 4.19 (1H, m), 3.77 (1H, m), 3.61 (1H, m).13C NMR (DMSO-d6): ^ 157.0, 149.1, 146.3, 139.6,124.7, 77.8, 73.6, 63.6, 61.7, 53.8. 9-((3aR,4R,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol- 4-yl)-9H-purin-6-ol (28): A solution of compound 27 (90 mg, 0.32 mmol), p-toluenesulfonic acid (30 mg, 0.16 mmol) and 2,2-dimethoxypropane (3 mL, 24.5 mmol) in 10 mL of acetone and 2 mL of DMF was stirred overnight at 45oC. After neutralization with Et3N, the volatiles were removed under vacuum. The residue was purified by flash chromatography (DCM to DCM / Methanol = 5:1) to give compound 28 (68 mg).1H NMR (CD3OD): ^ 8.5 (1H, s), 8.09 (1H, s), 6.16 (1H, d, J = 4.0 Hz), 5.3 (1H, m), 5.07 (1H, m), 3.78 (3H, m), 1.67 (3H, s), 1.37 (3H, s).13C NMR (CD3OD): ^ 157.5, 148.5, 145.3, 139.7,111.7, 91.0, 89.7, 67.7, 63.6, 56.7, 26.2, 23.9. isopropyl ((S)-(((3aS,4R,6R,6aR)-6-(6-hydroxy-9H-purin-9-yl)-2,2-dimethyl tetrahydro thieno[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (29): To a solution of compound 28 (50 mg, 0.15 mmol) in 3 mL of DMF and 3 mL of THF at 0oC was addedtBuMgCl. The reaction mixture was stirred at this temperature for 30 min before addition of isopropyl (S)-(perfluorophenoxy) -(phenoxy) phosphoryl)-L-alaninate (84 mg, 0.18 mmol). The mixture was stirred at room temperature for 2 h, then poured into 30 mL of saturated NH4Cl and extracted with ethyl acetate (30 mL x 2). The organic layer was evaporated under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH =10:1) to give compound 29 (74 mg).1H NMR (CD3OD): ^ 8.28 (1H, s), 8.08 (1H, s), 7.2-7.4 (5H, m), 6.2 (1H, s ), 5.41 ( (1H, dd, J = 5.6, 1.6 Hz), 5.20 (1H, dd, J =5.6, 1.6 Hz), 4.9 (1H, m), 4.47 (1H, m), 4.27 (1H, m), 3.87 (1H, m), 1.59 (3H, s), 1.35 (3H, s), 1.32 (3H, d, J = 7.2 Hz), 1.21 (6H, d, J = 2.8 Hz).31P NMR (CD3OD): ^ 3.28.13C NMR (CD3OD): ^ 173.1, 157.5, 150.6, 148.1, 145.5, 139.8, 129.5, 124.9, 120.0, 112.0, 89.1, 85.8, 68.9, 68.0, 67.5, 53.8, 50.3, 26.2, 24.0, 20.6, 19.1. isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro thiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (30): A solution of compound 29 (67 mg, 0.11 mmol) in 5 mL of 80% formic acid in water was stirred overnight at room temperature. The volatiles were removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH =6:1) to give compound 30 (40 mg).1H NMR (CD3OD): ^ 8.39 (1H, s), 8.09 (1H, s), 7.2-7.4 (5H, m), 6.03 (1H, d, J = 8.0 Hz), 4.98 (1H, m), 4.79 (1H, m), 4.55 (1H, m), 4.38 (2H, m), 3.96 (1H, m), 3.70 (1H, m), 1.37 (3H, d, J = 8.0 Hz), 1.23 (3H, d, J = 8.0 Hz), 1.22 (3H, d, J = 4.0 Hz).31P NMR (CD3OD): d 3.42.13C NMR (CD3OD): ^ 173.0, 157.5, 150.8, 149.0, 145.3, 139.9, 129.4, 124.8, 124.5, 120.0, 77.6, 73.6, 68.8, 67.3, 62.7, 50.4, 20.6, 20.5, 19.1. Synthesis of compounds 34 (2R,3S,4R)-2-((benzoyloxy)methyl)-5-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrothiophene-3,4-diyl dibenzoate (33): To a solution of compound 1 (1.487 g, 3.11 mmol), PPh3(1.632 g, 6.22 mmol) and 2,6- dichloro,7-deazapurine (0.64 g, 3.42 mmol) in 36 mL of THF was added DIAD (1.23 ml, 6.22 mmol) dropwise at 0oC. The mixture was stirred at room temperature overnight and the solvent was removed under vacuum. The residue was purified by flash chromatography (Hexanes to hexanes / ethyl acetate = 3:1) to give crude compound 31 (1.337 g) as an inseparable mixture of isomers. The crude product was reacted with a saturated solution of NH3 in MeOH (25 mL) in a steel bomb at 95oC overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH = 5:1) to give compound 32 (140 mg) as an inseparable ^, ^ mixture of isomers. A solution of the intermediate 32 (140 mg, 0.44 mmol), p-toluenesulfonic acid (50 mg) and 2,2-dimethoxypropane (3 mL) in acetone (3 mL) and DMF (3 mL) was heated at 45-50oC overnight before addition of Et3N (0.1 mL). The solvent was removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH = 20:1) to give ^ isomer 33 (42 mg, slow moving product on TLC) ^^^^ isomer (57 mg, fast moving product on TLC) was also isolated. ^ isomer:1H NMR (CD3OD): d 7.37 (1H, d, J = 4.0 Hz), 6.62 (1H, d, J = 4.0 Hz), 6.25 (1H, d, J = 4.0 Hz), 5.17 (1H, m), 5.01 (1H, m), 3.87 (1H, m), 3.78 (1H, m), 1.61 (3H, s), 1.35 (3H, s).13C NMR (CD3OD): ^ 158.6, 153.0, 150.5, 122.7, 112.1, 101.7, 100.2, 88.6, 85.0, 66.0, 63.7, 55.4, 26.5, 24.2. ^ isomer:1H NMR (CD3OD): ^ 7.45 (1H, d, J = 4.0 Hz), 6.56 (1H, m), 5.94 (1H, m), 3.84 (1H, m), 3.76 (1H, m), 3.52 (1H, t, J=4.0 Hz), 1.49 (3H, s), 1.35 (3H, s).13C NMR (CD3OD): ^ 158.5, 152.9, 150.7, 125.3, 111.7, 101.1, 98.7, 88.3, 82.7, 64.2, 60.9, 54.0, 24.9, 23.2. (2R,3R,4S,5R)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrothiophene-3,4-diol (34): A solution of compound 33 (19 mg 0.061 mmol) in 2 ml of 80% formic acid was stirred overnight. The volatiles were removed, and the residue was purified by flash chromatography (DCM to DCM / MeOH =5:1) to give compound 34 (6.0 mg) as white solid.1H NMR (CD3OD): ^ 7.52 (1H, d, J = 4.0 Hz), 6.62 (1H, d, J = 4.0 Hz), 5.10 (1H, d, J = 8.0 Hz), 4.47 (1H, t, J = 4.0 Hz), 4.28 (1H, t, J = 4.0), 3.92 (1H, dd, J = 8.0, 4.0 Hz), 3.85 (1H, dd, J = 8.0, 4.0 Hz), 3.50 (1H, m).

