Purine nucleotide and nucleoside therapeutic compositions and uses related thereto

Abstract

Disclosed are purine nucleotide and nucleoside therapeutic compositions therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include enterovirus, tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.

Description

[0001] PURINE NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 643,715, filed May 7, 2024, the disclosure of which is incorporated herein by reference. STATEMENT ACKNOWLEDGING GOVERNMENT SUPPORT This invention was made with government support under Contract No. MCDC2005- 005 awarded by the Department of Defense and Grant No. U19AI1711403 awarded by the National Institutes of Health. The government has certain rights in the invention. Field This disclosure relates to purine nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections, for example, respiratory viruses, enteroviruses, tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections, and conditions caused by these viruses. Background New antiviral agents to treat or prevent a variety of viral infections are urgently needed. For example, the causative agents for Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively) and Chikungunya fever (CHIK) are vector- borne viruses (family Togaviridae, genus Alphavirus) that can be transmitted to humans through mosquito bites. The equine encephalitis viruses are CDC Category B pathogens, and the CHIK virus is Category C. There is considerable concern about the use of virulent strains of VEE virus, delivered via aerosol, as a bioweapon against warfighters. Animal studies have demonstrated that infection with VEE virus by aerosol exposure rapidly leads to a massive infection of the brain, with high mortality and morbidity. See Roy et al., Pathogenesis of aerosolized Eastern equine encephalitis virus infection in guinea pigs. Virol J, 2009, 6:170. What are needed are new compounds and treatments for viral infections. The compounds and methods disclosed herein addressed these needs. References cited herein are not an admission of prior art. Summary This disclosure relates to purine nucleotide and nucleoside therapeutic compositions and uses related thereto. Included are nucleosides optionally conjugated to a phosphorus oxide or salts thereof, prodrugs or conjugate compounds or salts thereof comprising an amino acid ester, lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, the disclosure relates to a compound having a structure represented by a formula: , Formula I or a pharmaceutically acceptable salt, derivative, or prodrug thereof, as defined herein; with the proviso that a compound having a structure represented by a formula is excluded therefrom: ,

[0002] . In Formula I, the various substituent groups are understood to have the meaning as further disclosed herein below. In certain embodiments, the disclosure contemplates derivatives of compounds disclosed herein, such as those containing one or more, the same or different, substituents. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein. In certain embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, or aqueous buffer, such as a saline or phosphate buffer. In certain embodiments, the disclosed pharmaceutical compositions can comprise a compound disclosed herein and a propellant. In certain embodiments, the propellant is an aerosolizing propellant such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFAs), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoropropane or combinations thereof. In certain embodiments, the disclosure contemplates a pressurized or unpressurized container comprising a compound or pharmaceutical composition as described herein. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer. In certain embodiments, the disclosure relates to methods of increasing bioavailability for treating or preventing a viral infection comprising administering an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection comprising administering an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. In certain embodiments, the viral infection is tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Zika virus infection, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, and RSV. In certain embodiments, the compound or pharmaceutical composition is administered orally, intravenously, or through the lungs, i.e., pulmonary administration. In certain embodiments, the disclosure relates to the use of a compound as described herein in the production of a medicament for the treatment or prevention of a viral infection, such as Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, or Zika virus infection. In certain embodiments, the disclosure relates to methods of making compounds disclosed herein by mixing starting materials and reagents disclosed herein under conditions such that the compounds are formed. Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Brief Description of the Figures FIG.1 shows representative disclosed compounds and activity in various viral assays carried out as described herein below. FIG.2 shows representative activity of EIDD-3525 versus a reference compound, EIDD-2749, in various viral assays carried out as described herein below in which time of addition of the test compound was assessed for activity. FIG.3 shows representative stability data for EIDD-3525 determined using simulated gastric fluid at the pH values and for the times as indicated in the figures and the assay was carried out as described herein below. FIG.4 shows representative stability data for EIDD-3525 determined using mouse plasma at the pH values and for the times as indicated in the figures and the assay was carried out as described herein below. FIG.5 shows representative stability data for EIDD-3525 determined using mouse liver microsomes at the pH values and for the times as indicated in the figures and the assay was carried out as described herein below. FIG.6 shows representative disclosed compounds and activity in various viral assays carried out as described herein below. FIG.7 shows representative disclosed compounds and activity in various viral assays carried out as described herein below. FIG.8 shows representative disclosed compounds and activity in various viral assays carried out as described herein below. FIG.9 shows representative pharmacokinetic data for EIDD-3525 at the dose levels shown in the figure. FIGs.10A-10B show representative tissue distribution data for EIDD-3525 (see FIG. 10A) and EIDD-3667 (see FIG.10B) at the dose levels shown in the figure. FIGs.11A-11E show representative intracellular concentration data of EIDD-3525 after incubation. Data are shown intracellular concentration obtained after incubation with Huh7 cells (FIG.11A); Vero cells (FIG.11B); MDCK cells (FIG.11C); HPBTE cells (FIG. 11D); and in the washout phase of Huh7 cells (FIG.11E). Detailed Description Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features, which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. This disclosure relates to 4’-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to nucleosides optionally conjugated to a phosphorus oxide or salts thereof. In certain embodiments, the disclosure relates to conjugate compounds or salts thereof comprising an amino acid ester, a lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer. In certain embodiments, the disclosure relates to phosphorus oxide prodrugs of 4’- halogen containing nucleosides for the treatment of positive-sense and negative-sense RNA viral infections through targeting of the virally encoded RNA-dependent RNA polymerase (RdRp). This disclosure also provides the general use of lipids and sphingolipids to deliver nucleoside analogs for the treatment of infectious disease and cancer. In certain embodiments, the disclosure relates to conjugate compounds or salts thereof comprising a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, the phosphorus oxide is a phosphate, phosphonate, polyphosphate, or polyphosphonate, wherein the phosphate, phosphonate or a phosphate in the polyphosphate or polyphosphonate is optionally a phosphorothioate or phosphoramidate. In certain embodiments, the lipid or sphingolipid is covalently bonded to the phosphorus oxide through an amino group or a hydroxyl group. The nucleotide or nucleoside comprises a heterocycle comprising two or more nitrogen heteroatoms, wherein the substituted heterocycle is optionally substituted with one or more, the same or different alkyl, halogen, or cycloalkyl. In certain embodiments, the sphingolipid is saturated or unsaturated 2-aminoalkyl or 2-aminooctadecane optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3-ol optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is saturated or unsaturated 2-aminooctadecane-3,5-diol optionally substituted with one or more substituents. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising any of the compounds disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline buffer comprising a saccharide. In certain embodiments, the composition may contain a second active agent such as a pain reliever, anti-inflammatory agent, non-steroidal anti-inflammatory agent, anti-viral agent, anti-biotic, or anti-cancer agent. In certain embodiments, the disclosure relates to methods of treating or preventing an infection comprising administering an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. Typically, the subject is diagnosed with or at risk of an infection from a virus, bacteria, fungi, protozoa, or parasite. In certain embodiments, the disclosure relates the methods of treating a viral infection comprising administering an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. In certain embodiments, the subject is a mammal, for example, a human. In certain embodiments, the subject is diagnosed with a chronic viral infection. In certain embodiments, administration is under conditions such that the viral infection is no longer detected. In certain embodiments, the subject is diagnosed with a RNA virus, DNA virus, or retroviruses. In certain embodiments, the subject is diagnosed with a virus that is a double stranded DNA virus, sense single stranded DNA virus, double stranded RNA virus, sense single stranded RNA virus, antisense single stranded RNA virus, sense single stranded RNA retrovirus or a double stranded DNA retrovirus. In certain embodiments, the subject is diagnosed with influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, coxsackie B virus, Coxsackie virus A1-A16 subtypes (and in certain embodiments, A2-8, A10, A11, A12, A14, and A16 subtypes), norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), chikungunya, Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), Ross River virus, Barmah Forest virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, Ebola virus, marburg virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis D, hepatitis E or human immunodeficiency virus (HIV). In certain embodiments, the subject is diagnosed with influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path), and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, coxsackie B virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), measles virus, mumps virus, respiratory syncytial virus, parainfluenza viruses 1 and 3, rinderpest virus, chikungunya, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), California encephalitis virus, Rift Valley fever virus (RVFV), heartland virus, La Crosse virus, Marpol virus, Severe fever thrombocytopenia syndrome virus, Pichinde virus, hantavirus, Tacaribe virus, Junin, rabies virus, Ebola virus, Marburg virus, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis D, hepatitis E or human immunodeficiency virus (HIV). As used herein, a “low pathogenicity” virus, e.g., “low pathogenicity influenza” or “low pathogencity H5N1”, refers to a virus strain that results in mild or asymptomatic infections. As used herein, a “high pathogenicity” virus, e.g., “high pathogenicity influenza” or “high pathogencity H5N1”, refers to a virus strain that results in up to 50% morbidity and mortality, up to 60% morbidity and mortality, up to 70% morbidity and mortality, up to 80% morbidity and mortality, up to 90% morbidity and mortality, or up to 100% morbidity and mortality. In certain embodiment, the disclosure relates to uses of compounds disclosed herein in the production or manufacture of a medicament for the treatment or prevention of an infectious disease, viral infection, or cancer. In certain embodiments, the disclosure relates to derivatives of compounds disclosed herein or any of the formula. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. In certain embodiments, a pharmaceutical agent, which may be in the form of a salt or prodrug, is administered in methods disclosed herein that is specified by a weight. This refers to the weight of the recited compound. If in the form of a salt or prodrug, then the weight is the molar equivalent of the corresponding salt or prodrug. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent. Definitions Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated. As used herein, the term “deuterium” or “D” refers to the isotopic abundance of D relative to H (hydrogen) is at least 50%, at least 75%, or at least 90%. As used herein, the term “phosphorus oxide” refers to any variety of chemical moieties that contain a phosphorus-oxygen (P-O or P=O) bond. When used as linking groups herein, the joined molecules may bond to oxygen or directly to the phosphorus atoms. The term is intended to include, but are not limited to phosphates, in which the phosphorus is typically bonded to four oxygens and phosphonates, in which the phosphorus is typically bonded to one carbon and three oxygens. A “polyphosphate” generally refers to phosphates linked together by at least one phosphorus-oxygen-phosphorus (P-O-P) bond. A “polyphosphonate” refers to a polyphosphate that contains at least one phosphorus-carbon (C-P-O-P) bond. In addition to containing phosphorus-oxygen bond, phosphorus oxides may contain a phosphorus-thiol (P-S or P=S) bond and / or a phosphorus-amine (P-N) bond, respectively referred to as phosphorothioate or phosphoramidate. In phosphorus oxides, the oxygen atom may form a double or single bond to the phosphorus or combinations, and the oxygen may further bond with other atoms such as carbon or may exist as an anion which is counter balanced with a cation, e.g., metal or quaternary amine. The term “subject” (alternatively “patient” or “participant”, as in a clinical trial participant) as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g., pigs), ovine (e.g., sheep), capra (e.g., goats), equine (e.g., horses), canine (e.g., domestic dogs), feline (e.g., house cats), Lagomorpha (rabbits), rodents (e.g., rats or mice), Procyon lotor (e.g., raccoons). In particular embodiments, the subject is human. The term “subject in need thereof” (alternatively “patient in need thereof”) as used herein refers to a subject diagnosed with, or suspected of having, a viral infection, such as infection by SARS-CoV-2 (either symptomatic or asymptomatic); a subject at risk of being exposed to a viral infection, such as at risk of being exposed to a viral infection, such as infection by SARS-CoV-2 (such as, for example, health care workers who may be at risk of exposure to SARS-CoV-2); a subject exposed to a viral infection, such as infection by SARS- CoV-2 (such as household contacts of COVID-19 patients or asymptomatic patients infected with SARS-CoV-2), as defined herein. 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. As used herein, the term "combination with" when used to describe administration with an additional treatment means that the agent can be administered prior to, together with, or after the additional treatment, or a combination thereof. As used herein, "alkyl" means a straight or branched chain saturated hydrocarbon moieties such as those containing from 1 to 24 carbon atoms. A “higher alkyl” refers to saturated hydrocarbon having 24 or more carbon atoms. A “C6-C16” refers to an alkyl containing 6 to 16 carbon atoms. Likewise a “C6-C22” refers to an alkyl containing 6 to 22 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1alkyl, C1-C2alkyl, C1-C3alkyl, C1-C4alkyl, C1- C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24alkyl. As used herein, the term “alkenyl” refers to unsaturated, straight or branched hydrocarbon moieties containing a double bond. Unless otherwise specified, C2-C24(e.g., C2- C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4) alkenyl groups are intended. Alkenyl groups may contain more than one unsaturated bond. Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl- 1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1- butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2- methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1- pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2- pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3- pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4- pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2- dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1- butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3- dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1- butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl- 2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl. The term “vinyl” refers to a group having the structure –CH=CH2; 1-propenyl refers to a group with the structure–CH=CH-CH3; and 2- propenyl refers to a group with the structure –CH2-CH=CH2. Asymmetric structures such as (Z1Z2)C=C(Z3Z4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. As used herein, the term “alkynyl” represents straight or branched hydrocarbon moieties containing a triple bond. Unless otherwise specified, C2-C24(e.g., C2-C24, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4) alkynyl groups are intended. Alkynyl groups may contain more than one unsaturated bond. Examples include C2-C6- alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3- butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1- butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2- propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3- methyl-1-pentynyl, 4-methyl-1-pentynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1- methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3- methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2- ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl. Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" 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" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which can be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can 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 term "aryl" refers to aromatic homocyclic (i.e., hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferably having 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group. The term "substituted aryl" refers to aryl groups substituted with one or more groups, preferably selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl, (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, and, the like, where optionally one or more pair of substituents together with the atoms to which they are bonded form a 3 to 7 member ring. As used herein, "heteroaryl" or “heteroaromatic” refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems can, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1-methylimidazol- 5-yl substituent. As used herein, "heterocycle" or "heterocyclyl" refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems can be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like. "Alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., -S-CH3). "Alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n- butoxy, s-butoxy, t-butoxy. "Alkylamino" refers an alkyl group as defined above with the indicated number of carbon atoms attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH3). "Alkanoyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a carbonyl bride (i.e., -(C=O)alkyl). "Alkylsulfonyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfonyl bridge (i.e., -S(=O)2alkyl) such as mesyl and the like, and "Arylsulfonyl" refers to an aryl attached through a sulfonyl bridge (i.e., - S(=O)2aryl). "Alkylsulfamoyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfamoyl bridge (i.e., -NHS(=O)2alkyl), and an "Arylsulfamoyl" refers to an alkyl attached through a sulfamoyl bridge (i.e., - NHS(=O)2aryl). "Alkylsulfinyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfinyl bridge (i.e., -S(=O)alkyl). The terms "cycloalkyl" and "cycloalkenyl" refer to mono-, bi-, or tri homocyclic ring groups of 3 to 15 carbon atoms which are, respectively, fully saturated and partially unsaturated. The term "cycloalkenyl" includes bi- and tricyclic ring systems that are not aromatic as a whole, but contain aromatic portions (e.g., fluorene, tetrahydronapthalene, dihydroindene, and the like). The rings of multi-ring cycloalkyl groups can be either fused, bridged and / or joined through one or more spiro unions. The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer, respectively, to cycloalkyl and cycloalkenyl groups substituted with one or more groups, preferably selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, and the like. The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine. 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 can be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context can include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=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 can be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl. The term "optionally substituted," as used herein, means that substitution with an additional group is optional and therefore it is possible for the designated atom to be unsubstituted. Thus, by use of the term “optionally substituted” the disclosure includes examples where the group is substituted and examples where it is not. As used herein, "salts" refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. In typical embodiments, the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The term “prodrug” refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound and / or improve efficacy of the parent compound. They may, for instance, be have comparatively improved bioavailable and / or of efficacy by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. In general, a prodrug can confer to the parent drug one improved efficacy, absorption, distribution, metabolic processing, and / or excretion. Prodrugs can improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract, for example. A prodrug can improve how selectively the drug interacts with cells or processes that are not its intended target. This reduces adverse or unintended effects of a drug, especially important in treatments for viral infection, which can have unintended and undesirable side effects. Prodrugs can thus be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate potentially undesirable properties in the parent molecule. The compounds of the present disclosure can be prodrugs as disclosed herein throughout. Examples of prodrugs that can be used to improve properties discussed above of disclosed compounds, e.g., to improve bioavailability, efficacy, and / or targeting, include esters, optionally substituted esters, branched esters, optionally substituted branched esters, carbonates, optionally substituted carbonates, carbamates, optionally substituted carbamates, thioesters, optionally substituted thioesters, branched thioesters, optionally substituted branched thioesters, thiocarbonates, optionally substituted thiocarbonates, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, L-amino acid esters, D-amino acid esters, N-substituted L-amino acid esters, N,N- disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D- amino acid esters, sulfenyl, optionally substituted sulfenyl, imidate, optionally substituted imidate, hydrazonate, optionally substituted hydrazonate, oximyl, optionally substituted oximyl, imidinyl, optionally substituted imidinyl, imidyl, optionally substituted imidyl, aminal, optionally substituted aminal, hemiaminal, optionally susbstituted hemiaminal, acetal, optionally substituted acetal, hemiacetal, optionally susbstituted hemiacetal, carbonimidate, optionally substituted carbonimidate, thiocarbonimidate, optionally substituted thiocarbonimidate, carbonimidyl, optionally substituted carbonimidyl, carbamimidate, optionally substituted carbamimidate, carbamimidyl, optionally substituted carbamimidyl, thioacetal, optionally substituted thioacetal, S-acyl-2-thioethyl, optionally substituted S-acyl-2-thioethyl, bis-(acyloxybenzyl)esters, optionally substituted bis- (acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, 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 with one or more substituents, a salt, in different hydration / oxidation states, e.g., substituting a single or double bond, substituting a hydroxy group for a ketone, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen atom or replacing an amino group with a hydroxyl group or vice versa. Replacing a carbon with nitrogen in an aromatic ring is a contemplated derivative. The derivative may be a prodrug. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in the chemical literature or as in synthetic or organic chemistry text books, 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. Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the disclosure includes all such possible isomers, as well as mixtures of such isomers. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present disclosure includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. It is understood that use of a wedge or hash is only one representation of a stereochemical descriptor. All stereoisomers, including enantiomers and diastereomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio, are included within Formulas to XXXIb and are provided by the present disclosure. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. It is understood that enantiomeric and / or diastereomeric forms exist of a given structure, and that flat bonds indicate that all stereoisomeric forms of the depicted structure may be present. Moreover, where enantiomeric and / or diastereomeric forms exist of a given structure, flat bonds and the presence of a “*” symbol indicate that the composition is made up of at least 60%, at least 70%, at least 80%, or at least 90%, by weight, of a single isomer with unknown stereochemistry. It is further understood that where enantiomeric and / or diastereomeric forms exist of a given structure, wedged or hashed bonds indicate the composition is made up of at least 60%, at least 70%, at least 80%, or at least 90%, by weight, of a single enantiomer or diastereomer with known stereochemistry. As appropriate, combinations of the above notation may be used. Exemplified species may contain stereogenic centers with known stereochemistry and stereogenic centers with unknown stereochemistry, stereochemistry. Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non- superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36Cl, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. The compounds described in the disclosure can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates. Unless stated to the contrary, the disclosure includes all such possible solvates. The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co- crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid. It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the disclosure includes all such possible tautomers. It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the disclosure can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the disclosure includes all such possible polymorphic forms. Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification. Disclosed are the components to be used to prepare the compositions of the disclosure as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C- E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the disclosure. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the disclosure. As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E / Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.). Compounds In certain embodiments, the disclosure relates to nucleosides conjugated to a phosphorus moiety and pharmaceutically acceptable salts thereof. In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5aand R5bis independently selected from hydrogen and C1-C6 alkyl; wherein R6is selected from hydrogen, alkyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and lipid; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C0- C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, (C0-C6 alkanediyl)C3-C12 heteroaryl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, halogen, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, -(C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, C1-C6 alkyl, C1- C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22alkyl, C11-C22alkoxy, and aryl substituted with an C6-C18 alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms. In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5aand R5bis independently selected from hydrogen and C1-C6alkyl; wherein R6is selected from hydrogen, alkyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and lipid; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C0- C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, (C0-C6 alkanediyl)C3-C12 heteroaryl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, halogen, cyano, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, -(C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, C1-C6alkyl, C1- C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12heterocyclyl, and (C0-C6alkanediyl)C3-C12heteroaryl; wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, and (C0-C6alkanediyl)C3-C12heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22 alkyl, C11-C22 alkoxy, and aryl substituted with an C6-C18alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms; and with the proviso that a compound having a structure represented by a formula is excluded therefrom: , , ,