[0008] Synthesis of compounds 36 and 37 (2R,3S,4R)-2-((benzoyloxy)methyl)-5-(2,4-diazido-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrothiophene-3,4-diyl dibenzoate (36): A solution of 2,6-diazido,7 deazapurine (1.59 g, 8.7 mmol) and BSA (2.13 mL, 9.6 mmol) in 40 mL of acetonitrile was stirred at 65oC for 30 min. TMSOTf was added to the mixture, followed by compound 1 (2.058 g, 3.96 mmol). The mixture was stirred at 65oC overnight. The volatiles were removed under vacuum and the residue was diluted with a saturated solution of NaHCO3(50 mL) and extracted with ethyl acetate (50 mL x 2). The organic layer was evaporated under vacuum and the residue was purified by flash chromatography (Hexanes to hexanes / ethyl acetate = 2:1) to give product 35 (650 mg) as a 1:0.8 ^^^ mixture. To a solution of compound 35 in 20 mL of methanol was added 10 mL of ammonium hydroxide in methanol and the mixture was stirred at room temperature overnight. The volatiles were removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH = 5:1) to give compound 36 (155 mg) as an inseparable mixture of ^^^ isomers (ratio 1:1).1H NMR (CD3OD): ^ 7.35 (1H, d, J = 8.0 Hz), 6.62 (1H, d, J = 4.0 Hz), 5.10 (1H, d, J = 8.0 Hz), 4.47 (1H, t, J = 4.0 Hz), 4.28 (1H, t, J = 4.0), 3.92 (1H, dd, J = 8.0, 4.0 Hz), 3.85 (1H, dd, J = 8.0, 4.0 Hz), 3.50 (1H, m).4.65, 4.42 (1H, m), 4.34 (1H, m), 4.13 (1H, m), 4.0 (1H, m), 3.91 (1H, m), 3.72 (2H, m), 3.47 (1H, m). (3R,4S,5R)-2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrothiophene-3,4-diol (37) : To a solution of compound 36 (91 mg, 0.26 mmol) in 5 mL of methanol was added Pd(OH)2 / C. The reaction mixture was flushed with nitrogen, then flushed with H2 and stirred under H2atmosphere overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography (DCM to DCM / MeOH = 5:1) to give compound 37 (40 mg) as a mixture of^^^^ isomers (ratio 1:1).1H NMR (DMSO-d6): ^ 10.74 (bs), 10.68 (bs), 6.73 (2H, d, J = 8.0 Hz), 6.37 (1H, s), 5.63 (1H, bs), 5.55 (1H, bs), 5.30 (1H, m), 5.15 (1H, b), 5.05 (1H, bs), 4.78 (1H, m), 3.8-4.0 (3H, m), 3.20 (1H, m). Cellular Toxicity Assays The toxicity of the compounds was assessed in Vero, human PBM, CEM (human lymphoblastoid), MT-2, and HepG2 cells, as described previously (see Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob. Agents Chemother. 1990, 34, 1061-67). Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to solvent were included as negative controls. The cytotoxicity was obtained from the concentration-response curve using the median effective method described previously (see Chou T.-C. & Talalay P. Adv. Enzyme Regul.1984, 22, 27-55; Belen’kii M.S. & Schinazi R.F. Antiviral Res.1994, 25, 1-11). The results are shown in Table 8 below: Mitochondrial Toxicity Assays in HepG2 Cells: i) Effect of Compounds on Cell Growth and Lactic Acid Production: The effect on the growth of HepG2 cells can be determined by incubating cells in the presence of 0 µM,0.1 µM, 1 µM, 10 µM and 100 µM drug. Cells (5 x 104per well) can be plated into 12-well cellculture clusters in minimum essential medium with nonessential amino acids supplemented with 10% fetal bovine serum, 1% sodium pyruvate, and 1% penicillin / streptomycin and incubated for 4 days at 37°C. At the end of the incubation period the cell number can be determined using a hemocytometer. Also taught by Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM. "Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells," Antimicrob. Agents Chemother.2000; 44: 496-503. To measure the effects of the compounds on lactic acid production, HepG2 cells from a stock culture can be diluted and plated in 12-well culture plates at 2.5 x 104cells per well. Various concentrations (0 µM, 0.1 µM, 1 µM, 10 µM and 100 µM) of compound can be added, and the cultures can be incubated at 37°C in a humidified 5% CO2atmosphere for 4 days. At day 4, the number of cells in each well can be determined and the culture medium collected. The culture medium can then be filtered, and the lactic acid content in the medium determined using a colorimetric lactic acid assay. Since lactic acid product can be considered a marker for impaired mitochondrial function, elevated levels of lactic acid production detected in cells grown in the presence of test compounds indicates a drug-induced cytotoxic effect. ii) Effect on Compounds on Mitochondrial DNA Synthesis: a real-time PCR assay to accurately quantify mitochondrial DNA content has been developed (see Stuyver LJ, Lostia S, Adams M, Mathew JS, Pai BS, Grier J, Tharnish PM, Choi Y, Chong Y, Choo H, Chu CK, Otto MJ, Schinazi RF. Antiviral activities and cellular toxicities of modified 2',3'- dideoxy-2',3'-didehydrocytidine analogs. Antimicrob. Agents Chemother.2002; 46: 3854-60). This assay can be used in all studies described in this application that determine the effect of compounds on mitochondrial DNA content. In this assay, low-passage- number HepG2 cells are seeded at 5,000 cells / well in collagen-coated 96-well plates. Test compounds are added to the medium to obtain final concentrations of 0 µM, 0.1 µM, 10 µM and 100 µM. On culture day 7, cellular nucleic acids can be prepared by using commercially available columns. These kits co-purify RNA and DNA, and hence, total nucleic acids are eluted from the columns. The mitochondrial cytochrome c oxidase subunit II (COXII) gene and the ß-actin or rRNA gene can be amplified from 5 µl of the eluted nucleic acids using a multiplex Q-PCR protocol with suitable primers and probes for both target and reference amplifications. For COXII the following sense, probe and antisense primers can be used Since equal amplification efficiencies are obtained for all genes, the comparative CT method can be used to investigate potential inhibition of mitochondrial DNA synthesis. The comparative CT method uses arithmetic formulas in which the amount of target (COXII gene) is normalized to the amount of an endogenous reference (the ß-actin or rRNA gene) and is relative to a calibrator (a control with no drug at day 7). The arithmetic formula for this approach is given by 2-∆∆CT, where ∆∆CT is (CT for average target test sample - CT for target control) - (CT for average reference test -CT for reference control) (see Johnson MR, K Wang, JB Smith, MJ Heslin, RB Diasio. Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction. Anal. Biochem. 2000; 278:175-184). A decrease in mitochondrial DNA content in cells grown in the presence of drug indicates mitochondrial toxicity. Mitochondrial Toxicity- Glu / Gal Protocol Summary HepG2 cells are plated on 96 or 384 well tissue culture polystyrene plates. After 24 hr the cells are dosed with test compound at a range of concentrations and incubated for 72 hr in medium supplemented with either galactose or glucose. Test compounds are said to cause mitochondrial toxicity if the cells grown in galactose-containing medium are more sensitive to the test compound than the cells grown in glucose-containing medium. Objective: To measure the sensitivity of HepG2 cells grown in medium containing either galactose or glucose to the test compound. Experimental Procedure HepG2 human hepatocellular carcinoma cells are plated on 96 or 384-well tissue culture polystyrene plates containing either galactose or glucose containing medium supplemented with 10 % fetal bovine serum and antibiotics and incubated overnight. The cells are dosed with increasing concentrations of the test compound (final DMSO concentration 0.5 %; typical final test compound concentrations of 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 μM for an eight point dose response curve; n = 3 replicates per concentration) and the cells are incubated for 72 hr. Appropriate controls are simultaneously used as quality controls. Cell viability is measured using Hoechst staining and cell counting by a HCS reader. Mitochondrial Toxicity Assays in Neuro2A Cells To estimate the potential of the compounds described herein to cause neuronal toxicity, mouse Neuro2A cells (American Type Culture Collection 131) can be used as a model system (see Ray AS, Hernandez-Santiago BI, Mathew JS, Murakami E, Bozeman C, Xie MY, Dutschman GE, Gullen E, Yang Z, Hurwitz S, Cheng YC, Chu CK, McClure H, Schinazi RF, Anderson KS. Mechanism of anti-human immunodeficiency virus activity of beta-D-6- cyclopropylamino-2’,3’-didehydro-2’,3’-dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 1994-2001). The concentrations necessary to inhibit cell growth by 50% (CC50) can be measured using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide dye- based assay, as described. Perturbations in cellular lactic acid and mitochondrial DNA levels at defined concentrations of drug can be carried out. ddC and AZT can be used as control nucleoside analogs. Assay for Bone Marrow Cytotoxicity Primary human bone marrow mononuclear cells can be obtained. CFU-GM assays is carried out using a bilayer soft agar in the presence of 50 units / mL human recombinant granulocyte / macrophage colony-stimulating factor, while BFU-E assays used an ethylcellulose matrix containing 1 unit / mL erythropoietin (see Sommadossi JP, Carlisle R. Toxicity of 3’-azido-3’-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl) guanine for normal human hepatopoietic progenitor cells in vitro. Antimicrob. Agents Chemother. 1987; 31: 452-454; Sommadossi, JP, Schinazi, RF, Chu, CK, and Xie, MY. Comparison of cytotoxicity of the (-) and (+) enantiomer of 2’,3’-dideoxy-3’-thiacytidine in normal human bone marrow progenitor cells. Biochem. Pharmacol. 1992; 44:1921- 1925). Each experiment can be performed in duplicate in cells from three different donors. AZT is used as a positive control. Cells can be incubated in the presence of the compound for 14-18 days at 37°C with 5% CO2, and colonies of greater than 50 cells can be counted using an inverted microscope todetermine the IC50. The 50% inhibitory concentration (IC50) can be obtained by least-squareslinear regression analysis of the logarithm of drug concentration versus BFU-E survival fractions. Statistical analysis can be performed with Student’s t test for independent non- paired samples. In vitro human mitochondrial RNA polymerase (POLRMTTM) assay In vitro RNA nucleotide incorporation assays with POLRMTTMcan be performed. Briefly,32P-radiolabeled RNA can be hybridized to 3 molar excess of the appropriate DNA template.125 nM of POLRMTTMcan be incubated with 500 nM of 5’-radiolabled RNA / DNA hybrid, 10 mM MgCl2 and 100 μM of the corresponding nucleoside triphosphate. For non- nucleoside analogs, 100 μM of inhibitor can be added at the same time as 100 μM UTP. Incorporation can be allowed to proceed for 2 h at 30°C and reactions are stopped by the addition of 10 mM EDTA and formamide. Samples are visualized on 20% denaturing polyacrylamide gel. Data can be analyzed by normalizing the product fraction for each nucleoside triphosphate analog to that of the corresponding natural nucleoside triphosphate. Effect of Nucleotide Analogs on the DNA Polymerase and Exonuclease Activities of Mitochondrial DNA Polymerase γ i) Purification of Human Polymerase γ: The recombinant large and small subunits of polymerase γ can be purified as described previously (see Graves SW, Johnson AA, Johnson KA. Expression, purification, and initial kinetic characterization of the large subunit of the human mitochondrial DNA polymerase. Biochemistry.1998, 37, 6050-8; Johnson AA, Tsai Y, Graves SW, Johnson KA. Human mitochondrial DNA polymerase holoenzyme: reconstitution and characterization. Biochemistry 2000; 39: 1702-8). The protein concentration can be determined spectrophotometrically at 280 nm, with extinction coefficients of 234,420, and 71,894 M-1 cm-1 for the large and the small subunits of polymerase γ, respectively. ii) Kinetic Analyses of Nucleotide Incorporation: Pre-steady-state kinetic analyses can be performed to determine the catalytic efficiency of incorporation (k / K) for DNA polymerase γ for nucleoside-TP and natural dNTP substrates. This allowed determination of the relative ability of this enzyme to incorporate modified analogs and predict toxicity. Pre-steady-state kinetic analyses of incorporation of nucleotide analogs by DNA polymerase γ would be carried out essentially as described previously (see Murakami E, Ray AS, Schinazi RF, Anderson KS. Investigating the effects of stereochemistry on incorporation and removal of 5-fluorocytidine analogs by mitochondrial DNA polymerase gamma: comparison of D- and L-D4FC-TP. Antiviral Res. 2004, 62, 57-64; Feng JY, Murakami E, Zorca SM, Johnson AA, Johnson KA, Schinazi RF, Furman PA, Anderson KS. Relationship between antiviral activity and subject toxicity: comparison of the incorporation efficiencies of 2’,3’-dideoxy-5-fluoro-3’- thiacytidine-triphosphate analogs by human immunodeficiency virus type 1 reverse transcriptase and human mitochondrial DNA polymerase. Antimicrob Agents Chemother. 2004, 48, 1300-6). Briefly, a pre-incubated mixture of large (250 nM) and small (1.25 mM) subunits of polymerase γ and 60nM DNA template / primer in 50mM Tris-HCl, 100 mM NaCl, pH 7.8, can be added to a solution containing MgCl2(2.5 mM) and various concentrations of nucleotide analogs. Reactions can be quenched and analyzed as described previously. Data can be fit to the same equations as described above. iii) Assay for Human Polymerase γ 3’ 5’ Exonuclease Activity: The human polymerase γ exonuclease activity can be studied by measuring the rate of formation of the cleavage products in the absence of dNTP. The reaction can be initiated by adding MgCl2(2.5mM) to a pre-incubated mixture of polymerase γ large subunit (40nM), small subunit (270nM), and 1,500nM chain-terminated template / primer in 50mM Tris-HCl, 100mM NaCl, pH 7.8, and quenched with 0.3M EDTA at the designated time points. All reaction mixtures would be analyzed on 20% denaturing polyacrylamide sequencing gels (8M urea), imaged on a Bio-Rad GS-525 molecular image system, and quantified with Molecular Analyst (Bio- Rad). Products formed from the early time points would be plotted as a function of time. Data would be fitted by linear regression with Sigma Plot (Jandel Scientific). The slope of the line can be divided by the active enzyme