[0003] . In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5aand R5bis independently selected from hydrogen and C1-C6alkyl; wherein R6is selected from hydrogen, alkyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and lipid; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, =S, C1-C6alkyl, C1-C6haloalkyl, (C0- C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, (C0-C6alkanediyl)C3-C12heteroaryl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, and (C0-C6alkanediyl)C3-C12heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, halogen, cyano, hydroxy, -O-C1-C6alkyl, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, - (C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, NR50aR50b, C1- C6alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each occurrence of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0- C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3- C12 heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22 alkyl, C11-C22 alkoxy, and aryl substituted with an C6-C18alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms. In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: , optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, optionally substituted S-thiocarbonate, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyl, optionally substituted oxymethoxythiocarbonyl, optionally substituted oxymethylcarbonyl, optionally substituted oxymethylthiocarbonyl, L-amino acid esters, D-amino acid esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted sulfenyl, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally susbstituted hemiaminal, optionally substituted acetal, optionally susbstituted hemiacetal, optionally substituted carbonimidate, optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, optionally substituted thioacetal, optionally substituted S-acyl-2- thioethyl, optionally substituted bis-(acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and BAB-esters, wherein R1is optionally substituted with one or more, the same or different, R10; wherein Ar1is selected from a 3-12 membered carbocycle, 3-12 membered heterocarbocycle, a 5-12 membered aryl, and a 5-12 heteroaryl; wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5, R5aand R5bis independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R5is optionally substituted with one or more, the same or different, R10; wherein each of R6, R6’, R6’’, and R6’’’is independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, formyl, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid, wherein R6, R6’, R6’’, and R6’’’can each be optionally substituted with one or more, the same or different, R10; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R8is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R8is optionally substituted with one or more, the same or different, R10; wherein R9is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R9is optionally substituted with one or more, the same or different, R10; wherein R7, R7’, R8, and R9can form a ring with the α-carbon they are attached to and the amino group attached to the α-carbon, wherein the ring is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C0- C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, (C0-C6 alkanediyl)C3-C12 heteroaryl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, halogen, cyano, hydroxy, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, - (C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, NR50aR50b, C1- C6alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each occurrence of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0- C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3- C12heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22 alkyl, C11-C22 alkoxy, and aryl substituted with an C6-C18alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms. In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: , , , , wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5aand R5bis independently selected from hydrogen and C1-C6 alkyl; wherein R6is selected from hydrogen, alkyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and lipid; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C0- C6alkanediyl)C5-C8cycloalkyl, C0-C6alkanediyl)C3-C12heterocyclyl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, and (C0-C6alkanediyl)C3-C12heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, -(C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, C1-C6 alkyl, C1- C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22alkyl, C11-C22alkoxy, and aryl substituted with an C6-C18 alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms. In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: , wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5aand R5bis independently selected from hydrogen and C1-C6 alkyl; wherein R6is selected from hydrogen, alkyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, and lipid; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, =S, C1-C6alkyl, C1-C6haloalkyl, (C0- C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, cyano, hydroxy, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, -(C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, NR50aR50b, C1- C6 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each occurrence of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0- C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3- C12 heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22alkyl, C11-C22alkoxy, and aryl substituted with an C6-C18 alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms. In certain embodiments, the disclosure relates to a compound of Formula I, , Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: , optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, optionally substituted S-thiocarbonate, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyl, optionally substituted oxymethoxythiocarbonyl, optionally substituted oxymethylcarbonyl, optionally substituted oxymethylthiocarbonyl, L-amino acid esters, D-amino acid esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted sulfenyl, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally susbstituted hemiaminal, optionally substituted acetal, optionally susbstituted hemiacetal, optionally substituted carbonimidate, optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, optionally substituted thioacetal, optionally substituted S-acyl-2- thioethyl, optionally substituted bis-(acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and BAB-esters, wherein R1is optionally substituted with one or more, the same or different, R10; wherein Ar1is selected from a 3-12 membered carbocycle, 3-12 membered heterocarbocycle, a 5-12 membered aryl, and a 5-12 heteroaryl; wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5, R5aand R5bis independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R5is optionally substituted with one or more, the same or different, R10; wherein each of R6, R6’, R6’’, and R6’’’is independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, formyl, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid, wherein R6, R6’, R6’’, and R6’’’can each be optionally substituted with one or more, the same or different, R10; wherein R6is optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R8is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R8is optionally substituted with one or more, the same or different, R10; wherein R9is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R9is optionally substituted with one or more, the same or different, R10; wherein R7, R7’, R8, and R9can form a ring with the α-carbon they are attached to and the amino group attached to the α-carbon, wherein the ring is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, =O, hydroxyl, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C3-C12heterocyclyl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, cyano, hydroxy, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, -(C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, NR50aR50b, C1- C6alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each occurrence of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0- C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3- C12heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22 alkyl, C11-C22 alkoxy, and aryl substituted with an C6-C18alkyl group; wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms. In certain embodiments, a disclosed formula is with the proviso that a compound having a structure represented by a formula is excluded therefrom: ,

[0004] , , ,

[0005] ,

[0006] In certain embodiments, a disclosed formula is with the proviso that a compound having a structure represented by a formula is excluded therefrom:

[0007] . and In certain embodiments, R1is a group having a structure represented by a formula:

[0008] In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids. In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids. In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and non-essential fatty acids that have one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur. In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids that have one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur. In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids that is optionally substituted. In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids that is optionally substituted. In certain embodiments, the lipid is a fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids that have one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur that is optionally substituted. In certain embodiments, the lipid is an unsaturated, polyunsaturated, omega unsaturated, or omega polyunsaturated fatty alcohol, fatty amine, or fatty thiol derived from essential and / or non-essential fatty acids that have one or more of its carbon units substituted with an oxygen, nitrogen, or sulfur that is also optionally substituted. In certain embodiments, the lipid is hexadecyloxypropyl. In certain embodiments, the lipid is 2-aminohexadecyloxypropyl. In certain embodiments, the lipid is 2-aminoarachidyl. In certain embodiments, the lipid is 2-benzyloxyhexadecyloxypropyl. In certain embodiments, the lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl. In certain embodiments, the lipid is a sphingolipid of the formula: wherein, R12of the sphingolipid is hydrogen, alkyl, C(=O)R16, C(=O)OR16, or C(=O)NHR16; R13of the sphingolipid is hydrogen, fluoro, OR16, OC(=O)R16, OC(=O)OR16, or OC(=O)NHR16; R14of the sphingolipid is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons optionally substituted with one or more halogen or hydroxy or a structure of the following formula: wherein n is 8 to 14 or less than or equal to 8 to less than or equal to 14, o is 9 to 15 or less than or equal to 9 to less than or equal to 15, the total or m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14, the total of m and o is 9 to 15 or less than or equal to 9 to less than or equal to 15; or wherein n is 4 to 10 or less than or equal to 4 to less than or equal to 10, o is 5 to 11 or less than or equal to 5 to less than or equal to 11, the total of m and n is 4 to 10 or less than or equal to 4 to less than or equal to 10, and the total of m and o is 5 to 11 or less than or equal to 5 to less than or equal to 11; or wherein n is 6 to 12 or n is less than or equal to 6 to less than or equal to 12, the total of m and n is 6 to 12 or n is less than or equal to 6 to less than or equal to 12; R15of the sphingolipid is OR16, OC(=O)R16, OC(=O)OR16, or OC(=O)NHR16; R16of the sphingolipid is hydrogen, cyano, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, or lipid; wherein R16is optionally substituted with one or more, the same or different R17; and R17of the sphingolipid is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl. In certain embodiments, R12of the sphingolipid is H, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl,1-propylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or phenyl. In certain embodiments, the sphingolipid is a sphingolipid of the formula: wherein, R12of the sphingolipid is hydrogen, hydroxy, fluoro, OR16, OC(=O)R16, OC(=O)OR16, or OC(=O)NHR16; R13of the sphingolipid is hydrogen, hydroxy, fluoro, OR16, OC(=O)R16, OC(=O)OR16, or OC(=O)NHR16; R14of the sphingolipid is a saturated or unsaturated alkyl chain of greater than 6 and less than 22 carbons optionally substituted with one or more halogens or a structure of the following formula: wherein n is 8 to 14 or less than or equal to 8 to less than or equal to 14, the total or m and n is 8 to 14 or less than or equal to 8 to less than or equal to 14; R16of the sphingolipid is hydrogen, cyano, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, or lipid; wherein R16is optionally substituted with one or more, the same or different R17; and R17of the sphingolipid is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, esteryl, formyl, carboxy, carbamoyl, amido, or acyl. In certain embodiments, R16of the sphingolipid is H, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl,1-propylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl. Suitable sphingolipids include, but are not limited to, sphingosine, ceramide, or sphingomyelin, or 2-aminoalkyl optionally substituted with one or more substituents. Other suitable sphingolipids include, but are not limited to, 2-aminooctadecane-3,5- diol; (2S,3S,5S)-2-aminooctadecane-3,5-diol; (2S,3R,5S)-2-aminooctadecane-3,5-diol; 2- (methylamino)octadecane-3,5-diol; (2S,3R,5S)-2-(methylamino)octadecane-3,5-diol; 2- (dimethylamino)octadecane-3,5-diol; (2R,3S,5S)-2-(dimethylamino)octadecane-3,5-diol; 1- (pyrrolidin-2-yl)hexadecane-1,3-diol; (1S,3S)-1-((S)-pyrrolidin-2-yl)hexadecane-1,3-diol; 2- amino-11,11-difluorooctadecane-3,5-diol; (2S,3S,5S)-2-amino-11,11-difluorooctadecane-3,5- diol; 11,11-difluoro-2-(methylamino)octadecane-3,5-diol; (2S,3S,5S)-11,11-difluoro-2- (methylamino)octadecane-3,5-diol; N-((2S,3S,5S)-3,5-dihydroxyoctadecan-2-yl)acetamide; N-((2S,3S,5S)-3,5-dihydroxyoctadecan-2-yl)palmitamide;1-(1- aminocyclopropyl)hexadecane-1,3-diol; (1S,3R)-1-(1-aminocyclopropyl)hexadecane-1,3- diol; (1S,3S)-1-(1-aminocyclopropyl)hexadecane-1,3-diol; 2-amino-2-methyloctadecane-3,5- diol; (3S,5S)-2-amino-2-methyloctadecane-3,5-diol; (3S,5R)-2-amino-2-methyloctadecane- 3,5-diol; (3S,5S)-2-methyl-2-(methylamino)octadecane-3,5-diol; 2-amino-5-hydroxy-2- methyloctadecan-3-one; (Z)-2-amino-5-hydroxy-2-methyloctadecan-3-one oxime; (2S,3R,5R)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3S,5R)-2-amino-6,6- difluorooctadecane-3,5-diol; (2S,3S,5S)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3R,5S)-2-amino-6,6-difluorooctadecane-3,5-diol; and (2S,3S,5S)-2-amino-18,18,18- trifluorooctadecane-3,5-diol, which can be optionally substituted with one or more substituents. In exemplified embodiments of Formula I, R1is hydrogen, , , a In exemplified embodiments of Formula I, R5is lipid, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t- hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N- dimethylamino, N,N-diethylamino, and N,N-dipropylamino. In exemplified embodiments of Formula I, R6is hydrogen, hydroxyl, fluoro, chloro, amino, lipid, methyl, methoxy, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s- pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N- propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino. In exemplified embodiments of Formula I, R7is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino. In exemplified embodiments of Formula I, R8is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino. In exemplified embodiments of Formula I, R9is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino. In some embodiments, the compound is a compound having a structure represented by a formula: , wherein each of R1, R2a, R2b, and R3are independently hydrogen or a prodrug moiety as disclosed herein, provided that at least one of R1, R2a, R2b, and R3is a prodrug moiety as disclosed herein; and wherein R1and R2a, R1and R2b, R1and R3, R2aand R3, or R2band R3can form a bridging prodrug moiety as disclosed herein. In some embodiments, the compound is a compound having a structure represented by a formula: , wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: , , , , optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, optionally substituted S-thiocarbonate, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyl, optionally substituted oxymethoxythiocarbonyl, optionally substituted oxymethylcarbonyl, optionally substituted oxymethylthiocarbonyl, L-amino acid esters, D-amino acid esters, N-substituted L-amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted sulfenyl, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally susbstituted hemiaminal, optionally substituted acetal, optionally susbstituted hemiacetal, optionally substituted carbonimidate, optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, optionally substituted thioacetal, optionally substituted S-acyl-2- thioethyl, optionally substituted bis-(acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and BAB-esters, wherein R1is optionally substituted with one or more, the same or different, R10; wherein Ar1is selected from a 3-12 membered carbocycle, 3-12 membered heterocarbocycle, a 5-12 membered aryl, and a 5-12 heteroaryl; wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein each of R2y, R2z, and R3yis independently selected from hydrogen, C1-C6alkyl, (C=O)C1-C6alkyl, (C=O)NR40C1-C6alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6alkyl; wherein said alkyl groups are optionally independently substituted with one or more, the same or different, R10; wherein R1and R2zcan together form a 5-7 membered heterocyclic ring; wherein R1and R3ycan together form a 5-7 membered heterocyclic ring; wherein R1and R3ycan together form a 5-7 membered heterocyclic ring; wherein R2yand R2zcan together form a 5-7 membered heterocyclic ring; wherein R2yand R3ycan together form a 5-7 membered heterocyclic ring; wherein R2zand R3ycan together form a 5-7 membered heterocyclic ring; wherein R10is in each case independently deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl; wherein R5is selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R5is optionally substituted with one or more, the same or different, R10; wherein each of R6, R6’, R6’’, and R6’’’is independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, formyl, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid; wherein R6, R6’, R6’’, and R6’’’can each be optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R8is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R8is optionally substituted with one or more, the same or different, R10; wherein R9is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R9is optionally substituted with one or more, the same or different, R10; wherein R7, R7’, R8, and R9can form a ring with the α-carbon they are attached to and the amino group attached to the α-carbon, wherein the ring is optionally substituted with one or more, the same or different, R10; wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is in each case independently deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl; and wherein lipid is independently a C11-C22alkyl, C11-C22alkoxy, or aryl substituted with an C6- C18 alkyl group. In some embodiments, the compound is a compound having a structure represented by a formula:

[0009] pharmaceutically acceptable salt thereof. In exemplary embodiments, the disclosed compound is selected from: , ,