concentration in the reaction to calculate the kexo for exonuclease activity (see Murakami E, Ray AS, Schinazi RF, Anderson KS. Investigating the effects of stereochemistry on incorporation and removal of 5- fluorocytidine analogs by mitochondrial DNA polymerase gamma: comparison of D- and L-D4FC-TP. Antiviral Res.2004; 62: 57-64; Feng JY, Murakami E, Zorca SM, Johnson AA, Johnson KA, Schinazi RF, Furman PA, Anderson KS. Relationship between antiviral activity and subject toxicity: comparison of the incorporation efficiencies of 2’,3’-dideoxy-5-fluoro-3’-thiacytidine-triphosphate analogs by human immunodeficiency virus type 1 reverse transcriptase and human mitochondrial DNA polymerase. Antimicrob Agents Chemother.2004; 48: 1300-6). Inhibition of Human DNA Polymerases by NTP’s Study Objectives To determine whether a nucleoside-triphosphate analog inhibits human DNA polymerases Alpha, Beta and Gamma and to calculate IC50values. Materials and Methods Human DNA Polymerase Alpha – Enzyme can be purchased from ChimerxTM(cat#1075) and assayed based on their recommendations with some modifications. The 2’-Me- UTP was treated with inorganic pyrophosphatase to remove any pyrophosphate contamination. A final concentration of 500 µM 2’-Me-UTP can be incubated with 1 mM DTT, 50 mM Tris, 50 mM NaCl, 6 mM MgCl2, and 1 unit of pyrophosphatase for 1 hour at 37ºC followed by inactivation at 95ºC for 10 minutes. A mixture of 0.05 units of Human DNA Polymerase Alpha and a 5’end radiolabeled 24nt DNA primer anneal to a 48nt DNA template can be mixed with increasing concentrations of compound from 0 to 100 µM in 60 mM Tris-HCl (pH 8.0), 5 mM magnesium acetate, 0.3 mg / ml bovine serum albumin, 1 mM dithiothreitol, 0.1 mM spermine, 0.05 mM of each dCTP, dGTP, dTTP, dATP in a final reaction volume of 20 µl for 5 min at 37ºC (all concentrations represent final concentrations after mixing). The reactions can be stopped by mixing with 0.3 M (final) EDTA. Products are separated on a 20% polyacrylamide gel and quantitated. Results from the experiments can be fit to a dose response equation, (y min +((y max)-(y min))) / (1+(compound concentration) / IC50)^slope) to determine IC50 values. Data can be normalized to controls. Human DNA Polymerase Beta – Enzyme can be purchased and assayed. A mixture of 0.1 units of Human DNA Polymerase Beta and a 5’end radiolabeled 24nt DNA primer anneal to a 48nt DNA template can be mixed with increasing concentrations of compound from 0 to 100 µM in 50 mM Tris-HCl (pH 8.7), 10 mM KCl, 10 mM MgCl2, 0.4 mg / ml bovine serum albumin, 1 mM dithiothreitol, 15% (v / v) glycerol, and 0.05 mM of each dCTP, dGTP, dTTP, dATP in a final reaction volume of 20 µl for 5 min at 37ºC (all concentrations represent final concentrations after mixing). The reactions can be stopped by mixing with 0.3 M (final) EDTA. Products can be separated on a 20% polyacrylamide gel and quantitated. Results from the experiments can be fit to a dose response equation, (y min +((y max)-(y min))) / (1+(compound concentration) / IC50)^slope) to determine IC50values. Data can be normalized to controls. Human DNA Polymerase Gamma – Enzyme can be purchased and assayed. A mixture of 0.625 units of Human DNA Polymerase Gamma and a 5’end radiolabeled 24nt DNA primer anneal to a 36nt DNA template can be mixed with increasing concentrations of compound from 0 to 100 µM in 50 mM Tris-HCl (pH 7.8), 100 mM NaCl, 5 mM MgCl2, and 0.05 mM of each dCTP, dGTP, dTTP, dATP in a final reaction volume of 20 µl for 200 min at 37ºC (all concentrations represent final concentrations after mixing). The reactions can be stopped by mixing with 0.3 M (final) EDTA. Products can be separated on a 20% polyacrylamide gel and quantitated. Results from the experiments can be fit to a dose response equation, (y min +((y max)-(y min))) / (1+(compound concentration) / IC50)^slope) to determine IC50 values. Data can be normalized to controls. Cellular Pharmacology in HepG2 cells HepG2 cells are obtained and are grown in 225 cm2tissue culture flasks in minimal essential medium supplemented with non-essential amino acids, 1% penicillin-streptomycin. The medium is renewed every three days, and the cells are subcultured once a week. After detachment of the adherent monolayer with a 10 minute exposure to 30 mL of trypsin-EDTA and three consecutive washes with medium, confluent HepG2 cells are seeded at a density of2.5 x106cells per well in a 6-well plate and exposed to 10 µM of [3H] labeled active compound(500 dpm / pmol) for the specified time periods. The cells are maintained at 37°C under a 5% CO2atmosphere. At the selected time points, the cells are washed three times with ice-cold phosphate-buffered saline (PBS). Intracellular active compound and its respective metabolites are extracted by incubating the cell pellet overnight at -20°C with 60% methanol followed by extraction with an additional 20 pal of cold methanol for one hour in an ice bath. The extracts are then combined, dried under gentle filtered air flow and stored at -20°C until HPLC analysis. Determining the Efficacy of the Compounds against RSV Antiviral Screening Assay: The quantification of RSV titer was determined by both counting fluorescent focus units (FFU) and measuring syncytia size, given that RSV was expressing mKate2. HEp-2 cells were seeded in 96-well plates and allowed to reach 70% confluence within 24 hours. Prior to RSV infection, HEp-2 cells were pre-incubated with selected compounds for 2 hours. Next, fresh compounds were serially diluted 10-fold in serum-free EMEM and added to 50 to 100 FFU kRSV-A2 in equal volume. Then, 50 ^L of the compound-virus mixture was transferred onto HEp-2 cell monolayers in triplicates in 96-well plates, followed by spinoculation at 3,000 rpm for 30 min at room temperature. The plates were then overlaid with a 0.75% methylcellulose suspension in complete EMEM and incubated at 37oC for 36-48 hours. FFU and syncytia size were quantified. Determining the Efficacy of the Compounds against HIV in macrophages In certain embodiments, this disclosure relates to compounds, methods and compositions for treating or preventing HIV. More specifically, the invention describes certain nucleoside and nucleotide analogs, pharmaceutically acceptable salts, or other derivatives thereof, and the use thereof in the treatment of HIV, especially in myeloid cells including macrophages. See WO2019133712. Macrophages are non-dividing cells that are unique from lymphocytes due to multiple factors including: 1) non-dividing phenotype, 2) low dNTP levels, 3) similar ratios of dNTP / rNTP, 3) unique receptor expression profile, 4) antigen presenting and phagocytic capacity as part of the innate immune response. Macrophages are a systemic viral reservoir for HIV, and unlike lymphocytes, demonstrate suboptimal accumulation of antiviral agents at intracellular concentrations which efficiently eliminate ongoing HIV infection. Antiviral Screening Assay: The antiviral activity is shown in Tables below: Table 1 Anti- Anti- Anti- Anti- C9D 4.1 18.1 8.4 5 D D D 9 0 0 Table 2 Anti-RSV activity H 2 M Anti-HIV activity

[0009] Table 3 Cytotoxicity CC M p2 N D D Table 4 Cytotoxicity 2 36 Pla s a s a y: Human, mouse or hamster plasma (450 µL) were exposed to 10 µM of compound and incubated at 37 ˚C. At 0, 5, 15, 30, 60, 90 and 120 min. Then 50 µL of plasma sample was mixed with 200 µL of ice-cold methanol (70%). Fifty µL supernatant was dried and reconstituted in 100 µL H2O. Propantheline bromide was used as positive control. The supernatant was then subjected to LC-MS analysis. Cellular pharmacology: The uptake and egress of Compounds is measured in cell culture in HAE cells, as well as a variety of other cells. The cell culture involved HAE cells seeded at a density of 0.15 × 106 / well, and other cells were seeded at a density of 1 × 106 / well. To measure uptake, the compound is incubated in cells for 4 hours at a concentration of 10 µM. To measure egress of the compound from the cells, the cells are pre-treated for 24 hr at a concentration of 10 µM, at which time the media was replaced, then cells are harvested at 0, 2, 4, 6, 8, 12, 24, and 32 hours. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims

CLAIMS What is claimed is:

1. A method for treating or preventing a Pneumoviridae infection, comprising administering an effective amount of a compound of Formula (A) to a subject in need thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is H, deuterium, CN; R2is H, deuterium, F; R2’ is OH, F, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid , an optionally substituted -O-C(O)-R’, an optionallysubstituted -O-C(O)SR', an optionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’, provided that when R2is F, R2’is not OH, R’ is PEG, aryl, heteroaryl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, or C3-7 cycloalkyl, wherein optional substituents are selected from the group consisting of halo, C 1 - 12haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido, carboxyl derivatives, alkylamino, di-C 1 -12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine,sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester;R 11 and R11’ are, independently, H, deuterium, C1-20 alkyl, C1-20 alkene, C1-20 alkyne,the carbon chain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein thesubstituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl;or R 11 and R11’ are independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl,-CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R11’and the NR12form a 2- pyrrolidinyl ring, wherein R11or R12’and the 2-pyrrolidinyl ring are optionally substituted withone or more, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy,amino, amido, carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R12 and R12’ are, independently, H, C1-20 alkyl, C1-20 alkene, C1-20 alkyne;R3is H; R3’ is OH, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid an optionally substituted -O-C(O)-R’, anoptionally substituted -O-C(O)substituted -O-C(O)SR', an optionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’; R4 is H, deuterium, F, C1-5alkyl, C1-5alkene, C1-5alkyne, N3, CH2-halogen;R5is and R5’are, independently, H, deuterium, CH3, CH2F, CHF2, or CF3, wherein,when R5is Me, the carbon to which it is attached may be wholly or partially R or S or anymixture thereof, or R5and R5’can combine to form a C3-7 cycloalkyl ring;R6is H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acidester, an N-substituted D-amino acid , an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino ester, (acyloxybenzyl)ether,optionally substituted bis-acyloxybenzyl)ester, substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)SR', an optionally substituted -C(S)SR’, PEG ester, PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a lipid ester, a lipid carbonate (in which a lipid is an optionally substituted C12- 22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22alkoxy), O-P(O)R8R8’, or a mono-, di-, or triphosphate, wherein,when chirality exists at the phosphorous center, it may be wholly or partially Rpor Spor anymixture thereof; R8and R8’are independently selected from the group consisting of:(a) OR15where R15selected from the group consisting of ,, Li, Na, K, substituted or unsubstituted C1-20alkyl, substituted or unsubstitutedoptionally substituted -C(NR’)OR’, optionally substituted -C(NR’)SR’, optionally substituted -C(NR’)N(R’)2, optionally substituted -C(O)N(R’)2, C1-4(alkyl)aryl, benzyl, C1-6haloalkyl, C2-3(alkyl)OC1-20alkyl, C2-3(alkyl)OC2-20alkene, C2-3(alkyl)OC2-20alkyne, CH2-O-C(O)C1-20alkyl, CH2-O-C(O)C2-20alkene, CH2-O-C(O)C2-20alkyne, CH2-O- C(O)-O-C1-20alkyl, CH2-O-C(O)-O-C2-20alkene, CH2-O-C(O)-O-C2-20alkyne, aryl, andheteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionally substitutedwith zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16and (CH2)0-6CON(R16)2;where R16is independently H, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, the carbon chain derived from a fatty alcohol or C1-20alkyl substituted with a C1-6alkyl, C1-6alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, C1-5alkene,C1-5alkyne, C3-7 cycloalkyl or C1-5alkyl substituted with a C1-6 alkyl, alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10andR17 R17A O N (b) the ester of a D- or L-amino acid H OR18, wherein R17Ais H or C1-2alkyl; R17 and R18 are, independently, H, C1-20 alkyl, C1-20 alkene, C1-20 alkyne, the carbonchain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; or R17is independently selected from H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; Base is selected from the group consisting of:yl, C-(C2-6)alkynyl, C-(C3-7)cycloalkyl, C-(C1-6) haloalkyl, C-(C1-6)hydroxyalkyl, C-OR , C-NR10R10’, C-halo, C-CN, -C-C(O)-NR10R10’or N; X2and X2’are independently H, deuterium, halo, -(C1-3)alkyl, -(C1-3)fluoroalkyl, OR9’or NR10R10’; R9’is H, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3-7)cycloalkyl, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, an (acyloxybenzyl)ester, an (acyloxybenzyl)ether, an optionally substituted bis- acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12-alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a PEG ester, a PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O- C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid ester, or a lipid carbonate, wherein a lipid is an optionally substituted C12-22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22alkynyl or an optionally substituted C12-22alkoxy); R10and R10’are independently H, OH, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3- 7)cycloalkyl, an L-amino acid amide, a D-amino acid amide, (acyloxybenzyl)amide, (acyloxybenzyl)amine, optionally substituted (acyloxybenzyl)esters, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12 alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, PEG amide, PEG carbamate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid amide,an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, or a lipid carbamate, wherein a lipid is an optionally substituted C12-22alkyl, an optionally substituted C12-22alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22 alkoxy), with the proviso that R10and R10’cannot both be OH.

2. A method for treating or preventing a Pneumoviridae infection as in claim 1 comprising administering a treatment or preventative amount of a compound of Formula (B) to a patient in need of treatment or prevention thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3, R4, R5, R5’and R16are as defined in Formula A; A is O or S; and D is selected from the group consisting of: (a) OR15where R15is selected from the group consisting of H, substituted orunsubstituted CH2-O-C(O)C1-20alkyl, substituted or unsubstituted CH2-O-C(O)C2-20alkene, substituted or unsubstituted CH2-O-C(O)C2-20alkyne, substituted or unsubstituted CH2-O-C(O)- O-C1-20alkyl, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkene, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkyne, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, substituted or unsubstituted C3-6cycloalkyl, C1-4(alkyl)aryl, benzyl, C1-6haloalkyl, C2-3(alkyl)OC1-20alkyl,aryl, and heteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionallysubstituted with zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16and (CH2)0-6CON(R16)2;R17 R17A O N (b) the ester of a D- or L-amino acid H OR18, wherein R17Ais H or C1-2alkyl; R17 and R18 are independently H, C1-20 alkyl, the carbon chain from a natural aminoacid or an unnatural amino acid, the carbon chain derived from a fatty alcohol or C1-20 alkyloptionally substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substitutedheteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl,alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; or R17is H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; and ofor unsubstituted (C2-10)alkene, substituted or unsubstituted (C2-10)alkyne, C1-4(alkyl)aryl, aryl, heteroaryl, and C1-6 haloalkyl.

3. A method for treating or preventing a Pneumoviridae infection as in claim 1 comprising administering a treatment or preventative amount of a compound of Formula (C) to a patient in need of treatment or prevention thereof:Formula C or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3and R3’are as defined in Formula A; R4’ is selected from the group consisting of H , deuterium, CN, substituted orunsubstituted (C1-8)alkyl, substituted or unsubstituted (C2-8)alkenyl, substituted orunsubstituted (C2-8)alkynyl, substituted or unsubstituted (C1-8) haloalkyl;R6’ is selected from the group consisting of - P(O)R8R8’, or a mono-, di-, ortriphosphate, wherein, when chirality exists at the phosphorous center, it may be wholly orpartially Rpor Spor any mixture thereof;R8as defined in Formula A, 4. The method of claims 1-3, wherein the compound is one of the following compounds: (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrothiophene- 3,4-diol ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl)methyl isobutyrate, (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isobutyryloxy)methyl)tetrahydrothio phene-3,4-diyl bis(2-methylpropanoate), ((R)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl) methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro thiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-7-hydroxy-2-isopropoxytetrahydro-4H- thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxideisopropyl ((4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-7-hydroxy-2-oxidotetrahydro- 4H-thieno[3,2-d][1,3,2]dioxaphosphinin-2-yl)alaninate (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-2-(2-(tert-butyldisulfaneyl)phenethoxy)- 7-hydroxytetrahydro-4H-thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxide (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrothiophene-2-carbonitrile, ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl isobutyrate (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((isobutyryloxy)methyl)tetrahydrothiophene-3,4-diyl bis(2-methylpropanoate), ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl L-valinate, isopropyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, isopropyl ((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(fluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-methylpyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide; or a pharmaceutically acceptable salt or prodrug thereof.