[0010] ,

[0011] , pharmaceutically acceptable salt thereof. In an exemplary embodiment, the disclosure pertains to a compound having a structure represented by formula: pharmaceutically acceptable salt thereof. Infectious Diseases The compounds and pharmaceutical formulations provided herein can be used to treat viral infectious diseases. Disclosed herein are methods of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of Formula I; a compound having a structure represented by formula: pharmaceutically acceptable salt thereof; or a compound having a structure represented by a formula: ,

[0012] , or pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable excipient. Also disclosed herein are methods of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of Formula I; a compound having a structure represented by formula: pharmaceutically acceptable salt thereof; or a compound having a structure represented by a formula:

[0013] ,

[0014] or pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable excipient. Disclosed are uses of a disclosed compound, e.g., one or more compound of Formula I, or a pharmaceutically acceptable salt thereof; an effective amount of a compound of Formula I; a compound having a structure represented by formula: pharmaceutically acceptable salt thereof; or a compound having a structure represented by a formula:

[0015] ,

[0016] , or pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable excipient. in the manufacture of a medicament for the treatment of a viral infectious disease. Also disclosed are uses of a disclosed compound, e.g., one or more compound of Formula I, or a pharmaceutically acceptable salt thereof; a compound having a structure represented by formula: pharmaceutically acceptable salt thereof; or a compound having a structure represented by a formula:

[0017] ,

[0018] , or pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable excipient.in the manufacture of a medicament for the treatment of a viral infectious disease. Disclosed are methods of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I; a compound having a structure represented by formula: pharmaceutically acceptable salt thereof; or a compound having a structure represented by a formula:

[0019] ,

[0020] , or pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable excipient. and a pharmaceutically acceptable excipient; wherein the subject is administered a loading dose of the pharmaceutical composition in a first treatment period; and wherein the subject is administered a treatment dose of the pharmaceutical composition in a second treatment period following the first treatment period. Also disclosed are methods of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of Formula I; an effective amount of a compound of Formula I; a compound having a structure represented by formula: pharmaceutically acceptable salt thereof; or a compound having a structure represented by a formula:

[0021] ,

[0022] , or a pharmaceutically acceptable salt thereof; or combinations thereof; and a pharmaceutically acceptable excipient; wherein the subject is administered a loading dose of the pharmaceutical composition in a first treatment period; and wherein the subject is administered a treatment dose of the pharmaceutical composition in a second treatment period following the first treatment period. In exemplary embodiments, the first treatment period is days 1-5 following diagnosis of the viral infection or presentation for preventing the viral infection; the first treatment period is days 1-2 following diagnosis of the viral infection or presentation for preventing the viral infection; the first treatment period is day 1 following diagnosis of the viral infection or presentation for preventing the viral infection; and other periods as encompassed by the foregoing. In exemplary embodiments, the first treatment period is 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, or 24 hours prior to infection or exposure to a virus, and the second treatment period is a period of treatment following infection comprising 1-7 days of treatment following infection, e.g., for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after initial viral infection. As disclosed elsewhere herein, the dosing following infection may be daily, every other day, and the like. In exemplary embodiments, the loading dose is about 1.1-fold to about 10-fold the treatment dose; the loading dose is about 1.5-fold to about 5-fold the treatment dose; the loading dose is about 1.5-fold to about 2.5-fold the treatment dose; and other loading doses as encompassed by the foregoing. In exemplary embodiments, the loading dose is administered once daily, two times daily, three times daily, or four times daily, or alternatively, every other day, every third day and the like, and other periods of administration as contemplated within the foregoing. In some embodiments, the loading dose is administered at least twice daily. In further embodiments, the loading dose divided equally among the number of times administered daily. The during dosing of a loading dose, as described in the foregoing regarding doses per day, can be repeated and occur for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days. In exemplary embodiments, the treatment is delayed or late following initial diagnosis or presentation of the viral infection, that is, treatment initiates after some number of days after diagnosis or presentation of the viral infection, e.g., at days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, and then continues for a suitable period of time, e.g., for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days after initiation. Examples of viral infections include but are not limited to, infections caused by RNA viruses (including negative stranded RNA viruses, positive stranded RNA viruses, double stranded RNA viruses and retroviruses) or DNA viruses. All strains, types, and subtypes of RNA viruses and DNA viruses are contemplated herein. Examples of RNA viruses include, but are not limited to picornaviruses, which include aphthoviruses (for example, foot and mouth disease virus O, A, C, Asia 1, SAT1, SAT2 and SAT3), cardioviruses (for example, encephalomycarditis virus and Theiller’s murine encephalomyelitis virus), enteroviruses (for example polioviruses 1, 2 and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, human echoviruses 1-7, 9, 11-12, 24, 27, 29-33, human enteroviruses 68-71, porcine enteroviruses 8-10 and simian enteroviruses 1-18), erboviruses (for example, equine rhinitis virus), hepatovirus (for example human hepatitis A virus and simian hepatitis A virus), kobuviruses (for example, bovine kobuvirus and Aichi virus), parechoviruses (for example, human parechovirus 1 and human parechovirus 2), rhinovirus (for example, rhinovirus A, rhinovirus B, rhinovirus C, HRV16, HRV16 (VR-11757), HRV14 (VR-284), or HRV1A (VR-1559), human rhinovirus 1-100 and bovine rhinoviruses 1-3) and teschoviruses (for example, porcine teschovirus). Additional examples of RNA viruses include caliciviruses, which include noroviruses (for example, Norwalk virus), sapoviruses (for example, Sapporo virus), lagoviruses (for example, rabbit hemorrhagic disease virus and European brown hare syndrome) and vesiviruses (for example vesicular exanthema of swine virus and feline calicivirus). Other RNA viruses include astroviruses, which include mamastorviruses and avastroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (for example, Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine encephalitis virus, Eastern Getah virus, Everglades virus, Venezuelan equine encephalitis virus, Ross River virus, Barmah Forest virus and Aura virus) and rubella viruses. Other examples of RNA viruses are the coronaviruses, which include, human respiratory coronaviruses such as SARS-CoV (including SARS-CoV-2 and variants thereof including, but not limited to the more virulent strains that recently appeared in Brasil, known as P.1; the United Kingdom, known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7; and in South Africa; known as 20H / 501Y.V2 or B.1.351; as well as further varients and lineages that derive therefrom), HCoV-229E, HCoV-NL63 and HCoV-OC43. Coronaviruses also include bat SARS-like CoV, Middle East Respiratory Syndrome coronavirus (MERS), turkey coronavirus, chicken coronavirus, feline coronavirus and canine coronavirus. Coronaviruses are enveloped positive-sense RNA viruses that cause a large percentage of respiratory illness in humans. The two previous coronaviruses to emerge and cause human illness were SARS and MERS. There were more than 8,000 human cases of SARS with 774 deaths. Since 2012, there have been more than 2,500 cases of MERS with 919 deaths. In 2019 a new coronavirus, SARS-CoV-2, was discovered in humans in Wuhan, China and presently there is an ongoing pandemic with a large loss of life. SARS-CoV-2 is a highly pathogenic human pathogen. SARS-CoV-2 causes disease referred to as COVID-19. COVID-19 can include severe respiratory disease in humans, endothelial disease including stroke and neurological disease that includes dizziness, impaired consciousness, acute cerebrovascular disease, epilepsy, hyposmia, hypopsia, and neuralgia (medRxiv, 2020, 1-26). SARS-CoV-2 entry into the CNS may be promoted through viral interaction with ACE2 receptors after dissemination of the virus in the systemic circulation or across the cribriform plate. Additional RNA viruses include arteriviruses (for example, equine arterivirus, porcine reproductive and respiratory syndrome virus, lactate dehyrogenase elevating virus of mice and simian hemorraghic fever virus). Other RNA viruses include the rhabdoviruses, which include lyssaviruses (for example, rabies, Lagos bat virus, Mokola virus, Duvenhage virus and European bat lyssavirus), vesiculoviruses (for example, VSV-Indiana, VSV-New Jersey, VSV-Alagoas, Piry virus, Cocal virus, Maraba virus, Isfahan virus and Chandipura virus), and ephemeroviruses (for example, bovine ephemeral fever virus, Adelaide River virus and Berrimah virus). Additional examples of RNA viruses include the filoviruses. These include the Marburg and Ebola viruses (for example, EBOV-Z, EBOV-S, EBOV-IC and EBOV-R). The paramyxoviruses are also RNA viruses. Examples of these viruses are the rubulaviruses (for example, mumps, parainfluenza virus 5, human parainfluenza virus type 2, Mapuera virus and porcine rubulavirus), avulaviruses (for example, Newcastle disease virus), respoviruses (for example, Sendai virus, human parainfluenza virus type 1 and type 3, bovine parainfluenza virus type 3), henipaviruses (for example, Hendra virus and Nipah virus), morbilloviruses (for example, measles, Cetacean morvilliirus, Canine distemper virus, Peste des-petits-ruminants virus, Phocine distemper virus and Rinderpest virus), pneumoviruses (for example, human respiratory syncytial virus (RSV) A2, B1 and S2, bovine respiratory syncytial virus and pneumonia virus of mice), metapneumoviruses (for example, human metapneumovirus and avian metapneumovirus). Additional paramyxoviruses include Fer-de- Lance virus, Tupaia paramyxovirus, Menangle virus, Tioman virus, Beilong virus, J virus, Mossman virus, Salem virus and Nariva virus. Additional RNA viruses include the orthomyxoviruses. These viruses include influenza viruses and strains (e.g., influenza A, influenza A strain A / Victoria / 3 / 75, influenza A strain A / Puerto Rico / 8 / 34, influenza A H1N1 (including but not limited to A / WS / 33, A / NWS / 33 and A / California / 04 / 2009 strains), influenza B, influenza B strain Lee, and influenza C viruses) H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7), as well as avian influenza (for example, strains H5N1, H5N1 Duck / MN / 1525 / 81, H5N2, H7N1, H7N7 and H9N2) thogotoviruses and isaviruses. Orthobunyaviruses (for example, Akabane virus, California encephalitis, Cache Valley virus, Snowshoe hare virus,) nairoviruses (for example, Nairobi sheep virus, Crimean-Congo hemorrhagic fever virus Group and Hughes virus), phleboviruses (for example, Candiru, Punta Toro, Rift Valley Fever, Sandfly Fever, Naples, Toscana, Sicilian and Chagres), and hantaviruses (for example, Hantaan, Dobrava, Seoul, Puumala, Sin Nombre, Bayou, Black Creek Canal, Andes and Thottapalayam) are also RNA viruses. Arenaviruses such as lymphocytic choriomeningitis virus, Lujo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV and WWAV are also RNA viruses. Borna disease virus is also an RNA virus. Hepatitis D (Delta) virus and hepatitis E are also RNA viruses. Additional RNA viruses include reoviruses, rotaviruses, birnaviruses, chrysoviruses, cystoviruses, hypoviruses partitiviruses and totoviruses. Orbiviruses such as African horse sickness virus, Blue tongue virus, Changuinola virus, Chenuda virus, Chobar GorgeCorriparta virus, epizootic hemorraghic disease virus, equine encephalosis virus, Eubenangee virus, Ieri virus, Great Island virus, Lebombo virus, Orungo virus, Palyam virus, Peruvian Horse Sickness virus, St. Croix River virus, Umatilla virus, Wad Medani virus, Wallal virus, Warrego virus and Wongorr virus are also RNA viruses. Retroviruses include alpha retroviruses (for example, Rous sarcoma virus and avian leukemia virus), beta retroviruses (for example, mouse mammary tumor virus, Mason-Pfizer monkey virus and Jaagsiekte sheep retrovirus), gamma retroviruses (for example, murine leukemia virus and feline leukemia virus, deltra retroviruses (for example, human T cell leukemia viruses (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1 and STLV-2), epsilon retriviruses (for example, Walleye dermal sarcoma virus and Walleye epidermal hyperplasia virus 1), reticuloendotheliosis virus (for example, chicken syncytial virus, lentiviruses (for example, human immunodeficiency virus (HIV) type 1, human immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immunodeficiency virus, equine infectious anemia virus, feline immunodeficiency virus, caprine arthritis encephalitis virus and Visna maedi virus) and spumaviruses (for example, human foamy virus and feline syncytia-forming virus). The virally encoded RNA-dependent-RNA polymerase (RdRp) forms a replication complex with other virally encoded proteins as well as host cell proteins and catalyzes RNA- template directed RNA synthesis. This protein is responsible for synthesizing antigenomic complementary RNA, genomic RNA for progeny viruses, and capped, nonpolyadenylated viral mRNA. Ribonucleoside analogs selectively inhibit the primary pathway of genetic information flow for these viruses (the copying of RNA from RNA) by acting on or through the virally encoded RdRp via their active 5’-triphosphate metabolite. A ribonucleoside analog (after phosphorylation to the corresponding 5’-triphosphate by host intracellular kinases) can act as a competitive, alternative substrate inhibitor of the RdRp and stop nascent chain RNA synthesis after incorporation; or, it can be utilized as a substrate by the RdRp and be incorporated into nascent chain RNA, rendering it non-functional by perturbing its secondary structure. Examples of DNA viruses include polyomaviruses (for example, simian virus 40, simian agent 12, BK virus, JC virus, Merkel Cell polyoma virus, bovine polyoma virus and lymphotrophic papovavirus), papillomaviruses (for example, human papillomavirus, bovine papillomavirus, adenoviruses (for example, adenoviruses A-F, canine adenovirus type I, canined adeovirus type 2), circoviruses (for example, porcine circovirus and beak and feather disease virus (BFDV)), parvoviruses (for example, canine parvovirus), erythroviruses (for example, adeno-associated virus types 1-8), betaparvoviruses, amdoviruses, densoviruses, iteraviruses, brevidensoviruses, pefudensoviruses, herpes viruses 1,2, 3, 4, 5, 6, 7 and 8 (for example, herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, Kaposi’s sarcoma associated herpes virus, human herpes virus-6 variant A, human herpes virus-6 variant B and cercophithecine herpes virus 1 (B virus)), poxviruses (for example, smallpox (variola), cowpox, monkeypox, vaccinia, Uasin Gishu, camelpox, psuedocowpox, pigeonpox, horsepox, fowlpox, turkeypox and swinepox), and hepadnaviruses (for example, hepatitis B and hepatitis B-like viruses). Chimeric viruses comprising portions of more than one viral genome are also contemplated herein. In certain embodiments, the RNA viruses that can be treated by compounds and compositions of this disclosure include enteroviruses. The genus Enterovirus (EV) belonging to the Picornaviridae family comprises 13 species, of which seven are human viruses. Four of the species are: (1) EV-A such as coxsackievirus (CV)-A6, CV-A10, CV-A16 and EV- A71, (2) EV-B such as the CV-B viruses, echoviruses (ECHO) and CV-A9, (3) EV-C such as polioviruses (PV) and CV-A21, and (4) EV-D such as EV-D68 and EV-D70. Other species include rhinoviruses RV-A, RV-B and RV-C which are comprised of over 100 different numbered RVs. EV RNA contains a single open reading frame (ORF) flanked by two untranslated regions (UTRs), 5′ UTR and 3′ UTR. The ORF encodes a single polyprotein that is cleaved into P1, P2 and P3 proteins. The P1 protein is proteolytically cleaved to produce capsid proteins VP1–4. P2 and P3 are cleaved to produce non-structural (NS) proteins 2A, 2B, 2C and 3A, 3B, 3C, 3D, respectively. The role of the capsid proteins is to enclose the genetic material and to recognize cellular receptors during viral entry. The NS proteins are crucial for replication, translation and subversion of host cell machinery. The capsid proteins are suitable targets for antiviral development due to their role in cellular entry and uncoating of the genetic material. The diverse viruses in the genus EV are known to cause a range of diseases such as hand, foot and mouth disease (HFMD), encephalitis, aseptic meningitis, myocarditis and various respiratory diseases. While some EV infections are mild, the symptoms can be severe in the very young and immunodeficient individuals. In recent years, viruses such as EV-A71 and CV-A16 have emerged as serious public health threats, as they have caused major outbreaks of HFMD in China and South East Asia. Additionally, EV-D68 has caused a large outbreak of severe lower respiratory infections in North America in 2014. Therefore, broad- spectrum antiviral drugs that could inhibit multiple EVs across the genus will be instrumental to overcome the public health burden caused by these EVs. The compounds and compositions of this disclosure can be used to treat or prevent diseases caused by enterovirus and to reduce enterovirual burden. In addition, the compounds and compositions of this disclosure can be combined with other drugs to treat enterovirus as provided herein. Anasir et al., J Biomed Sci (2021) 28, 10:5-12 provides a review of enteroviruses and antiviral agents for treating the same, the disclosure of which is incorporated herein by reference in its entirety. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection comprising administering an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. In certain exemplary embodiments, a method of treating or preventing a Zika virus infection is provided, the method comprising administering an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. In certain embodiments, the viral infection is, or is caused by, an alphavirus, flavivirus or coronaviruses orthomyxoviridae or paramyxoviridae, or RSV, influenza, Powassan virus or filoviridae or ebola. In certain embodiments, the viral infection is, or is caused by, a virus selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, Barmah Forest virus, Powassan virus, Zika virus, and Chikungunya virus. In certain exemplary embodiments, the viral infection is, or is caused by, a Zika virus. In certain embodiments, the compound is administered by inhalation through the lungs. In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus (including SARS-CoV-2 and variants thereof including, but not limited to the more virulent strains that recently appeared in Brasil, known as P.1; the United Kingdom, known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7; and in South Africa; known as 20H / 501Y.V2 or B.1.351; as well as further varients and lineages that derive therefrom), MERS coronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), Dengue virus, Zika virus, chikungunya, Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), Ross River virus, Barmah Forest virus, yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, ebola virus, marburg virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV), The Human T-lymphotropic virus Type I (HTLV-1), Friend spleen focus-forming virus (SFFV) or Xenotropic MuLV-Related Virus (XMRV). In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with a Zika virus infection. In certain embodiments, the subject is diagnosed with influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path), and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus (including SARS-CoV-2 and variants thereof including, but not limited to the more virulent strains that recently appeared in Brasil, known as P.1; the United Kingdom, known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7; and in South Africa; known as 20H / 501Y.V2 or B.1.351; as well as further varients and lineages that derive therefrom), MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza viruses 1 and 3, rinderpest virus, chikungunya, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), California encephalitis virus, Japanese encephalitis virus, Rift Valley fever virus (RVFV), hantavirus, Dengue virus serotypes 1, 2, 3 and 4, Zika virus, West Nile virus, Tacaribe virus, Junin, rabies virus, ebola virus, marburg virus, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma- associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV). In certain embodiments, the subject is diagnosed with a Zika virus infection. In certain embodiments, the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis. In exemplary embodiments, the disclosure relates to treating or preventing an infection by viruses, bacteria, fungi, protozoa, and parasites, e.g., comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient. In some embodiments, the disclosure relates to methods of treating a viral infection comprising administering a compound herein to a subject that is diagnosed with, suspected of, or exhibiting symptoms of a viral infection. Viruses are infectious agents that can typically replicate inside the living cells of organisms. Virus particles (virions) usually consist of nucleic acids, a protein coat, and in some cases an envelope of lipids that surrounds the protein coat. The shapes of viruses range from simple helical and icosahedral forms to more complex structures. Virally coded protein subunits will self-assemble to form a capsid, generally requiring the presence of the virus genome. Complex viruses can code for proteins that assist in the construction of their capsid. Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called a nucleocapsid. Viruses are transmitted by a variety of methods including direct or bodily fluid contact, e.g., blood, tears, semen, preseminal fluid, saliva, milk, vaginal secretions, lesions; droplet contact, fecal-oral contact, or as a result of an animal bite or birth. A virus has either DNA or RNA genes and is called a DNA virus or a RNA virus respectively. A viral genome is either single-stranded or double-stranded. Some viruses contain a genome that is partially double-stranded and partially single-stranded. For viruses with RNA or single-stranded DNA, the strands are said to be either positive-sense (called the plus-strand) or negative-sense (called the minus-strand), depending on whether it is complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is identical to viral mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. DNA nomenclature is similar to RNA nomenclature, in that the coding strand for the viral mRNA is complementary to it (negative), and the non-coding strand is a copy of it (positive). Antigenic shift, or reassortment, can result in novel strains. Viruses undergo genetic change by several mechanisms. These include a process called genetic drift where individual bases in the DNA or RNA mutate to other bases. Antigenic shift occurs when there is a major change in the genome of the virus. This can be a result of recombination or reassortment. RNA viruses often exist as quasispecies or swarms of viruses of the same species but with slightly different genome nucleoside sequences. The genetic material within viruses, and the method by which the material is replicated, vary between different types of viruses. The genome replication of most DNA viruses takes place in the nucleus of the cell. If the cell has the appropriate receptor on its surface, these viruses enter the cell by fusion with the cell membrane or by endocytosis. Most DNA viruses are entirely dependent on the host DNA and RNA synthesizing machinery, and RNA processing machinery. Replication usually takes place in the cytoplasm. RNA viruses typically use their own RNA replicase enzymes to create copies of their genomes. The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNAs from their genomes to produce proteins and replicate themselves, but different mechanisms are used to achieve this. Viral genomes may be single-stranded (ss) or double-stranded (ds), RNA or DNA, and may or may not use reverse transcriptase (RT). Additionally, ssRNA viruses may be either sense (plus) or antisense (minus). This classification places viruses into seven groups: I, dsDNA viruses (e.g. adenoviruses, herpesviruses, poxviruses); II, ssDNA viruses (plus )sense DNA (e.g. parvoviruses); III, dsRNA viruses (e.g. reoviruses); IV, (plus)ssRNA viruses (plus)sense RNA (e.g. picornaviruses, togaviruses); V, (minus)ssRNA viruses (minus)sense RNA (e.g. orthomyxoviruses, Rhabdoviruses); VI, ssRNA-RT viruses (plus)sense RNA with DNA intermediate in life-cycle (e.g. retroviruses); and VII, dsDNA-RT viruses (e.g. hepadnaviruses). Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS). Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry of the target cell, the viral RNA genome is converted to double-stranded DNA by a virally encoded reverse transcriptase. This viral DNA is then integrated into the cellular DNA by a virally encoded integrase, along with host cellular co-factors. There are two species of HIV. HIV-1 is sometimes termed LAV or HTLV-III. HIV infects primarily vital cells in the human immune system such as helper T cells (CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to other viral or bacterial infections. Subjects with HIV typically develop malignancies associated with the progressive failure of the immune system. The viral envelope is composed of two layers of phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and a HIV protein known as Env. Env contains glycoproteinsgp120, and gp41. The RNA genome consists of at structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS) and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat env and rev) encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles. HIV-1 diagnosis is typically done with antibodies in an ELISA, Western blot, orimmunoaffinity assays or by nucleic acid testing (e.g., viral RNA or DNA amplification). HIV is typically treated with a combination of antiviral agent, e.g., two nucleoside- analogue reverse transcription inhibitors and one non-nucleoside-analogue reverse transcription inhibitor or protease inhibitor. The three-drug combination is commonly known as a triple cocktail. In certain embodiments, the disclosure relates to treating a subject diagnosed with HIV by administering a pharmaceutical composition disclosed herein in combination with two nucleoside-analogue reverse transcription inhibitors and one non- nucleoside-analogue reverse transcription inhibitor or protease inhibitor. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, and efavirenz. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir and raltegravir. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, ritonavir and darunavir. In certain embodiments, the disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, ritonavir and atazanavir. Banana lectin (BanLec or BanLec-1) is one of the predominant proteins in the pulp of ripe bananasand has binding specificity for mannose and mannose-containing oligosaccharides. BanLec binds to the HIV-1 envelope protein gp120. In certain embodiments, the disclosure relates to treating viral infections, such as HIV, by administering a compound disclosed herein in combination with a banana lectin. Therapeutic agents in some cases may suppress the virus for a long period of time. Typical medications are a combination of interferon alpha and ribavirin. Subjects may receive injections of pegylated interferon alpha. Genotypes 1 and 4 are less responsive to interferon-based treatment than are the other genotypes (2, 3, 5 and 6). In certain embodiments, the disclosure relates to treating a subject with HCV by administering a compound disclosed herein to a subject exhibiting symptoms or diagnosed with HCV. In certain embodiments, the compound is administered in combination with interferon alpha and another antiviral agent such as ribavirin, and / or a protease inhibitor such as telaprevir or boceprevir. In certain embodiments, the subject is diagnosed with genotype 2, 3, 5, or 6. In other embodiments, the subject is diagnosed with genotype 1 or 4. In certain embodiments, the subject is diagnosed to have a virus by nucleic acid detection or viral antigen detection. Cytomegalovirus (CMV) belongs to the Betaherpesvirinae subfamily of Herpesviridae. In humans it is commonly known as HCMV or Human Herpesvirus 5 (HHV-5). Herpesviruses typically share a characteristic ability to remain latent within the body over long periods. HCMV infection may be life threatening for patients who are immunocompromised. In certain embodiments, the disclosure relates to methods of treating a subject diagnosed with cytomegalovirus or preventing a cytomegalovirus infection by administration of a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In typical embodiments, the subject is an organ transplant recipient, undergoing hemodialysis, diagnosed with cancer, receiving an immunosuppressive drug, and / or diagnosed with an HIV-infection. In certain embodiments, the subject may be diagnosed with cytomegalovirus hepatitis, the cause of fulminant liver failure, cytomegalovirus retinitis (inflammation of the retina, may be detected by ophthalmoscopy), cytomegalovirus colitis (inflammation of the large bowel), cytomegalovirus pneumonitis, cytomegalovirus esophagitis, cytomegalovirus mononucleosis, polyradiculopathy, transverse myelitis, and subacute encephalitis. In certain embodiments, a compound disclosed herein is administered in combination with an antiviral agent such as valganciclovir or ganciclovir. In certain embodiments, the subject undergoes regular serological monitoring. HCMV infections of a pregnant subject may lead to congenital abnormalities. Congenital HCMV infection °Ccurs when the mother suffers a primary infection (or reactivation) during pregnancy. In certain embodiments, the disclosure relates to methods of treating a pregnant subject diagnosed with cytomegalovirus or preventing a cytomegalovirus infection in a subject at risk for, attempting to become, or currently pregnant by administering compound disclosed herein. Subjects who have been infected with CMV typically develop antibodies to the virus. A number of laboratory tests that detect these antibodies to CMV have been developed. The virus may be cultured from specimens obtained from urine, throat swabs, bronchial lavages and tissue samples to detect active infection. One may monitor the viral load of CMV- infected subjects using PCR. CMV pp65 antigenemia test is an immunoaffinity based assay for identifying the pp65 protein of cytomegalovirus in peripheral blood leukocytes. CMV should be suspected if a patient has symptoms of infectious mononucleosis but has negative test results for mononucleosis and Epstein-Barr virus, or if they show signs of hepatitis, but have negative test results for hepatitis A, B, and C. A virus culture can be performed at any time the subject is symptomatic. Laboratory testing for antibody to CMV can be performed to determine if a subject has already had a CMV infection. The enzyme-linked immunosorbent assay (or ELISA) is the most commonly available serologic test for measuring antibody to CMV. The result can be used to determine if acute infection, prior infection, or passively acquired maternal antibody in an infant is present. Other tests include various fluorescence assays, indirect hemagglutination, (PCR), and latex agglutination. An ELISA technique for CMV-specific IgM is available. Hepatitis B virus is a hepadnavirus. The virus particle, (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The genome of HBV is made of circular DNA, but the DNA is not fully double-stranded. One end of the strand is linked to the viral DNA polymerase. The virus replicates through an RNA intermediate form by reverse transcription. Replication typically takes place in the liver where it causes inflammation (hepatitis). The virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people. Blood tests for these proteins and antibodies are used to diagnose the infection. Hepatitis B virus gains entry into the cell by endocytosis. Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host chaperones. The partially double stranded viral DNA is then made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of viral mRNAs. The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome. The hepatitis B surface antigen (HBsAg) is typically used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection if it is being cleared by the host. The infectious virion contains an inner "core particle" enclosing viral genome. The icosahedral core particle is made of core protein, alternatively known as hepatitis B core antigen, or HBcAg. IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be used as a serological marker. Hepatitis B e antigen (HBeAg) may appear. The presence of HBeAg in the serum of the host is associated with high rates of viral replication. Certain variants of the hepatitis B virus do not produce the 'e' antigen, If the host is able to clear the infection, typically the HBsAg will become undetectable and will be followed by IgG antibodies to the hepatitis B surface antigen and core antigen, (anti-HBs and anti HBc IgG). The time between the removal of the HBsAg and the appearance of anti-HBs is called the window period. A person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously. Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers. Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase levels and inflammation of the liver that may be identified by biopsy. Nucleic acid (PCR) tests have been developed to detect and measure the amount of HBV DNA in clinical specimens. Acute infection with hepatitis B virus is associated with acute viral hepatitis. Acute viral hepatitis typically begins with symptoms of general ill health, loss of appetite, nausea, vomiting, body aches, mild fever, dark urine, and then progresses to development of jaundice. Chronic infection with hepatitis B virus may be either asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), possibly leading to cirrhosis. Having chronic hepatitis B infection increases the incidence of hepatocellular carcinoma (liver cancer). During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to most of the liver injury associated with HBV infection. By killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, CTLs eliminate the virus. Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver. Therapeutic agents can stop the virus from replicating, thus minimizing liver damage. In certain embodiments, the disclosure relates to methods of treating a subject diagnosed with HBV by administering a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In certain embodiments, the compound is administered in combination with another antiviral agent such as lamivudine, adefovir, tenofovir, telbivudine, and entecavir, and / or immune system modulators interferon alpha-2a and pegylated interferon alpha-2a (Pegasys). In certain embodiments, the disclosure relates to preventing an HBV infection in an immunocompromised subject at risk of infection by administering a pharmaceutical composition disclosed herein and optionally one or more antiviral agents. In certain embodiments, the subject is at risk of an infection because the sexual partner of the subject is diagnosed with HBV. In certain embodiments, pharmaceutical compositions disclosed herein are administered in combination with a second antiviral agent, such as ABT-450, ABT-267, ABT-333, ABT-493, ABT-530, abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin , raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine and combinations thereof. In certain embodiments, pharmaceutical compositions disclosed herein can be coformulated and administered in combination with a second antiviral agent selected from:

[0023] . In certain embodiments, coformulated and administered in combination with a second antiviral agent selected from: . In certain embodiments, can be coformulated and administered in combination with a second antiviral agent selected from: . In certain embodiments, pharmaceutical compositions disclosed herein can be coformulated and administered in combination with a second antiviral agent selected from WO 2016 / 106050 or WO 2017 / 156380. In certain embodiments, can be coformulated and administered in combination with a second antiviral agent selected from WO 2016 / 106050 or WO 2017 / 156380. In certain embodiments, can be coformulated and administered in combination with a second antiviral agent selected from WO 2016 / 106050 or WO 2017 / 156380. In exemplified embodiments, , , . In exemplified embodiments, ,

[0024] . In exemplified embodiments, , . In exemplified embodiments, , ,

[0025] can be combined with

[0026]  . In exemplified embodiments, , , pharmaceutical or physiological salt thereof , pharmaceutical orphysiological salt thereof can be found in combination in host cells, tissues, and / or organs that are and are not infected with a virus. In exemplified embodiments, pharmaceutical or physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. In exemplified embodiments, pharmaceutical or physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. In exemplified embodiments, pharmaceutical or physiological

[0027] salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. In exemplified embodiments, pharmaceutical or physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. I physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. I physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. I physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. I physiological salt thereof can be found in combination pharmaceutical or physiological salt thereof in host plasma or whole blood. In yet another aspect, the at least two direct acting antiviral agents comprises a drug combination selected from the group consisting of: a compound of this invention, with one or more of ABT-450 and / or ABT-267, and / or ABT-333, and / or ABT-493, and / or ABT-530; a novel compound of this invention with a compound disclosed in any of US 2010 / 0144608; US 61 / 339,964; US 2011 / 0312973; WO 2009 / 039127; US 2010 / 0317568; 2012 / 151158; US 2012 / 0172290; WO 2012 / 092411; WO 2012 / 087833; WO 2012 / 083170; WO 2009 / 039135; US 2012 / 0115918; WO 2012 / 051361; WO 2012 / 009699; WO 2011 / 156337; US 2011 / 0207699; WO 2010 / 075376; US 7,9105,95; WO 2010 / 120935; WO 2010 / 111437; WO 2010 / 111436; US 2010 / 0168384 or US 2004 / 0167123; a compound of this invention with one or more of Simeprevir, and / or GSK805; a compound of this invention with one or more of Asunaprevir, and / or Daclastavir, and / or BMS-325; a compound of this invention with one or more of GS-9451, and / or Ledisasvir and / or Sofosbuvir, and / or GS-9669; a compound of this invention with one or more of ACH-2684, and / or ACH-3102, and / or ACH-3422; a compound of this invention with one or more of Boceprevir, and / or MK-8742; a compound of this invention with one or more of Faldaprevir and / or Deleobuvir; a compound of this invention with PPI-668; a compound of this invention with one or more of telaprevir and / or VX-135; a compound of this invention with one or more of Samatasvir and / or IDX-437; a compound of this invention with PSI-7977 and / or PSI-938, a compound of this invention with BMS-790052 and / or BMS-650032; a compound of this invention with GS-5885 and / or GS-9451; a compound of this invention with GS-5885, GS-9190 and / or GS-9451; a compound of this invention in combination with BI-201335 and / or BI-27127; a compound of this invention in combination with telaprevir and / or VX-222; a compound of this invention combination with PSI-7977 and / or TMC-435; and a compound of this invention in combination with danoprevir and / or R7128. In one aspect of the disclosure, an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter spp, BacteroidesBacteroides spp, BurkholderiaBurkholderia spp, Campylobacter spp, Chlamydia spp, Chlamydophila spp, Clostridium spp, Enterobacter spp, Enterococcus spp, Escherichia spp, Fusobacterium spp, Gardnerella spp, Haemophilus spp, Helicobacter spp, Klebsiella spp, Legionella spp, Moraxella spp, Morganella spp, Mycoplasma spp, Neisseria spp, Peptococcus spp, PeptostreptococcusPeptostreptococcus spp, Proteus spp, Pseudomonas spp, SalmonellaSalmonella spp, Serratia spp., StaphylococcusStaphylococcus spp, Streptoccocus spp, Stenotrophomonas spp, or Ureaplasma spp. In one aspect of the disclosure, an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumanii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter lwoffi, Bacteroides bivius, Bacteroides fragilis , Burkholderia cepacia, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia urealyticus, Chlamydophila pneumoniae, Clostridium difficile, Enterobacter aerogenes, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Gardnerella vaginalis, Haemophilus par influenzae, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, penicillin-resistant Streptococcus pneumoniae, penicillin-susceptible Streptococcus pneumoniae, PeptostreptococcusPeptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus , Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis, Proteus mirabilis, Pseudomonas aeruginosa, quinolone-resistant Staphylococcus aureus, quinolone-resistant Staphylococcus epidermis, SalmonellaSalmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Salmonella typhimurium, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptoccocus agalactiae, Streptoccocus pneumoniae, Streptoccocus pyogenes, Stenotrophomonas maltophilia, Ureaplasma urealyticum, vancomycin-resistant Enterococcus faecium, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus epidermis, Mycobacterium tuberculosis, Clostridium perfringens, Klebsiella oxytoca, Neisseria miningitidis, Proteus vulgaris, or coagulase-negative StaphylococcusStaphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, or Staphylococcus saprophytic). In one aspect of the disclosure "infection" or "bacterial infection" refers to aerobes, obligate anaerobes, facultative anaerobes, gram-positive bacteria, gram-negative bacteria, gram-variable bacteria, or atypical respiratory pathogens. In some embodiments, the disclosure relates to treating a bacterial infection such as a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, or a urinary tract infection. In some embodiments, the disclosure relates to treating a bacterial infection such as an infection caused by drug resistant bacteria. In some embodiments, the disclosure relates to treating a bacterial infection such as community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as penicillin-resistantpenicillin-resistant streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and vancomycin- resistant enterococci, syphilis, ventilator-associated pneumonia, intra-abdominal infections, gonorrhoeae, meningitis, tetanus, or tuberculosis. In some embodiments, the disclosure relates to treating a fungal infections such as infections caused by tinea versicolor, microsporum, trichophyton, epidermophyton, candidiasis, cryptococcosis, or aspergillosis. In some embodiments, the disclosure relates to treating an infection caused by protozoa including, but not limited to, malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or dysentery. Certain compounds disclosed herein are useful to prevent or treat an infection of a malarial parasite in a subject and / or for preventing, treating and / or alleviating complications and / or symptoms associated therewith and can then be used in the preparation of a medicament for the treatment and / or prevention of such disease. The malaria may be caused by Plasmodium falciparum, P. vivax, P. ovale, or P. malariae. In one embodiment, the compound is administered after the subject has been exposed to the malaria parasite. In another embodiment, a compound disclosed herein is administered before the subject travels to a country where malaria is endemic. The compounds or the above-mentioned pharmaceutical compositions may also be used in combination with one or more other therapeutically useful substances selected from the group comprising antimalarials like quinolines (e.g., quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine); peroxide antimalarials (e.g., artemisinin, artemether, artesunate); pyrimethamine-sulfadoxine antimalarials (e.g., Fansidar); hydroxynaphtoquinones (e.g., atovaquone); acroline-type antimalarials (e.g., pyronaridine); and antiprotozoal agents such as ethylstibamine, hydroxystilbamidine, pentamidine, stilbamidine, quinapyramine, puromycine, propamidine, nifurtimox, melarsoprol, nimorazole, nifuroxime, aminitrozole and the like. In an embodiment, compounds disclosed herein can be used in combination one additional drug selected from the group consisting of chloroquine, artemesin, qinghaosu, 8- aminoquinoline, amodiaquine, arteether, artemether, artemisinin, artesunate, artesunic acid, artelinic acid, atovoquone, azithromycine, biguanide, chloroquine phosphate, chlorproguanil, cycloguanil, dapsone, desbutyl halofantrine, desipramine, doxycycline, dihydrofolate reductase inhibitors, dipyridamole, halofantrine, haloperidol, hydroxychloroquine sulfate, imipramine, mefloquine, penfluridol, phospholipid inhibitors, primaquine, proguanil, pyrimethamine, pyronaridine, quinine, quinidine, quinacrineartemisinin, sulfonamides, sulfones, sulfadoxine, sulfalene, tafenoquine, tetracycline, tetrandine, triazine, salts or mixture thereof. Compounds of the present disclosure can be administered in combination with a second agent, e.g., including, but not limited to, an antiviral agent such as a direct-acting antiviral agent, an indirect acting antiviral agent, and a host-directed antiviral agent. In various aspects, compounds of the present disclosure can be administered in combination with a second agent, including, but not limited to, immunomodulators, such as interleukin 6 (IL-6) inhibitors, corticosteroids, TNF-inhibitors, and other immune-dependent therapies; antibody therapies, such as convalescent plasma therapies, hyperimmune globulin therapies, monoclonal antibodies, polyclonal antibodies, and neutralizing antibodies; soluble guanylate cyclase stimulator, such as riociguat; cannibidiols; and vaccines. The additional therapies contemplated include biological products that are biosimilar to any biological product or therapy expressly listed herein. In further various aspects, compounds of the present disclosure can be administered in combination with a second agent, including, but are not limited to 2,3,4,5,6-pentafluoro-N-(3- fluoro-4-methoxyphenyl) benzene sulfonamide, 3',4'-didehydro-4'deoxy-8'-norvin- caleukoblastine, 47D11, 5-fluorouracil, abatacept, abacavir, abiraterone acetate, ABT-450 and / or ABT-267, and / or ABT-333, ABX464, abibertinib, acalabrutinib, ACE2-Fc, ACE- MAB (STI-4920, CMAB020), acetylsalicylic acid, acetaminophen, ACT-20, Actemra, Actemra / RoActemra, acyclovir, adefovir, adalimumab, adipose mesenchymal cells, AdMSCs (autologous adipose-derived stem cells), ADR-001, adrecizumab (HAM8101), ADX- 629 / reproxalap, AK-119, Alferon N, Allocetra (leukocyte cell based therapy), AlloStim, Allorx stem cells, AL T-100 ( enamptcumab ), AL T-803, altretamine, amantadine, Amnioboost, amiodarone, Ampion, ampligen, amprenavir, arbidol, asunaprevir, atazanavir, atripla, Anaferon, Anakinra, AMG-3777, anhydrovinblastine, anti-nCoV nanoviricides, aprepitant, AP-003 (AntiCovir), APL-9 (pegylated synthetic cyclic peptide), APX-115, AQCH, AR-701, ARO-COV, AS-1411, ascorbic acid, asunercept, atovaquone / azithromycin, AT-100 (rhSP-D), AT-301, AT-H201, ATI-450, ATR-002, auristatin, avdoralimab (IPH5401), axatilimab, AZD-1061, AZD-7442, alvelestat (AZD-9668), AZD-8895, azvudine, azvudine / tetrandrine, azithromycin, baloxivir, BI-201335, BI-27127, boceprevir, bardoxolone, bardoxolone methyl, baricitinib, BBT-032, bemcentinib, BGE-175, BIO-300, BIOMEDIVR, bevacizumab, bexarotene, bicalutamide, BIO-1106, BLD-2660, BLD-2736, BOLD-I 00, brequinar sodium, brilacidin, bromhexine hydrochloride, BTL-TML00l, bleomycin, BMS-986253, BMS 184476, BT-086, BT-588, BXCL501, BXT-25, bucillarnine, budesonide, cidofovir, combivir, daclatasvir, cachectin, acalabrutinib, camrelizumab, camrelizumab / thymosin, captopril, CardioIRx, carrimycin, cavaltinib, comostat, camostat mesylate, canakinumab, CAP-1002, carboplatin, carmustine, CB5064 analogs, CD24Fc (recombinant fusion protein), cepharanthine, cemadotin, cenicriviroc, canthaquine, CERC- 002, chlorambucil, chloropromazine, cholecalciferol, ciclesonide, cisplatin, ci-trimoxazole, CK-0802, clazakizumab, clarithromycin, CLBS-119, CM4620-IE, colchicine, CorLiCyte (umbilical cord lining stem cells), COVID-19 aptamer therapy, COVID-19 human mAb, COVID-19 neutralizing antibodies, COVID-19 siRNA therapy, COVID-HIG, COVID-EIG, spike glycoproteins, CoviGlobulin, COVI-GUARD (STI-1499), CPI-006, crizanlizumab, cryptophycin, CSL-324, CT-P59, CTAP-101, CV-15, CVL-218, cyclosporine, cell replacement therapies, cyclophosphamide, CYNK-001, cytarabine, danoprevir, darunavir, delavirdine, deleobuvir, didanosine, disoxaril, docosanol, dacarbazine, dactolisib, dactinomycin, dalargin, DAS-181, dapagliflozin, dapansurtrile, daunorubicin, decitabine, dexamethasone, DNL 758 (SAR443122, RIPKl inhibitor), dipyridamole, DMX-200, DS- 2319, deupirfenidone, duvelisib, DV-890, DWRX-2003, docetaxol, dolastatin, doxetaxel, doxorubicin (adriamycin), DP-710, edoxudine, efavirenz, enfuvirtide, ensitrelvir, entecavir, EB-05, EB-201, ebastine, eculizumab, EDP-1815, efineptakin alfa, emapalumab, emtricitabine, ensifentrine, ENU-200, enoxaparin, enzalutarnide, epaspire, etanercept, etoposide, eravacycline, favipiravir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, famotidine, finasteride, fingolimod, flebogamma (IGIV31), fluvoxarnine, foalumab (NI-0401, TZLS-401), fostamatinib, flutarnide, FSD-201, FW1022, FT516, ganciclovir, GS- 5882, GS-9190, GS-9451, Gamunex (IGIV-C), ganetespib, GC-376, Giapreza, GLS-1200, garadacimab, GC-5131A (hyperimmune globulin), GIGA-2050 rCIG), gimsilumab, GNS561, GP1681, GSK-2586881 / APN-l, GSK-4182136, GTB-3550 (Trike 161533), haNK:CD-16, HB-adMSCs, HFB30132A, HLCM-051, heparin, hydrocortisone, hydroxyurea, ibuprofen, ibudilasst (MN-166), icosapent ethyl, IC14, IDB-003, IFX-l / BDB-1, IgY-110, IMM101 IMS00l, IMS002, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, ifosfarnide, imatinib, infliximab, INM-005, interferon alfa, interferon alfa 1B, interferon alfa 2B, interferon beta IA, interferon beta 1B, interleukin-6, interleukin-7, isoquercetin, itanapraced (CHF-5074), itolizumab, ivermectin, IVIG, JS012 (monoclonal antibody, LY- CoV016), jaktinib, kagocel, KB109, K-NK-1D101, KTH-222, lamivudine, laninamivir octanoate, ledisavir, lopinavir or lopinavir / ritonavir, loviride, lactoferrin, LAM-002A (apilimod dimesylate), lanadelumab, lamellasome, LB-1148, larazotide, leflunornide, lenzilumab, leronlimab (monoclonal antibody), levilimab (BCD-089), levarnisole, liarozole, linagliptin, lipocurc, losartan, livilimab, lomustine (CCNU), lonidarnine, losmapimod, lostartan, LY-CoV555 (LY-3819253), LY-3127804, molnupiravir, moroxydine, methisazone, mannitol, maraviroc, mastinib, mavrilimumab, MDV3100, mechlorethamine, MEDI-3506, melatonin, melphalan, meplazumab, merimepodib, Mesenchymal stem cells (MSCs), mesencure (cell replacement), metablok (anti-inflammatory), metformin, methotrexate, methylprednisolone, mitomycin, mivobulin isethionate, mosedipimod (EC-18), MP-0420, MP-0423, MRx4DP0004, N-acetylcysteine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L- valyl-L-prolyl- 1-Lproline-t-butylamide, nelfinavir, nevirapine, nexavir, namilumab (IZN- 101), nangibotide, narsoplimab, nebulized domase alfa, NED-260, Niagen (nicotinamide riboside; Vitamin B3), NK cell therapy, niclosamide, nilutamide, nintedanib, nitric oxide, nivolumab, NL-CVXl, NLP-21, NP-02, N-120 (ifenprodil), novaferon, NT-17 (efineptakin alfa), NTR-441, oseltamivir, °Ctagam, olokizumab, omeprazole, onapristone, opaganib, OP- 101, OT-101 (trabedersen), otilimab, ozanimod, paxlovid, penciclovir, peramivir, pirodavir, pleconaril, pocapavir, podophyllotoxin, PPI-668, PSI-7977, PSI-938, paclitaxel, pacritinib, panaphix, pamrevlumab, paracetamol, PAXLOVIDTM, PB1046, PTC299, pegylated interferon alpha, pegylated interferon alpha 2b, pegylated interferon lambda, pembrolizumab, PL-8177, pirfenidone, plitidepsin (aplidin), PneumoBlast, polyoxidonium, prazosin, prednimustine, prednisolone, prednisone, pritumumab, procarbazine, prolastin, PTC-299, pyronaridine / artesunate, radotinib, RAPA-501, raltegravir, remdesivir, ribavirin, rimantadine, ritonavir, ravulizumab, razuprotafib, interferon beta 1 agonists, RECC327, REGN-COV2 (antibody cocktail), reparixin, rintatolimod (ampligen), RLF-100 (aviptadil), RLS-0071, STI- 5656 (abivertinib), Rhu-pGSN (gelsolin), rhizoxin, RPR109881, RoActemra, RUCONEST (conestat alfa), ruxolitinib, SAB-185, SAR443122, sarilumab, SARS-CoV-2 antibodies, SARS-Co V-2 monoclonal antibodies, SARS-Co V-2 poly clonal antibodies, SARS-Co V-2 neutrali pyramidine, samatasvir, saquinavir, simeprevir, sofosbuvir, stavudine, SCTA0l, Leukine (sargramostim), selenexor, sevoflurane, sertenef, siltuximab, sildenafil citate, silymarin, simvastatin, sirolimus, sirukumab, SIW A-318, solnatide, SNG-001, ST-266, stem cell educator therapy, STI-1499, STI-2020dna (COVI-MAB), STI-4398 (Covidtrap), stramustine phosphate, streptozocin, T cell therapies (TargNaturTa), TAK-671, TAK-888, TATX-36, TATX-99, TCB-007, TJ003234 / TJM-2, TP508, TRV027, TD-0903, TLC19, TMC-435, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, tekruma, tafenoquine, tamoxifen, tasonermin, taxanes, taxol, tetradrine, thalidomide, thimerosal, thymalfasin, tinzaparin, tocilizumab, tofacitinib, toremifene, tradipitant, tranexamic acid, trans sodium crocetinate (TSC), tramadol, tretinoin, TXA127 (antiotensin-(1-7) peptide), TY027, TZLS-501, UNI-911, ulinastatin, upamostat, valaciclovir, valganciclovir, vapendavir, vicriviroc, vidarabine, viramidine zalcitabine, vafidemstat, valsartan, icosapent ethyl, vazegepant, VBI-S, VERU-111, VHH72-Fc, vinblastine, vincristine, vindesine sulfate, vinflunine, VIR-2703 ALN-COV), VIR-7831, VIR-7832, Vitamin C, Vitamin D, VX-135, VX-222, XAV-19, Xpro-1595, XRx-101, zanamivir, zidovudine, zing antibodies, zanubrutinib, zilucoplan, zinc; and / or a such as a compound disclosed in any of US 2010 / 0144608, US 61 / 339,964, US 2011 / 0312973, WO 2009 / 039127, US 2010 / 0317568, 2012 / 151158, US 2012 / 0172290, WO 2012 / 092411, WO 2012 / 087833, WO 2012 / 083170, WO 2009 / 039135, US 2012 / 0115918, WO 2012 / 051361, WO 2012 / 009699, WO 2011 / 156337, US 2011 / 0207699, WO 2010 / 075376,; US 7,9105,95, WO 2010 / 120935, WO 2010 / 111437, WO 2010 / 111436, US 2010 / 0168384 or US 2004 / 0167123; and salts and / or prodrugs thereof, as well as combinations thereof, or a prodrug of the foregoing as appropriate; and / or a physiological or pharmaceutical salt thereof, as appropriate; and / or combinations thereof. In a particular embodiment, compounds of the present disclosure can be administered in combination with a second antiviral including, but not limited to, abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, baloxivir, BI-201335, BI-27127, boceprevir, cidofovir, combivir, daclatasvir, danoprevir, darunavir, delavirdine, deleobuvir, didanosine, disoxaril, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, ensitrelvir, entecavir, favipiravir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5882, GS-9190, GS-9451, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, laninamivir °Ctanoate, ledisavir, lopinavir or lopinavir / ritonavir, loviride, maraviroc, molnupiravir, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, paxlovid, peginterferon alfa-2a, penciclovir, peramivir, pirodavir, pleconaril, pocapavir, podophyllotoxin, PPI-668, PSI-7977, PSI-938, raltegravir, remdesivir, ribavirin, rimantadine, ritonavir, pyramidine, samatasvir, saquinavir, simeprevir, sofosbuvir, stavudine, TMC-435, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vapendavir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, zidovudine, a compound disclosed in any of US 2010 / 0144608, US 61 / 339,964, US 2011 / 0312973, WO 2009 / 039127, US 2010 / 0317568, 2012 / 151158, US 2012 / 0172290, WO 2012 / 092411, WO 2012 / 087833, WO 2012 / 083170, WO 2009 / 039135, US 2012 / 0115918, WO 2012 / 051361, WO 2012 / 009699, WO 2011 / 156337, US 2011 / 0207699, WO 2010 / 075376,; US 7,9105,95, WO 2010 / 120935, WO 2010 / 111437, WO 2010 / 111436, US 2010 / 0168384 or US 2004 / 0167123, VX-135, VX-222, and salts and / or prodrugs thereof, as well as combinations thereof. In a particular embodiment, compounds of the present disclosure can be administered in combination with a second antiviral agent such as a host-directed antiviral agent, including, but not limited to, IFN-α-2a (including pegylated forms thereof; and used alone or in combination with ribavirin), IFN-α-2b (including pegylated forms thereof; and used alone or in combination with ribavirin), IFN-α-N3, IFN-β-1a (including pegylated forms thereof; and used alone or in combination with ribavirin), IFN-β-1b (including pegylated forms thereof; and used alone or in combination with ribavirin), podofilox, interferon alfacon-1, imiquimod, one or more sincatechin, maraviroc, DAS181, R448 (cabozantinib), eztimibe, obatoclax, glycyrrhizin, concanamycin, daptomycin, LJ001, thapsigargin, dynasore, MLS000394177, MLS000733230, MLS000730532, bisindolylmaleimide I, calphostin C, chelerythrine, enzastaurin, staurosporine, fattiviracin, rintatolimod, GS9620, RO6864018, RO7020531, AL-034, imiquimod, GS9688, CL097, PF-04878691 or 852A, CPG10101, IMO-2125, SD-101, inarigivir (SB 9200), quercetin, A23187, phorbol myristate acetate, CI1033, a SIP agonist, a PPAR agonist, and combinations thereof. In a particular embodiment, a second agent, e.g., an antiviral agent, as disclosed herein is administered together with one of the following compounds: , , , and combinations thereof. In a particular embodiment, a second agent, e.g., an antiviral agent, as disclosed herein is administered together with one of the following compounds:

[0028] , , and a combination thereof. In a particular embodiment, a second agent, e.g., an antiviral agent, as disclosed herein is administered together with one of the following compounds:

[0029] , and combinations of the foregoing. In a particular embodiment, a second agent, e.g., an antiviral agent, as disclosed herein is administered together with one of the following compounds: , , ,

[0030] ,

[0031] , , , , , , , ,

[0032] ,

[0033] , a pharmaceutically acceptable salt, solvate, or polymorph thereof Methods for treating a virus infection disclosed herein, e.g., enterovirus, RSV, influenza, VEEV, EEEV, HCV and other viruses provided herein, in a subject are also provided. The methods comprise administering the compounds of this disclosure to provide at least two direct acting antiviral agents (DAAs), for example molnupiravir or ribavirin, for a duration of no more than twelve weeks, or for another duration as set forth herein, for example for acute infections for less than one week, e.g., 5 days. Preferably, the two or more direct acting antiviral agents (DAAs) are administered in amounts effective to provide a sustained virological response (SVR) or achieve another desired measure of effectiveness in a subject. In some embodiments, the methods further comprise administering an inhibitor of cytochrome P-450 (such as ritonavir) to the subject to improve the pharmacokinetics or bioavailability of one or more of the DAAs. As another aspect, methods for treating a virus infection disclosed herein, e.g., enterovirus, RSV, influenza, VEEV, EEEV, HCV and other viruses provided herein, in a subject are provided comprising administering (a) protease inhibitor, (b) at least one polymerase inhibitor, wherein at least one is a polymerase of this disclosure and combinations thereof, with or without (c) molnupiravir. Preferably, the compounds are administered in amounts effective to provide high rates of SVR or another measure of effectiveness in the subject. As non-limiting examples, the compounds can be co-formulated and administered once daily, and the treatment regimen preferably lasts for one to five days to a week. As still another aspect, methods for treating a virus infection disclosed herein, e.g., enterovirus, RSV, influenza, VEEV, EEEV, HCV and other viruses provided herein, in a subject are provided comprising administering at least two DAAs, wherein one of the DAAs is a compound of this disclosure. Preferably, the at least two DAAs are administered to the subjects in amounts effective to result in SVR or another measure of effectiveness in at least about 70% of the population, preferably at least 90% of the population. In the foregoing methods as well as methods described herein below, the DAAs can be selected from the group consisting of protease inhibitors, nucleoside or nucleotide polymerase inhibitors (one of which is provided herein), non-nucleoside polymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NS5A inhibitors, NS5B inhibitors, cyclophilin inhibitors, and combinations of any of the foregoing. For example, in some embodiments, the DAAs used in the present methods comprise or consist of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor provided herein. In some embodiments, the at least two DAAs comprise at least one viral inhibitor, e.g., an inhibitor of enterovirus, RSV, influenza, VEEV, EEEV, HCV and other viruses provided herein, and at least one NS5A inhibitor. By way of example, the polymerase inhibitor of this disclosure can be administered at a total daily dosage from about 100 mg to about 250 mg, and the NS5A inhibitor can be administered in a total daily dose from about 25 mg to about 200 mg. Ritonavir (or another cytochrome P-4503A4 inhibitor) can be co- administered with to improve the pharmacokinetics and bioavailability of the compounds. In the foregoing methods as well as methods described herein, the DAAs can be administered in any effective dosing schemes and / or frequencies, for example, they can each be administered daily. Each DAA can be administered either separately or in combination, and each DAA can be administered at less once a day, at least twice a day, or at least three times a day. In some aspects, the present technology provides methods for treating a virus infection disclosed herein, e.g., enterovirus, RSV, influenza, VEEV, EEEV, HCV and other viruses provided herein, in a subject are provided comprising administering to a subject in need thereof at least two DAAs, wherein the subject is not administered with interferon during said duration. In some aspects, the at least two DAAs with or without ribavirin are administered in an amount effective to result in SVR. Some methods further comprise administering an inhibitor of cytochrome P450 to the subject. The duration of the treatment regimens in some aspects is no more than sixteen weeks (e.g., the duration being 16 weeks; or the duration being 14, 12 or 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 weeks or daily for 1-7 days, e.g. one, two, three, four, five, six, or seven days). The treatment includes administering ribavirin but does not include administering interferon. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The two DAAs can be administered concurrently or sequentially. For example, one DAA can be administered once daily, and the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered concurrently (e.g., once daily). As a further aspect, methods for treating enterovirus in a subject are provided. The methods comprise administering nucleoside or nucleotide compounds of this disclosure. In addition, the methods comprise administering nucleoside or nucleotide compounds of this disclosure in combination with a second antiviral agent active against enteroviruses. In certain embodiments, the disclosure relates to methods of treating a subject diagnosed with an infection caused by enterovirus or preventing an enterovirus infection by administration of a compound or composition disclosed herein. In certain embodiments, the subject is immune- compromised, immune-deficient or immune-suppressed (i.e., a subject in whom any part of the immune system is not working normally, or is working sub-normally, in other words in whom any part of the immune response, or an immune activity is reduced or impaired, whether due to disease or clinical intervention or other treatment, or in any way). In certain embodiments, the nucleoside or nucleotide compounds of this disclosure can be combined with a second antiviral agent as provided in Anasir et al., J Biomed Sci (2021) 28, 10:5-12. Anasir et al. provide a review of antiviral agents for treating enteroviruses, the disclosure of which is incorporated herein by reference in its entirety. The combination therapy may provide “synergy” and “synergistic effect”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Also disclosed are methods of producing a drug triphosphate, the method comprising: providing a plurality of cells; contacting the plurality of cells with a disclosed compound, e.g., a compound Formula c; and incubating the plurality of cells and the amount of the compound or pharmaceutical composition for period effective to form the drug triphosphate. In some instances, the plurality of cells are in vivo. In is contemplated that in some instances, the contacting is administering to a subject in need thereof. Cancer In a typical embodiment, the disclosure relates to a method treating cancer comprising administering to a patient a compound disclosed herein. In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof for uses in treating cancer. In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate. In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas. In some embodiments, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumors of the central nervous system and their metastases, and also for the treatment of glioblastomas. In some embodiments, compounds disclosed herein could be used in the clinic either as a single agent by itself or in combination with other clinically relevant agents. This compound could also prevent the potential cancer resistance mechanisms that may arise due to mutations in a set of genes. The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the disclosure, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); and proteosome inhibitors (for example bortezomib [Velcade®]); and the agent anegrilide [Agrylin®]; and the agent alpha- interferon; (ii) cytostatic agents such as anti-estrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents that inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-a mine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib), and 6-acrylamido-N-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase kinase (MEK1 / 2) and for example inhibitors of protein kinase B (PKB / Akt), for example inhibitors of Src tyrosine kinase family and / or Abelson (AbI) tyrosine kinase family such as dasatinib (BMS-354825) and imatinib mesylate (Gleevec™); and any agents that modify STAT signalling; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™]) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin °Cvβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4; (vii) antisense therapies, for example those which are directed to the targets listed above, such as an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies, and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid®]. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this disclosure, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. In one aspect of the disclosure, an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter spp, Bacteroides spp, Burkholderia spp, campylobacter spp, chlamydia spp, chlamydophila spp, clostridium spp, enterobacter spp, enterococcus spp, escherichia spp, fusobacterium spp, gardnerella spp, haemophilus spp, helicobacter spp, klebsiella spp, legionella spp, moraxella spp, morganella spp, mycoplasma spp, neisseria spp, peptococcus spp Peptostreptococcus spp, proteus spp, pseudomonas spp, Salmonella spp, serratia spp., Staphylococcus spp, streptoccocus spp, stenotrophomonas spp, or ureaplasma spp. In one aspect of the disclosure, an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumanii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter Iwoffi, Bacteroides bivius, Bacteroides fragilis , Burkholderia cepacia, campylobacter jejuni, chlamydia pneumoniae, chlamydia urealyticus , chlamydophila pneumoniae, clostridium difficile, enterobacter aerogenes, enterobacter cloacae, enterococcus faecalis, enterococcus faecium, escherichia coli, gardnerella vaginalis, haemophilus par influenzae, haemophilus influenzae, helicobacter pylori, klebsiella pneumoniae, legionella pneumophila, methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus, moraxella catarrhalis, morganella morganii, mycoplasma pneumoniae, neisseria gonorrhoeae, penicillin-resistantpenicillin- resistant streptococcus pneumoniae, penicillin-susceptible streptococcus pneumoniae, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus , Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis, proteus mirabilis, pseudomonas aeruginosa, quino lone-resistant Staphylococcus aureus, quinolone-resistant Staphylococcus epidermis, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Salmonella typhimurium, serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, streptoccocus agalactiae, streptococcus pneumoniae, streptococcus pyogenes, stenotrophomonas maltophilia, ureaplasma urealyticum, vancomycin-resistant enterococcus faecium, vancomycin-resistant enterococcus faecalis, vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus epidermis, mycobacterium tuberculosis, clostridium perfringens, klebsiella oxytoca, neisseria miningitidis, proteus vulgaris, or coagulase-negative Staphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, or Staphylococcus saprophytic ). In one aspect of the disclosure "infection" or "bacterial infection" refers to aerobes, obligate anaerobes, facultative anaerobes, gram-positive bacteria, gram-negative bacteria, gram-variable bacteria, or atypical respiratory pathogens. In some embodiments, the disclosure relates to treating a bacterial infection such as a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, or a urinary tract infection. In some embodiments, the disclosure relates to treating a bacterial infection such as an infection caused by drug resistant bacteria. In some embodiments, the disclosure relates to treating a bacterial infection such as community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as penicillin-resistantpenicillin-resistant streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and vancomycin- resistant enterococci, syphilis, ventilator-associated pneumonia, intra-abdominal infections, gonorrhoeae, meningitis, tetanus, or tuberculosis. In some embodiments, the disclosure relates to treating a fungal infections such as infections caused by tinea versicolor, microsporum, trichophyton, epidermophyton, candidiasis, cryptococcosis, or aspergillosis. In some embodiments, the disclosure relates to treating an infection caused by protozoa including, but not limited to, malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or dysentery. Certain compounds disclosed herein are useful to prevent or treat an infection of a malarial parasite in a subject and / or for preventing, treating and / or alleviating complications and / or symptoms associated therewith and can then be used in the preparation of a medicament for the treatment and / or prevention of such disease. The malaria may be caused by Plasmodium falciparum, P. vivax, P. ovale, or P. malariae. Formulations Pharmaceutical compositions disclosed herein may be in the form of pharmaceutically acceptable salts, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below). When the compounds of the disclosure contain an acidic group as well as a basic group, the compounds of the disclosure may also form internal salts, and such compounds are within the scope of the disclosure. When a compound of the disclosure contains a hydrogen- donating heteroatom (e.g., NH), the disclosure also covers salts and / or isomers formed by the transfer of the hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference. The compounds described herein may be administered in the form of prodrugs. A prodrug can include a covalently bonded carrier that releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds. Methods of structuring a compound as a prodrug are known, for example, in Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids. It has been shown that ester prodrugs are readily degraded in the body to release the corresponding alcohol. See e.g., Imai, Drug Metab Pharmacokinet. (2006) 21(3):173-85, entitled “Human carboxylesterase isozymes: catalytic properties and rational drug design.” Pharmaceutical compositions for use in the present disclosure typically comprise an effective amount of a compound of Formula I and a pharmaceutically acceptable excipient or an effective amount of a disclosed compound and a suitable pharmaceutical acceptable carrier. The preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound 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. Reference is made to U.S. Pat. No.6,372,778, U.S. Pat. No.6,369,086, U.S. Pat. No.6,369,087 and U.S. Pat. No.6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. Generally, for pharmaceutical use, the compounds may be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient, and optionally one or more further pharmaceutically active compounds. The pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and / or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the disclosure, e.g., about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage. The compounds can be administered by a variety of routes including the oral, °Cular, rectal, transdermal, subcutaneous, sublingual, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used. The compound will generally be administered in an "effective amount", by which is meant any amount of a compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight of the patient per day, every other day, twice weekly, or weekly, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, every other day, twice weekly, or weekly, which may be administered as a single daily, every other day, twice weekly, or weekly dose, or divided over one or more daily, every other day, twice weekly, or weekly doses. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease / symptoms to be treated. Reference is made to U.S. Pat. No.6,372,778, U.S. Pat. No.6,369,086, U.S. Pat. No.6,369,087 and U.S. Pat. No. 6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. For an oral administration form, the compound can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, cornstarch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. When administered by nasal aerosol or inhalation, the compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the disclosure or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation may additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. For subcutaneous or intravenous administration, the compounds, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds may also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. When rectally administered in the form of suppositories, the formulations may be prepared by mixing the compounds of formula I with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. In certain embodiments, it is contemplated that these compositions can be extended release formulations. Typical extended release formations utilize an enteric coating. Typically, a barrier is applied to oral medication that controls the location in the digestive system where it is absorbed. Enteric coatings prevent release of medication before it reaches the small intestine. Enteric coatings may contain polymers of polysaccharides, such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaloronic acid, chitin, chitosan and the like; other natural polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine; sodium poly(acrylic acid); poly(hydroxyalkylmethacrylates) (for example poly(hydroxyethylmethacrylate)); carboxypolymethylene (for example CarbopolTM); carbomer; polyvinylpyrrolidone; gums, such as guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellan gum, gum tragacanth, agar, pectin, gluten and the like; poly(vinyl alcohol); ethylene vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers, such as hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethyl-cellulose (HPMC), hydroxypropylethylcellulose (HPEC) and sodium carboxymethylcellulose (Na-CMC); as well as copolymers and / or (simple) mixtures of any of the above polymers. Certain of the above-mentioned polymers may further be crosslinked by way of standard techniques. The choice of polymer will be determined by the nature of the active ingredient / drug that is employed in the composition of the disclosure as well as the desired rate of release. In particular, it will be appreciated by the skilled person, for example in the case of HPMC, that a higher molecular weight will, in general, provide a slower rate of release of drug from the composition. Furthermore, in the case of HPMC, different degrees of substitution of methoxyl groups and hydroxypropoxyl groups will give rise to changes in the rate of release of drug from the composition. In this respect, and as stated above, it may be desirable to provide compositions of the disclosure in the form of coatings in which the polymer carrier is provided by way of a blend of two or more polymers of, for example, different molecular weights in order to produce a particular required or desired release profile. Microspheres of polylactide, polyglycolide, and their copolymers poly(lactide-co- glycolide) may be used to form sustained-release protein delivery systems. Proteins can be entrapped in the poly(lactide-co-glycolide) microsphere depot by a number of methods, including formation of a water-in-oil emulsion with water-borne protein and organic solvent- borne polymer (emulsion method), formation of a solid-in-oil suspension with solid protein dispersed in a solvent-based polymer solution (suspension method), or by dissolving the protein in a solvent-based polymer solution (dissolution method). One can attach poly(ethylene glycol) to proteins (PEGylation) to increase the in vivo half-life of circulating therapeutic proteins and decrease the chance of an immune response. Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl nucleosides or phosphate ester prodrug forms of the nucleoside compounds according to the present invention. It is appreciated that nucleosides of the present invention have several chiral centers and may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein. It is well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). Carbons of the nucleoside are chiral, their nonhydrogen substituents (the base and the CHOR groups, respectively) can be either cis (on the same side) or trans (on opposite sides) with respect to the sugar ring system. The four optical isomers therefore are represented by the following configurations (when orienting the sugar moiety in a horizontal plane such that the oxygen atom is in the back): cis (with both groups "up", which corresponds to the configuration of naturally °Ccurring β-D nucleosides), cis (with both groups "down", which is a nonnaturally °Ccurring β-L configuration), trans (with the C2' substituent "up" and the C4' substituent "down"), and trans (with the C2' substituent "down" and the C4' substituent "up"). The "D-nucleosides" are cis nucleosides in a natural configuration and the "L- nucleosides" are cis nucleosides in the nonnaturally °Ccurring configuration. Likewise, most amino acids are chiral (designated as L or D, wherein the L enantiomer is the naturally °Ccurring configuration) and can exist as separate enantiomers. Examples of methods to obtain optically active materials are known in the art, and 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 may 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. 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 °Ccurs 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 simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available. Some of the compounds described herein contain olefinic double bonds and unless otherwise specified, are meant to include both E and Z geometric isomers. In addition, some of the nucleosides described herein, may exist as tautomers, such as, keto-enol tautomers. The individual tautomers as well as mixtures thereof are intended to be encompassed within the compounds of the present invention. Combination Therapies The compound described herein can be administered adjunctively with other active compounds. These compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti- asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro- intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents. In a particular embodiment, the antiviral agent is a non-CNS targeting antiviral compound. “Adjunctive administration”, as used herein, means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents. The additional active agent(s) can be formulated for immediate release, controlled release, or combinations thereof. Specific examples of compounds that can be adjunctively administered with the compounds include, but are not limited to, aceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproxex, dizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, ginko bilboa, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, IPrindole, IPsapirone, ketaserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalicylate, methysergid(e), metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (an anti- narcoleptic), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprazin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propanolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxitine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenozine, thiazides, thioridazine, thiothixene, tiapride, tiasipirone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone and isomers, salts, and combinations thereof. In certain embodiments, the exemplary compounds and pharmaceutical compositions can be administered in combination with another antiviral agent(s) such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin , raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, Tenofovir Exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine and combinations thereof. In exemplified embodiments, the exemplary compounds and pharmaceutical . c In exemplified embodiments, can be administered in comination with In exemplified embodiments, can be administered in c In exemplified embodiments, the pharmaceutical composition comprises a compound of any one of Formula I and a pharmaceutically acceptable excipient. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is formulation is for oral delivery. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a capsule, a tablet, a cachet, a pill, a powder, a granule, an elixir, a tincture, a suspension, a syrup, or an emulsion. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation is for oral delivery and is a solid dosage form. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation for parenteral delivery. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation for parenteral delivery such as bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation for parenteral delivery such as subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. In exemplified embodiments, the pharmaceutical composition comprises a compound of any one of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation for pulmonary delivery. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation for pulmonary delivery comprising a propellant. In exemplified embodiments, the pharmaceutical composition comprises a compound of Formula I, or any compound species or combination of compound species as disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient that is a formulation for pulmonary delivery comprising a propellant such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFA), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoropropane or combinations thereof. In an exemplary embodiment, the compounds disclosed herein can be used in combination with other nucleoside or nucleotide analogs, including salts, polymorphs, and prodrug forms thereof, e.g., including one or more compound disclosed in WO 2015 / 038596, WO 2016 / 106050, WO 2017 / 106710, WO 2017 / 106710, WO 2017 / 155923, WO 2017 / 156380, WO 2017 / 189978, WO 2017 / 223421, WO 2019 / 113462, WO 2019 / 173602, WO 2021 / 137913, WO 2021 / 159044, WO 2022 / 174179, WO 2022 / 235874, and WO 2023 / 070058, each of which is included herein by reference. From the foregoing, it will be seen that aspects herein are well adapted to attain all the ends and objects hereinabove set forth together with other advantages which are obvious and which are inherent to the structure. While specific elements and steps are discussed in connection to one another, it is understood that any element and / or steps provided herein is contemplated as being combinable with any other elements and / or steps regardless of explicit provision of the same while still being within the scope provided herein. It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations. This is contemplated by and is within the scope of the claims. Since many possible aspects may be made without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings and detailed description is to be interpreted as illustrative and not in a limiting sense. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. Examples Example 1. Synthesis of EIDD-3525. In the detailed discussion of the synthesis of EIDD-3525 herein below, reference is made to the synthesis scheme immediately above and the compound numbers used therein. Compound 2: A solution TFA:H2O (4:1) 30 mL was added to a round bottom flask contains (3S,4S,5R)-5-((benzyloxy)methyl)-4-fluoro-2-methoxytetrahydrofuran-3-ol (1) (3.10 g, 12.10 mmol), and the mixture was stirred at rt for 6 hr. The reaction mixture was concentrated and purified by silica gel column chromatography, eluding with hexane: ethyl acetate (0-60 % gradient) to give (3S,4S,5R)-5-((benzyloxy)methyl)-4-fluorotetrahydrofuran- 2,3-diol (2) (2.10 g, 8.67 mmol, 71 % yield), as colorless liquid. Compound 3: A solution of (3S,4S,5R)-5-((benzyloxy)methyl)-4- fluorotetrahydrofuran-2,3-diol (2) (3.60 g, 14.86 mmol, 1.0 eq.) in pyridine (25 mL) was added acetic anhydride (5.60 mL, 59.4 mmol, 4 eq.) and stirred overnight at rt. The reaction was quenched with methanol (5 mL) and concentrated. The residue was purified by silica gel column chromatography, eluding with hexane: ethyl acetate (0-60 % gradient) to give (3S,4R,5R)-5-((benzyloxy)methyl)-4-fluorotetrahydrofuran-2,3-diyl diacetate (3) (4.25 g, 13.02 mmol, 88 % yield) as a mixture of diastereomers (3:1). Compound 4: A solution contains (3S,4R,5R)-5-((benzyloxy)methyl)-4- fluorotetrahydrofuran-2,3-diyl diacetate (3) (1.30 g, 3.98 mmol, 1.0 eq) and N6-benzoyl adenine (1.143 g, 4.78 mmol, 1.2 eq.) in acetonitrile (25 mL) at -20 ^C was added dropwise solution of SnCl4 (1.0 M in DCM, 8.76 mL, 2.2 eq.). The reaction was naturally warm to rt over the course of 3 hrs. The reaction mixture was cooled to 0 ^C, quenched with saturated NaHCO3 (60 mL), and stirred for 15 minutes. Ethyl acetate (100 mL) was added to the reaction mixture. The white solid formed was filtered through a celite pad. The filtrate was concentrated to remove ethyl acetate and acetonitrile. The remaining aqueous was extracted with ethyl acetate, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography, eluding with hexane: ethyl acetate (0-90 % gradient) to afford (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((benzyloxy)methyl)-4- fluorotetrahydrofuran-3-yl acetate (4) (1.20 g, 2.37 mmol, 59 % yield). Compound 5: A solution of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5- ((benzyloxy)methyl)-4-fluorotetrahydrofuran-3-yl acetate (4) (3.50 g, 6.92 mmol, 1.0 eq.) in DCM (60 mL) at -78 ^C. was added a solution of BCl31.0 M in DCM (34.6 mL, 34.6 mmol, 5.0 eq.). The reaction was warmed to -20 ^C and stirred for 2 hrs. at -20 ^C. The reaction was cooled to -78 ^C and quenched with a solution of triethylamine: methanol (1:1) (30 mL). The reaction was warmed to rt, concentrated, and diluted with ethyl acetate. The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified over silica gel column chromatography, eluding with hexane: ethyl acetate (0-90 % gradient) to afford (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-fluoro-5- (hydroxymethyl) tetrahydrofuran-3-yl acetate (5) (2.15 g, 5.17 mmol, 74% yield) as a white solid. Compound 6: A solution of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-fluoro- 5-(hydroxymethyl) tetrahydrofuran-3-yl acetate (5) (3.50 g, 8.43 mmol, 1.0 eq.) in pyridine (40 mL) was added tosyl chloride (2.41 g, 12.64 mmol, 1.5 eq.) and stirred for 16 hrs. at rt. The reaction was quenched with methanol (5 mL) and concentrated. The residue was washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified over silica gel column chromatography, eluding with hexane: ethyl acetate (0-90 %) to afford (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-fluoro-5-((tosyloxy)methyl) tetrahydrofuran-3-yl acetate (6) (4.10 g, 7.20 mmol, 85% yield) as white solid. Compound 7: A solution of (2R,3S,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-fluoro- 5-((tosyloxy)methyl)tetrahydrofuran-3-yl acetate (6) (2.0 g, 3.51 mmol, 1.0 eq.) in THF ( 60 mL) at 0 ^C was added potassium tert-butoxide ( 1.182 g, 10.54 mmol, 3.0 eq.) in 3 portions over a period of 1 hr. and then stirred for an additional 30 min at 0 ^C. The reaction mixture was quenched with saturated solution of NH4Cl (60 mL) and extracted with ethyl acetate. The organic phases were combined and dried over MgSO4, filtered, and concentrated. The crude residue was purified over silica gel column chromatography, eluding with hexane: ethyl acetate (0-90 % gradient) to afford N-(9-((2R,3S,4S)-4-fluoro-3-hydroxy-5- methylenetetrahydrofuran-2-yl)-9H-purin-6-yl) benzamide (7) (0.75 g, 0.21 mmol, 60 % yield) as white solid. EIDD-3525: Step 1. A solution of N-(9-((2R,3S,4S)-4-fluoro-3-hydroxy-5- methylenetetrahydrofuran-2-yl)-9H-purin-6-yl) benzamide (7) (0.70 g, 1.97 mmol.1.0 eq.) in acetonitrile (20 mL) at 0 ^C was treated with triethylamine trihydrofluoride (0.240 mL, 1.48 mmol, 0.75 eq.), followed by N-Iodosuccinimide (0.775 g, 3.45 mmol, 1.75 eq.). After stirred for 30 at 0 ^C, the ice bath was removed and further stirred for 2 additional hrs. The reaction mixture was quenched with saturated NaHCO3, and then saturated Na2SO4. The mixture was extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was dissolved in DCM (12 mL) and used without further purification in the next step. Step 2. A 50 mL three neck round bottom flask was charged with tetrabutylammonium hydrogen sulfate (0.167 g), potassium phosphate dibasic (0.754 g), and water (6 ml). The mixture was stirred for 15 min and then treated with the DCM solution of the crude material from step 1. Then MPCBA (1.359 g, >77 % pure) was added, and the reaction mixture was stirred overnight. The mixture was cooled to 0 ^C and slowly quenched with saturated solution of sodium thiosulfate. The mixture was stirred for 30 min at rt, then added saturated NaHCO3and stirred for 10 minutes. The mixture was extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over MgSO4, filtered, and concentrated. The crude was used without further purification. Step 3: The crude material from step 2 was dissolved in 7 M ammonia in methanol (30 mL) and stirred overnight at rt. The reaction was concentrated and purified by silica gel chromatography, eluding with DCM:MeOH (0-10 % gradient) to afford (2R,3S,4S,5S)-2-(6- amino-9H-purin-9-yl)-4,5-difluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol (EIDD-3525) (0.126 g, 0.44 mmol, 22 % yield from 3 steps). 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 8.22 (s, 1H), 6.35 (d, J = 5.4 Hz, 1H), 5.53 (dd, J = 7.7, 5.3 Hz, 1H), 5.40 (dd, J = 7.7, 5.3 Hz, 1H), 5.15 – 4.96 (m, 1H), 3.82 (dd, J = 5.8, 1.4 Hz, 2H).19F NMR (376 MHz, CD3OD) δ -125.19 (q, J = 6.0 Hz), -218.66 (dd, J = 51.8, 14.4 Hz).13C NMR (101 MHz, CD3OD) δ 156.18, 152.59, 148.85, 140.32, 119.44, 115.21 (dd, J = 237.3, 15.9 Hz), 89.74, 88.14 (dd, J = 198.4, 17.4 Hz), 71.70 (d, J = 16.5 Hz), 61.74 (d, J = 41.2 Hz). LCMS: calculated for C10H11F2N5O3[M+H]+ 288.09, found 288.20. Example 2. Synthesis of EIDD-3508. In the detailed discussion of the synthesis of EIDD-3508 herein below, reference is made to the synthesis scheme immediately above and the compound numbers used therein. Compound 2: To a flame-dried round bottomed flask charged with 4-chloro-5-fluoro- 7H-pyrrolo[2,3-d] pyrimidine (1) (92.00 mg, 0.54 mmol) was added 1 mL anhydrous MeCN. Then BSA (0.16 mL, 0.64 mmol) was added and stirred for 10 min at rt, ultimately dissolving the nucleobase. Added solid [(2R,3R,4S)-4,5-diacetoxy-3-fluoro-tetrahydrofuran-2-yl] methyl benzoate (1) (273.73 mg, 0.8 mmol) followed by an additional 1.5 mL anhydrous MeCN. Stirred to completely dissolve the carbohydrate and then added TMSOTf (0.19 mL, 1.07 mmol) dropwise. Stirred the mixture for 10 min at rt, then began heating to 80oC (pre- heat oil bath). After 1h10min, mixture was diluted with EtOAc (25 mL) and washed with sat. NaHCO3(25 mL) followed by brine (25 mL). Organic phase was dried over Na2SO4, loaded onto Celite, and purified by silica gel column chromatography (10% to 30% EtOAc w / isocratic hold at ~20% EtOAc). This material was repurified by silica gel column chromatography (isocratic 20% EtOAc / hexanes) to afford [(2R,3R,4S,5R)-4-acetoxy-5-(4- chloro-5-fluoro-pyrrolo[2,3-d] pyrimidin-7-yl)-3-fluoro-tetrahydrofuran-2-yl]methyl benzoate (2) (63.9 mg, 30% yield) as a foamy white solid. EIDD-3508: [(2R,3R,4S)-4-Acetoxy-5-(4-chloro-5-fluoro-pyrrolo[2,3-d] pyrimidin- 7-yl)-3-fluoro-tetrahydrofuran-2-yl] methyl 4-methylbenzoate (2) (63.90 mg, 0.14 mmol) was dissolved in 1,4-Dioxane (3.4 mL) and transferred to a pressure tube. Ammonium hydroxide (2.4 mL, 61.73 mmol) was added, the tube sealed, and the mixture was heated to 75oC. After overnight reaction, the reaction mixture was concentrated and purified over ISCO column chromatography (5% to 15% MeOH / DCM) to afford (3S,4S,5R)-2-(4-amino-5-fluoro- pyrrolo[2,3-d] pyrimidin-7-yl)-4-fluoro-5-(hydroxymethyl) tetrahydrofuran-3-ol EIDD-3508 (10.7 mg, 27% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.60 – 5.86 (m, 1H), 5.07 (dd, J = 54.8, 4.3 Hz, 1H), 4.76 (ddd, J = 25.1, 8.1, 4.3 Hz, 1H), 4.52 – 4.27 (m, 1H), 3.79 (dd, J = 2.9, 1.6 Hz, 2H).13C NMR (101 MHz, CD3OD) δ 156.27, 152.06, 145.24 (d, J = 125.6 Hz), 142.17, 105.22 (d, J = 27.3 Hz), 93.91, 92.10, 87.79, 83.90 (d, J = 22.2 Hz), 73.40 (d, J = 16.6 Hz), 61.51 (d, J = 11.7 Hz).19F NMR (376 MHz, CD3OD) δ - 170.11, -199.29 (ddd, J = 53.8, 27.9, 25.1 Hz). LCMS: calculated for C11H12F2N4O3[M+H]+ 287.09, found 287.10. Example 3. Assay Protocols. (1) Screening Assays for DENV, JEV, POWV, WNV, YFV, PTV, RVFV, CHIKV, EEEV, VEEV, WEEV, TCRV, PCV, JUNV, MPRLV. Primary cytopathic effect (CPE) reduction assay. Four-concentration CPE inhibition assays are performed. Confluent or near-confluent cell culture monolayers in 96-well disposable microplates are prepared. Cells are maintained in MEM or DMEM supplemented with FBS as required for each cell line. For antiviral assays the same medium is used but with FBS reduced to 2% or less and supplemented with 50 μg / ml gentamicin. The test compound is prepared at four log10 final concentrations, usually 0.1, 1.0, 10, and 100 μg / ml or μM. The virus control and cell control wells are on every microplate. In parallel, a known active drug is tested as a positive control drug using the same method as is applied for test compounds. The positive control is tested with each test run. The assay is set up by first removing growth media from the 96-well plates of cells. Then the test compound is applied in 0.1 ml volume to wells at 2X concentration. Virus, normally at <10050% cell culture infectious doses (CCID50) in 0.1 ml volume, is placed in those wells designated for virus infection. Medium devoid of virus is placed in toxicity control wells and cell control wells. Virus control wells are treated similarly with virus. Plates are incubated at 37oC with 5% CO2until maximum CPE is observed in virus control wells. The plates are then stained with 0.011% neutral red for approximately two hours at 37oC in a 5% CO2incubator. The neutral red medium is removed by complete aspiration, and the cells may be rinsed 1X with phosphate buffered solution (PBS) to remove residual dye. The PBS is completely removed and the incorporated neutral red is eluted with 50% Sorensen’s citrate buffer / 50% ethanol (pH 4.2) for at least 30 minutes. Neutral red dye penetrates into living cells, thus, the more intense the red color, the larger the number of viable cells present in the wells. The dye content in each well is quantified using a 96-well spectrophotometer at 540 nm wavelength. The dye content in each set of wells is converted to a percentage of dye present in untreated control wells using a Microsoft Excel computer-based spreadsheet. The 50% effective (EC50, virus-inhibitory) concentrations and 50% cytotoxic (CC50, cell-inhibitory) concentrations are then calculated by linear regression analysis. The quotient of CC50 divided by EC50 gives the selectivity index (SI) value. Secondary CPE / Virus yield reduction (VYR) assay. This assay involves similar methodology to what is described in the previous paragraphs using 96-well microplates of cells. The differences are noted in this section. Eight half-log10 concentrations of inhibitor are tested for