5. The method of any of claims 1-4, wherein the compounds can be present in the β-D or β-L configuration.

6. The method of any of claims 1-4, wherein Pneumoviridae is RSV.

7. The method of any of claims 1-4, wherein the compound is co-administered with one or more additional active compounds.

8. The method of claim 7 wherein the additional active compound is palivizumab or nirsevimab and / or ribavirin.

9. The use of a compound of any of claims 1-4 in the preparation of a medicament for use in treating or preventing a Pneumoviridae infection.

10. A pharmaceutical composition comprising a compound as in any of claims 1-4 and a pharmaceutically acceptable excipient.

11. A method for treating or preventing a Lentiviridae infection, comprising administering an effective amount of a compound of Formula (A) to a subject in need thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is H, deuterium, CN; R2is H, deuterium, F; R2’ is OH, F, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, anN,N-disubstituted D-amino acid , an optionally substituted-O-C(O)-R’, an optionallysubstituted -O-C(O)SR', anoptionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’, provided that when R2is F, R2’is not OH, R’ is PEG, aryl, heteroaryl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, or C3-7 cycloalkyl, wherein optional substituents are selected from the group consisting of halo, C 1 - 12haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido, carboxyl derivatives, alkylamino, di-C 1 -12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine,sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R11 and R11’ are, independently, H, deuterium, C1-20 alkyl, C1-20 alkene, C1-20 alkyne,the carbon chain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl;or R 11 and R11’ are independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl,-CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R11’and the NR12form a 2- pyrrolidinyl ring, wherein R11or R12’and the 2-pyrrolidinyl ring are optionally substituted withone or more, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy,amino, amido, carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, , sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R12 and R12’ are, independently, H, C1-20 alkyl, C1-20 alkene, C1-20 alkyne;R3is H;R3’ is OH, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, an optionally substituted -O-C(O)-R’, anoptionally substituted -O-C(O)O-R’, an substituted -O-C(O)SR', an optionallysubstituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’; R4 is H, deuterium, F, C1-5alkyl, C1-5alkene, C1-5alkyne, N3, CH2-halogen;R5is and R5’are, independently, H, deuterium, CH3, CH2F, CHF2, or CF3, wherein,when R5is Me, the carbon to which it is attached may be wholly or partially R or S or anymixture thereof, or R5and R5’can combine to form a C3-7cycloalkyl ring; R6is H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acidester, an N-substituted D-amino acid , an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-aminoester, (acyloxybenzyl)ether, optionally substituted bis-acyloxybenzyl)ester, optionally substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)SR', an optionally substituted -C(S)SR’, PEG ester, PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a lipid ester, a lipid carbonate (in which a lipid is an optionally substituted C12-22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22 alkoxy), O-P(O)R8R8’, or a mono-, di-, or triphosphate, wherein,when chirality exists at the phosphorous center, it may be wholly or partially Rpor Spor anymixture thereof; R8and R8’are independently selected from the group consisting of:(a) OR15where R15selected from the group consisting of H ,, Li, Na, K, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted optionally substituted -C(NR’)OR’, optionally substituted -C(NR’)SR’,optionally substituted -C(NR’)N(R’)2, optionally substituted -C(O)N(R’)2, C1-4(alkyl)aryl, benzyl, C1-6 haloalkyl, C2-3(alkyl)OC1-20alkyl, C2-3(alkyl)OC2-20alkene, C2-3(alkyl)OC2-20alkyne, CH2-O-C(O)C1-20alkyl, CH2-O-C(O)C2-20alkene, CH2-O-C(O)C2-20alkyne, CH2-O- C(O)-O-C1-20alkyl, CH2-O-C(O)-O-C2-20alkene, CH2-O-C(O)-O-C2-20alkyne, aryl, andheteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionally substitutedwith zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16and (CH2)0-6 CON(R16)2;where R16is independently H, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, the carbon chain derived from a fatty alcohol or C1-20alkyl substituted with a C1-6alkyl, C1-6alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, C1-5alkene,C1-5alkyne, C3-7 cycloalkyl or C1-5alkyl substituted with a C1-6 alkyl, alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; andR17 R17A (b) the ester of a D- or L-amino , wherein R17Ais H or C1-2alkyl;R 17 and R18 are, independently, H, C1-20C1-20 alkyne, the carbon chainderived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl,or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl,or cycloalkyl; orR17is independently selected from H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; Base is selected from the group consisting of:C-(C2-6)alkynyl, C-(C3-7)cycloalkyl, C-(C1-6) haloalkyl, C-(C1-6)hydroxyalkyl, C-OR9’, C- NR10R10’, C-halo, C-CN, -C-C(O)-NR10R10’or N; X2and X2’are independently H, deuterium, halo, -(C1-3)alkyl, -(C1-3)fluoroalkyl, OR9’or NR10R10’; R9’is H, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3-7)cycloalkyl, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, an (acyloxybenzyl)ester, an (acyloxybenzyl)ether, an optionally substituted bis- acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12-alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a PEG ester, a PEGcarbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O- C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid ester, or a lipid carbonate, wherein a lipid is an optionally substituted C12-22alkyl, an optionally substituted C12-22alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22 alkoxy); R10and R10’are independently H, OH, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3-7)cycloalkyl, an L-amino acid amide, a D-amino acid amide, (acyloxybenzyl)amide, (acyloxybenzyl)amine, optionally substituted (acyloxybenzyl)esters, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, PEG amide, PEG carbamate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid amide, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, or a lipid carbamate, wherein a lipid is an optionally substituted C12-22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22alkynyl or an optionally substituted C12-22alkoxy), with the proviso that R10and R10’cannot both be OH.

12. A method for treating or preventing a Lentiviral infection as in claim 11 comprising administering a treatment or preventative amount of a compound of Formula (B) to a patient in need of treatment or prevention thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3, R4, R5and R5’are as defined in Formula A;A is O or S; and D is selected from the group consisting of: (a) OR15where R15is selected from the group consisting of H, substituted orunsubstituted CH2-O-C(O)C1-20alkyl, substituted or unsubstituted CH2-O-C(O)C2-20alkene, substituted or unsubstituted CH2-O-C(O)C2-20alkyne, substituted or unsubstituted CH2-O-C(O)- O-C1-20alkyl, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkene, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkyne, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, substituted or unsubstituted C3-6cycloalkyl, C1-4(alkyl)aryl, benzyl, C1-6haloalkyl, C2-3(alkyl)OC1-20alkyl,aryl, and heteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionallysubstituted with zero to three substituents independently selected from the group consisting of(CH2)0-6CO2R16and (CH2)0-6 CON(R16)2;R17 R17A O N (b) the ester of a D- or L-amino acid, H OR18, R 17 and R18 are independentlyH, C1-20 alkyl, the carbon chain from a natural amino acid or an unnatural amino acid, thecarbon chain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein thesubstituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl;or R17is H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid,amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; and where R30is selected from the group consisting of substituted or unsubstituted C3-6 cycloalkyl, substitutedor or unsubstituted (C2-10)alkyne, C1-4(alkyl)aryl, aryl, heteroaryl, and C1-6 haloalkyl.

13. A method for treating or preventing a Lentiviridae infection as in claim 11 comprising administering a treatment or preventative amount of a compound of Formula (C) to a patient in need of treatment or prevention thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3and R3’are as defined in Formula A, R4’ is selected from the group consisting of H , deuterium, CN, substituted orunsubstituted (C1-8)alkyl, substituted or unsubstituted (C2-8)alkenyl, substituted or unsubstituted (C2-8)alkynyl, substituted or unsubstituted (C1-8) haloalkyl,R6’ is selected from the group consisting of - P(O)R8R8’, or a mono-, di-, ortriphosphate, wherein, when chirality exists at the phosphorous center, it may be wholly orpartially Rpor Spor any mixture thereof,R8and R8’are as defined in Formula A, 14. The method of claim 11-13, wherein the compound is one of the following compounds:(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrothiophene- 3,4-diol ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl)methyl isobutyrate, (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isobutyryloxy)methyl)tetrahydrothio phene-3,4-diyl bis(2-methylpropanoate), ((R)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl) methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro thiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-7-hydroxy-2-isopropoxytetrahydro-4H- thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxide isopropyl ((4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-7-hydroxy-2-oxidotetrahydro- 4H-thieno[3,2-d][1,3,2]dioxaphosphinin-2-yl)alaninate (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-2-(2-(tert-butyldisulfaneyl)phenethoxy)- 7-hydroxytetrahydro-4H-thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxide (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrothiophene-2-carbonitrile, ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl isobutyrate (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((isobutyryloxy)methyl)tetrahydrothiophene-3,4-diyl bis(2-methylpropanoate), ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl L-valinate, isopropyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, isopropyl ((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide,4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(fluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-methylpyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide; or a pharmaceutically acceptable salt or prodrug thereof.

15. The method of any of claims 11-14, wherein the compounds can be present in the β-D or β- L configuration.

16. The method of any of claims 11-14, wherein Lentiviridae virus is HIV.

17. The method of any of claims 11-14, wherein the compound is co-administered with one or more additional active compounds.

18. The method of claim 17, wherein the additional active agents are abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, zidovudine, doravirine, efavirenz, etravirine, nevirapine, rilpivirine, atazanavir, darunavir, fosamprenavir, ritonavir, tipranavir, fusion inhibitor, enfuvirtide, maraviroc, lenacapavir, attachment inhibitor, fostemsavir, ibalizumab- uiyk, cabotegravir, dolutegravir, raltegravir, or combinations thereof.

19. The use of a compound of any of claims 11-14 in the preparation of a medicament for use in treating or preventing a Lentiviral infection.

20. A method for treating or preventing a Coronaviridae infection, comprising administering an effective amount of a compound of Formula (A) to a subject in need thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is H, deuterium, CN; R2is H, deuterium, F; R2’ is OH, F, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, anN,N-disubstituted D-amino acid , an optionally substituted-O-C(O)-R’, an optionallysubstituted -O-C(O)SR', an optionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’, provided that when R2is F, R2’is not OH, R’ is PEG, aryl, heteroaryl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, or C3-7 cycloalkyl, wherein optional substituents are selected from the group consisting of halo, C 1 - 12haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido, carboxyl derivatives, alkylamino, di-C 1 -12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine,sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R11 and R11’ are, independently, H, deuterium, C1-20 alkyl, C1-20 alkene, C1-20 alkyne,the carbon chain derived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl,cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, or cycloalkyl; or R 11 and R11’ are independently H, CH3, hydrogen, methyl, isopropyl, sec-butyl,-CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R11’and the NR12form a 2- pyrrolidinyl ring, wherein R11or R12’and the 2-pyrrolidinyl ring are optionally substituted withone or more, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy,amino, amido, carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, , sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; R12 and R12’ are, independently, H, C1-20 alkyl, C1-20 alkene, C1-20 alkyne;R3is H; R3’ is OH, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid an optionally substituted -O-C(O)-R’, anoptionally substituted -O-C(O)substituted -O-C(O)SR', an optionally substituted -O-C(S)SR’, an optionally substituted -O-CH2-O-C(O)-R’, an optionally substituted -O-CH2-O-C(O)O-R’, an optionally substituted –O-CH2-CH2-S-C(O)-R’; R4 is H, deuterium, F, C1-5alkyl, C1-5alkene, C1-5alkyne, N3, CH2-halogen;R5is and R5’are, independently, H, deuterium, CH3, CH2F, CHF2, or CF3, wherein,when R5is Me, the carbon to which it is attached may be wholly or partially R or S or anymixture thereof, or R5and R5’can combine to form a C3-7cycloalkyl ring;R6is H, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acidester, an N-substituted D-amino acid , an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino ester, (acyloxybenzyl)ether,optionally substituted bis-acyloxybenzyl)ester, substituted (acyloxybenzyl)ester, an optionally substituted -C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)SR', an optionally substituted -C(S)SR’, PEG ester, PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a lipid ester, a lipid carbonate (in which a lipid is an optionally substituted C12- 22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22alkoxy), O-P(O)R8R8’, or a mono-, di-, or triphosphate, wherein,when chirality exists at the phosphorous center, it may be wholly or partially Rpor Spor anymixture thereof; R8and R8’are independently selected from the group consisting of:(a) OR15where R15selected from the group consisting of ,, Li, Na, K, substituted or unsubstituted C1-20alkyl, substituted or unsubstitutedoptionally substituted -C(NR’)OR’, optionally substituted -C(NR’)SR’, optionally substituted -C(NR’)N(R’)2, optionally substituted -C(O)N(R’)2, C1-4(alkyl)aryl, benzyl, C1-6haloalkyl, C2-3(alkyl)OC1-20alkyl, C2-3(alkyl)OC2-20alkene, C2-3(alkyl)OC2-20alkyne, CH2-O-C(O)C1-20alkyl, CH2-O-C(O)C2-20alkene, CH2-O-C(O)C2-20alkyne, CH2-O- C(O)-O-C1-20alkyl, CH2-O-C(O)-O-C2-20alkene, CH2-O-C(O)-O-C2-20alkyne, aryl, andheteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionally substitutedwith zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16and (CH2)0-6CON(R16)2;where R16is independently H, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, the carbon chain derived from a fatty alcohol or C1-20alkyl substituted with a C1-6alkyl, C1-6alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl, C1-5alkene,C1-5alkyne, C3-7 cycloalkyl or C1-5alkyl substituted with a C1-6 alkyl, alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; andR17 R17A O N (b) the ester of a D- or L-amino acid H OR18, wherein R17Ais H or C1-2alkyl;R 17 and R18 are, independently, H, C1-20 alkyl, C1-20 alkene, C1-20 alkyne, the carbon chainderived from a fatty alcohol or C1-20alkyl optionally substituted with a C1-6 alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5alkyl,or C1-5alkyl substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl,or cycloalkyl; or R17is independently selected from H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; Base is selected from the group consisting of:yl, C-(C2-6)alkynyl, C-(C3-7)cycloalkyl, C-(C1-6) haloalkyl, C-(C1-6)hydroxyalkyl, C-OR , C- NR10R10’, C-halo, C-CN, -C-C(O)-NR10R10’or N; X2and X2’are independently H, deuterium, halo, -(C1-3)alkyl, -(C1-3)fluoroalkyl, OR9’or NR10R10’; R9’is H, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3-7)cycloalkyl, an L-amino acid ester, a D-amino acid ester, an N-substituted L-amino acid ester, an N-substituted D-amino acid ester, an N,N-disubstituted L-amino acid ester, an N,N-disubstituted D-amino acid ester, an (acyloxybenzyl)ester, an (acyloxybenzyl)ether, an optionally substituted bis- acyloxybenzyl)ester, an optionally substituted (acyloxybenzyl)ester, an optionally substituted - C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12-alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, a PEG ester, a PEG carbonate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O- C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid ester, or a lipid carbonate, wherein a lipid is an optionally substituted C12-22 alkyl, an optionally substituted C12-22 alkenyl, an optionally substituted C12-22alkynyl or an optionally substituted C12-22alkoxy); R10and R10’are independently H, OH, -(C1-6)alkyl, -(C2-6)alkenyl, -(C2-6)alkynyl, -(C3- 7)cycloalkyl, an L-amino acid amide, a D-amino acid amide, (acyloxybenzyl)amide, (acyloxybenzyl)amine, optionally substituted (acyloxybenzyl)esters, an optionally substituted - C(O)-R’, an optionally substituted -C(O)O-R’, an optionally substituted -C(O)S-R’, an optionally substituted -C(S)S-R’, an optionally substituted C1-12 alkyl, an optionally substituted C2-12alkenyl, an optionally substituted C2-12alkynyl, an optionally substituted C3-6cycloalkyl, PEG amide, PEG carbamate, an optionally substituted -CH2-O-C(O)-R’, an optionally substituted -CH2-O-C(O)O-R’, an optionally substituted -CH2-CH2-S-C(O)-R’, a lipid amide,an optionally substituted -C(NR’)OR’, an optionally substituted -C(NR’)SR’, an optionally substituted -C(NR’)N(R’)2, an optionally substituted –O-C(O)N(R’)2, or a lipid carbamate, wherein a lipid is an optionally substituted C12-22alkyl, an optionally substituted C12-22alkenyl, an optionally substituted C12-22 alkynyl or an optionally substituted C12-22 alkoxy), with the proviso that R10and R10’cannot both be OH.

21. A method for treating or preventing a Coronaviridae infection as in claim 20 comprising administering a treatment or preventative amount of a compound of Formula (B) to a patient in need of treatment or prevention thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3, R4, R5and R5’are as defined in Formula A; A is O or S; and D is selected from the group consisting of: (a) OR15where R15is selected from the group consisting of H, substituted orunsubstituted CH2-O-C(O)C1-20alkyl, substituted or unsubstituted CH2-O-C(O)C2-20alkene, substituted or unsubstituted CH2-O-C(O)C2-20alkyne, substituted or unsubstituted CH2-O-C(O)- O-C1-20alkyl, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkene, substituted or unsubstituted CH2-O-C(O)-O-C2-20alkyne, substituted or unsubstituted C1-20alkyl, substituted or unsubstituted C1-20alkene, substituted or unsubstituted C1-20alkyne, substituted or unsubstituted C3-6cycloalkyl, C1-4(alkyl)aryl, benzyl, C1-6haloalkyl, C2-3(alkyl)OC1-20alkyl,aryl, and heteroaryl, such as phenyl and pyridinyl, wherein aryl and heteroaryl are optionallysubstituted with zero to three substituents independently selected from the group consisting of (CH2)0-6CO2R16and (CH2)0-6CON(R16)2;R17 R17A O N (b) the ester of a D- or L-amino acid, H OR18, wherein R17Ais H or C1-2alkyl;R 17 and R18 are independently H, C1-20 alkyl, the carbon chain from a natural amino acid oran unnatural amino acid, the carbon chain derived from a fatty alcohol or C1-20 alkyloptionally substituted with a C1-6alkyl, alkoxy, di(C1-6alkyl)- amino, fluoro, C3-10cycloalkyl, cycloalkyl-C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substitutedheteroaryl; wherein the substituents are C1-5alkyl, or C1-5alkyl substituted with a C1-6alkyl,alkoxy, di(C1-6alkyl)-amino, fluoro, C3-10cycloalkyl, or cycloalkyl; or R17is H, CH3, hydrogen, methyl, isopropyl, sec-butyl, -CH2CH(CH3)2, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2-3-indoyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2SCH3, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, or -CH2-3-imidazoyl, or R17and the NH form a 2- pyrrolidinyl ring, wherein R17and the 2-pyrrolidinyl ring are optionally substituted with one ormore, the same or different halo, C 1 - 12 haloalkyl, C1-16 alkyl, C2-16 alkenyl, C2-16 alkynyl, C3-7 cycloalkyl, hydroxyl, carboxyl, C 1 - 12 acyl, aryl, heteroaryl, C 1 - 6 acyloxy, amino, amido,carboxyl derivatives, alkylamino, di-C 1 - 12 - alkylamino, arylamino, C 1 - 12 alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, phosphonyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, boronic acid and boronic ester; and where R30is selected from the group consisting ofsubstituted or unsubstituted C3-6cycloalkyl, substituted or unsubstituted (C2-10)alkene, substituted or unsubstituted (C2-10)alkyne, C1-4(alkyl)aryl, aryl, heteroaryl, and C1-6 haloalkyl.

22. A method for treating or preventing a Coronaviridae infection as in claim 20 comprising administering a treatment or preventative amount of a compound of Formula (C) to a patient in need of treatment or prevention thereof:or a pharmaceutically acceptable salt or prodrug thereof, wherein: Base, R1, R2, R2’, R3and R3’are as defined in Formula A, R4’ is selected from the group consisting of H , deuterium, CN, substituted orunsubstituted (C1-8)alkyl, substituted or unsubstituted (C2-8)alkenyl, substituted orunsubstituted (C2-8)alkynyl, substituted or unsubstituted (C1-8) haloalkyl,R6’ is selected from the group consisting of - P(O)R8R8’, or a mono-, di-, ortriphosphate, wherein, when chirality exists at the phosphorous center, it may be wholly orpartially Rpor Spor any mixture thereof,R8as defined in Formula A, 23. The method of claims 20-22, wherein the compound is one of the following compounds: (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrothiophene- 3,4-diol ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl)methyl isobutyrate, (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((isobutyryloxy)methyl)tetrahydrothio phene-3,4-diyl bis(2-methylpropanoate), ((R)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrothiophen-2- yl) methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro thiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-7-hydroxy-2-isopropoxytetrahydro-4H- thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxideisopropyl ((4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-7-hydroxy-2-oxidotetrahydro- 4H-thieno[3,2-d][1,3,2]dioxaphosphinin-2-yl)alaninate (4aR,6R,7R,7aS)-6-(6-amino-9H-purin-9-yl)-2-(2-(tert-butyldisulfaneyl)phenethoxy)- 7-hydroxytetrahydro-4H-thieno[3,2-d][1,3,2]dioxaphosphinine 2-oxide (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrothiophene-2-carbonitrile, ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl isobutyrate (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- ((isobutyryloxy)methyl)tetrahydrothiophene-3,4-diyl bis(2-methylpropanoate), ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrothiophen-2-yl)methyl L-valinate, isopropyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, isopropyl ((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(fluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-methylpyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, 4-amino-7-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrothiophen-2- yl)-2-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide; or a pharmaceutically acceptable salt or prodrug thereof.

24. The method of any of claims 20-23, wherein the compounds can be present in the β-D or β-L configuration.

25. The method of any of claims 20-23, wherein Coronaviridae virus is severe acute respiratory syndrome associated coronavirus (SARS-CoV-1) and SARS-CoV-2 (also referredto as COVID-19) MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, or HCoV-HKU1, an endemic human coronavirus, epidemic coronavirus, or pandemic coronavirus.

26. The method of any of claims 20-23, wherein the subject is more than 55, 65, or 75 years old or diagnosed with a severe acute infection requiring intensive care.

27. The method of any of claims 20-23, wherein the subject is newborn, infant, or child less than 1 year old.

28. The method of any of claims 20-23, wherein the subject is an infant or a child.

29. The method of any of claims 20-23, wherein the compound is co-administered with one or more additional active compounds.

30. The method of claims 20-23, wherein the additional active agents are remdesivir, chloroquine, hydroxychloroquine, azithromycin, ivermectin, lopinavir, ritonavir, nitazoxanide, molnupiravir, nirmatrelvir and ritonavir, or combinations thereof.

31. The use of a compound of any of claims 20-23 in the preparation of a medicament for use in treating or preventing a coronaviral infection.

Images