antiviral activity and cytotoxicity. After sufficient virus replication °Ccurs, a sample of supernatant is taken from each infected well (three replicate wells are pooled) and held for the VYR portion of this test, if needed. Alternately, a separate plate may be prepared and the plate may be frozen for the VYR assay. After maximum CPE is observed, the viable plates are stained with neutral red dye. The incorporated dye content is quantified as described above. The data generated from this portion of the test are neutral red EC50, CC50, and SI values. Compounds observed to be active above are further evaluated by VYR assay. The VYR test is a direct determination of how much the test compound inhibits virus replication. Virus that was replicated in the presence of test compound is titrated and compared to virus from untreated, infected controls. Titration of pooled viral samples (collected as described above) is performed by endpoint dilution. This is accomplished by titrating log10 dilutions of virus using 3 or 4 microwells per dilution on fresh monolayers of cells by endpoint dilution. Wells are scored for presence or absence of virus after distinct CPE (measured by neutral red uptake) is observed. Plotting the log10 of the inhibitor concentration versus log10of virus produced at each concentration allows calculation of the 90% (one log10) effective concentration by linear regression. Dividing EC90 by the CC50 obtained in part 1 of the assay gives the SI value for this test. (2) Titer reduction assay for BSL4 viruses (EBOV, SUDV, MARV, LASV and NiV) A focus reduction assay will be used as the primary assay. Cells (Hela, A549, SW13 or VeroE6) maintained in DMEM with 10% FBS are plated to reach between 60-80% confluence in 96 or 384 well plates on the day of the assay. At this time, the medium is replaced with DMEM with 2% FBS and 50-µg / ml gentamicin). Compounds are diluted once by 300-fold and then both undiluted and diluted mixtures are added to iDOT Dispendix dispensing plates in DMSO. Compounds are then directly dispensed into the plates containing the cells and assay medium (DMEM with 2% FBS with 50-µg / ml gentamicin). If antibiotics are may be omitted a request should be made. The Dispendix iDOT machine uses 8 nL droplets to create 8-point dose curves with 3-fold changes in compound concentration between points. DMSO or other vehicle is backfilled into the plate to reach 0.25% in each well. This span allows coverage of 10 nM up to 25 µM for each compound. After 1 h virus is added at an MOI of between 0.1 to 0.3 (to prevent saturation of cells with virus) and incubated at 37°C. Infection is stopped when 1.5 rounds of virus replication have occurred (20-40 h depending on virus type). This time allows limited spread of virus between cells and is used as part of compound evaluation. Cells are then fixed in formalin to inactivate virus (following validated SOP) and then removed from the BSL4 lab. Formalin is removed, washed in PBS and cells are stained with virus specific antibodies. Each antibody is purchased from commercial sources (IBT bioservices and other suppliers) and used between 1:500 to 1:10,000 depending on activity. Cell nuclei are stained with Hoechst 33342 at 1:10,000. Plates are imaged using an automated microscope imager. Analysis of images uses CellProfiler software to read out assays giving both infectivity per cell (titer reduction) and virus antibody staining levels. Infection efficiency is calculated by infected cells / total cell nuclei as well as average cell staining intensity and normalized to vehicle treated cells. Antibody staining provides information on impact of number of infected cells and potential mechanism. Lack of infection often indicates cell entry blocks and decreases staining intensity suggests interference with virus replication. EC50 values are calculated by fitting dose-response curves to data in Graphpad Prism that provides comprehensive statistical analysis of data and plots including error bars on for data replicates. Cell nuclei are also counted. If treatments result in uniform reduction of cell nuclei across all replicates, this suggests cytotoxicity of the compound. (3) Virus Yield Reduction (VYR assay) BSL4 viruses (EBOV, SUDV, MARV, LASV and NiV) Active compounds are tested in a virus yield reduction (VYR) assay to measure changes in virus production. A dose range informed by the primary assay will be used with concentrations adjusted up or down to obtain an accurate EC50 data. Compounds are prepared using the iDOT and cells pre-incubated with compound for 1 h. Virus is added at an MOI of 0.2-0.4. After 30 minutes, cells are washed to remove excess virus. Cells are then allowed to incubate for up to 2 days in the presence of compound. The supernatant is collected and part is passed to a second plate of Vero cells and incubated for 30 min. Supernatant is washed off, a methylcellulose overlay added and the plate is incubated. The parent plate is fixed in formalin and processed as for the primary assay. The daughter plate is incubated for 36-72 h after which it is fixed and stained with virus specific antibody and Hoechst 33342. Plates are imaged as for the primary assay and the level of virus infection measured using CellProfiler software. Dose response curves are then fitted to the data. The parent and daughter plate data are compared to determine the level of virus yield from the parent. EC50 and EC90 data for the parent and daughter plates are obtained using Graphpad Prism that includes statistical measurements of replicate variance. The longer time of incubation of the parent plate allows more extensive analysis of cell-to-cell virus spread. CellProfiler will be used to measure foci diameter as an additional metric of compound activity. The daughter plate EC50 / EC90 is a measure of potency for late-stage replication inhibitors and is useful to give mechanism of action. Example 4. Anti-Dengue Virus Cytoprotection Assay. Cell Preparation -BHK21 cells (Syrian golden hamster kidney cells, ATCC catalog # CCL-I 0) , Vero cells (African green monkey kidney cells, ATCC catalog# CCL-81), or Huh- 7 cells (human hepatocyte carcinoma) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine,100 U / mL penicillin, and 100 µg / mL streptomycin in T-75 flasks prior to use in the antiviral assay. On the day preceding the assay, the cells were split 1:2 to assure they were in an exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemocytometer and Trypan Blue dye exclusion. Cell viability was greater than 95% for the cells to be utilized in the assay. The cells were resuspended at 3 x 103(5 x 105for Vero cells and Huh-7 cells) cells per well in tissue culture medium and added to flat bottom microtiter plates in a volume of 100 µL. The plates were incubated at 37°C / 5%C02 overnight to allow for cell adherence. Monolayers were observed to be approximately 70% confluent. Virus Preparation-The Dengue virus type 2 New Guinea C strain was obtained from ATCC (catalog# VR-1584) and was grown in LLC-MK2 (Rhesus monkey kidney cells; catalog #CCL-7.1) cells for the production of stock virus pools. An aliquot of virus pretitered in BHK21 cells was removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted into assay medium (DMEM supplemented with 2% heat-inactivated FBS, 2 mM L-glutamine, 100 U / mL penicillin, and 100 µg / mL streptomycin) such that the amount of virus added to each well in a volume of 100 µL was the amount determined to yield 85 to 95% cell killing at 6 days post-infection. Plate Format-Each plate contains cell control wells (cells only), virus control wells (cells plus virus), triplicate drug toxicity wells per compound (cells plus drug only), as well as triplicate experimental wells (drug plus cells plus virus). Efficacy and Toxicity XTT-Following incubation at 37°C in a 5% C02 incubator, the test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide). XTT-tetrazolium was metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product, allowing rapid quantitative analysis of the inhibition of virus-induced cell killing by antiviral test substances. XTT solution was prepared daily as a stock of 1 mg / mL in RPMI 1640. Phenazine methosulfate (PMS) solution was prepared at 0.15mg / mL in PBS and stored in the dark at -20°C. XTT / PMS stock was prepared immediately before use by adding 40 µL of PMS per ml of XTT solution. Fifty microliters ofXTT / PMS was added to each well of the plate and the plate was reincubated for 4 hours at 37°C. Plates were sealed with adhesive plate sealers and shaken gently or inverted several times to mix the soluble formazan product and the plate was read spectrophotometrically at 450 / 650 nm with a Molecular Devices Vmax plate reader. Data Analysis -Raw data was collected from the Softmax Pro 4.6 software and imported into a Microsoft Excel spreadsheet for analysis. The percent reduction in viral cytopathic effect compared to the untreated virus controls was calculated for each compound. The percent cell control value was calculated for each compound comparing the drug treated uninfected cells to the uninfected cells in medium alone. Example 5. Anti-RSV Cytoprotection Assay. Cell Preparation-HEp2 cells (human epithelial cells, A TCC catalog# CCL-23) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin, 100 µg / mL streptomycin 1 mM sodium pyruvate, and 0.1 mM NEAA, T-75 flasks prior to use in the antiviral assay. On the day preceding the assay, the cells were split 1:2 to assure they were in an exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemocytometer and Trypan Blue dye exclusion. Cell viability was greater than 95% for the cells to be utilized in the assay. The cells were resuspended at 1 x 104cells per well in tissue culture medium and added to flat bottom microtiter plates in a volume of 100 µL. The plates were incubated at 37°C / 5% C02 overnight to allow for cell adherence. Virus Preparation -The RSV strain Long and RSV strain 9320 were obtained from ATCC (catalog# VR-26 and catalog #VR-955, respectively) and were grown in HEp2 cells for the production of stock virus pools. A pretitered aliquot of virus was removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted into assay medium (DMEMsupplemented with 2% heat-inactivated FBS, 2 mM L-glutamine, 100 U / mL penicillin, 100 µg / mL streptomycin, 1 mM sodium pyruvate, and 0.1 mM NEAA) such that the amount of virus added to each well in a volume of 100 µL was the amount determined to yield 85 to 95% cell killing at 6 days post-infection. Efficacy and Toxicity XTT-Plates were stained and analyzed as previously described for the Dengue cytoprotection assay. Example 6. Anti-Influenza Virus Cytoprotection Assay. Cell Preparation-MOCK cells (canine kidney cells, ATCC catalog# CCL-34) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin, 100 µg / mL streptomycin 1 mM sodium pyruvate, and 0.1 mM NEAA, T-75 flasks prior to use in the antiviral assay. On the day preceding the assay, the cells were split 1:2 to assure they were in an exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemocytometer and Trypan Blue dye exclusion. Cell viability was greater than 95% for the cells to be utilized in the assay. The cells were resuspended at 1 x 104cells per well in tissue culture medium and added to flat bottom microtiter plates in a volume of 100 µL. The plates were incubated at 37°C / 5% C02 overnight to allow for cell adherence. Virus Preparation-The influenza A / PR / 8 / 34 (A TCC #VR-95), A / CA / 05 / 09 (CDC),A / NY / 18 / 09 (CDC) and A / NWS / 33 (ATCC #VR-219) strains were obtained from ATCC or from the Center of Disease Control and were grown in MDCK cells for the production of stock virus pools. A pretitered aliquot of virus was removed from the freezer (- 80°C)and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted into assay medium (DMEM supplemented with 0.5%BSA, 2 mM L-glutamine, 100 U / mL penicillin, 100 µg / mL streptomycin, 1 mM sodium pyruvate, 0.1 mM NEAA, and 1 µg / ml TPCK-treated trypsin) such that the amount of virus added to each well in a volume of 100 µL was the amount determined to yield 85 to 95% cell killing at 4 days post-infection. Efficacy and Toxicity XTT-Plates were stained and analyzed as previously described for the Dengue cytoprotection assay. Example 7. Anti-Hepatitis C Virus Assay. Cell Culture -The reporter cell line Huh-luc / neo-ET was obtained from Dr. Ralf Bartenschlager (Department of Molecular Virology, Hygiene Institute, University of Heidelberg, Germany) by ImQuest BioSciences through a specific licensing agreement. This cell line harbors the persistently replicating I389luc-ubi-neo / NS3-3’ / ET replicon containing the firefly luciferase gene-ubiquitin-neomycin phosphotransferase fusion protein and EMCV IRES driven NS3-5B HCV coding sequences containing the ET tissue culture adaptive mutations (E1202G, Tl2081, and K1846T). A stock culture of the Huh-luc / neo-ET was expanded by culture in DMEM supplemented with I 0% FCS, 2mM glutamine, penicillin (100 µU / mL) / streptomycin (100 µg / mL) and I X nonessential amino acids plus 1 mg / mL G418. The cells were split 1:4 and cultured for two passages in the same media plus 250 µg / mL G418. The cells were treated with trypsin and enumerated by staining with trypan blue and seeded into 96-well tissue culture plates at a cell culture density 7.5 x 103cells per well and incubated at 37˚C 5% C02for 24 hours. Following the 24 hour incubation, media was removed and replaced with the same media minus theG418 plus the test compounds in triplicate. Six wells in each plate received media alone as a no-treatment control. The cells were incubated an additional 72 hours at 37˚C 5%C02 then anti-HCV activity was measured by luciferase endpoint. Duplicate plates were treated and incubated in parallel for assessment of cellular toxicity by XTT staining. Cellular Viability- The cell culture monolayers from treated cells were stained with the tetrazolium dye XTT to evaluate the cellular viability of the Huh-luc / neo-ET reporter cell line in the presence of the compounds. Measurement of Virus Replication-HCV replication from the replicon assay system was measured by luciferase activity using the britelite plus luminescence reporter gene kit according to the manufacturer's instructions (Perkin Elmer, Shelton, CT). Briefly, one vial of britelite plus lyophilized substrate was solubilized in 10 mL of britelite reconstitution buffer and mixed gently by inversion. After a 5 minute incubation at room temperature, the britelite plus reagent was added to the 96 well plates at 100 µL per well. The plates were sealed with adhesive film and incubated at room temperature for approximately 10 minutes to lyse the cells. The well contents were transferred to a white 96-well plate and luminescence was measured within 15 minutes using the Wallac 1450 Microbeta Trilux liquid scintillation counter. The data were imported into a customized Microsoft Excel 2007 spreadsheet for determination of the 50% virus inhibition concentration (EC50). Example 8. Anti-Parainfluenza-3 Cytoprotection Assay. Cell Preparation- HEp2 cells (human epithelial cells, ATCC catalog# CCL-23) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U / mL penicillin, 100 µg / mL streptomycin 1 mM sodium pyruvate, and 0.1 mM NEAA, T-75 flasks prior to use in the antiviral assay. On the day preceding the assay, the cells were split 1:2 to assure they were in an exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemocytometer and Trypan Blue dye exclusion. Cell viability was greater than 95% for the cells to be utilized in the assay. The cells were resuspended at 1 x 104cells per well in tissue culture medium and added to flat bottom microtiter plates in a volume of 100 µL. The plates were incubated at 37°C / 5% C02overnight to allow for cell adherence. Virus Preparation - The Parainfluenza virus type 3 SF4 strain was obtained from ATCC (catalog# VR-281) and was grown in HEp2 cells for the production of stock virus pools. A pretitered aliquot of virus was removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted into assay medium (DMEM supplemented with 2% heat-inactivated FBS, 2 mM L- glutamine, 100 U / mL penicillin, and 100 µg / mL streptomycin) such that the amount of virus added to each well in a volume of 100 µL was the amount determined to yield 85 to 95% cell killing at 6 days post-infection. Plate Format - Each plate contains cell control wells (cells only), virus control wells (cells plus virus), triplicate drug toxicity wells per compound (cells plus drug only), as well a triplicate experimental wells (drug plus cells plus virus). Efficacy and Toxicity XTT- Following incubation at 37°C in a 5% C02incubator, the test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]- 2H-tetrazol hydroxide). XTT-tetrazolium was metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product, allowing rapid quantitative analysis of the inhibition of virus-induced cell killing by antiviral test substances. XTT solution was prepared daily as a stock of 1mg / mL in RPMI1640. Phenazine methosulfate (PMS) solution was prepared at 0.15mg / mL in PBS and stored in the dark at - 20°C. XTT / PMS stock was prepared immediately before use by adding 40 µL of PMS per ml of XTT solution. Fifty microliters of XTT / PMS was added to each well of the plate and the plate was reincubated for 4 hours at 37°C. Plates were sealed with adhesive plate sealers and shaken gently or inverted several times to mix the soluble fom1azan product and the plate was read spectrophotometrically at 450 / 650 nm with a Molecular Devices Vmax plate reader. Data Analysis - Raw data was collected from the Softmax Pro 4.6 software and imported into a Microsoft Excel spreadsheet for analysis. The percent reduction in viral cytopathic effect compared to the untreated virus controls was calculated for each compound. The percent cell control value was calculated for each compound comparing the drug treated uninfected cells to the uninfected cells in medium alone. Example 9. Influenza Polymerase Inhibition Assay. Virus Preparation - Purified influenza virus A / PR / 8 / 34 (1 ml) was obtained from Advanced Biotechnologies, Inc. (Columbia, MD), thawed and dispensed into five aliquots for storage at -80˚C until use. On the day of assay set up, 20 µL of 2.5% Triton N-101 was added to 180 µL of purified virus. The disrupted virus was diluted 1:2 in a solution containing 0.25% Triton and PBS. Disruption provided the source of influenza ribonucleoprotein (RNP) containing the influenza RNA-dependent RNA polymerase and template RNA. Samples were stored on ice until use in the assay. Polymerase reaction - Each 50 µL polymerase reaction contained the following: 5 µL of the disrupted RNP, 100 mM Tris-HCl (pH 8.0), 100 mM KCl, 5 mM MgCl2.1 mM dithiothreitol, 0.25% Triton N-101, 5 µCi of [α-32P] GTP, 100 µM ATP, 50 µM each (CTP, UTP), 1 µM GTP, and 200 µM adenyl (3'-5') guanosine. For testing the inhibitor, the reactions contained the inhibitor and the same was done for reactions containing the positive control (2'-Deoxy-2'-fluoroguanosine-5'-triphosphate). Other controls included RNP +reaction mixture, and RNP + I% DMSO. The reaction mixture without the ApG primer and NTPs was incubated at 30˚C for 20 minutes. Once the ApG and NTPs were added to the reaction mixture, the samples were incubated at 30˚C for 1 hour then immediately followed by the transfer of the reaction onto glass-fiber filter plates and subsequent precipitation with 10% trichloroacetic acid (TCA ). The plate was then washed five times with 5% TCA followed by one wash with 95% ethanol. Once the filter had dried, incorporation of [α-32P] GTP was measured using a liquid scintillation counter (Micro beta). Plate Format - Each test plate contained triplicate samples of the three compounds (6 concentrations) in addition to triplicate samples of RNP + reaction mixture (RNP alone), RNP + 1% DMSO, and reaction mixture alone (no RNP). Data Analysis - Raw data was collected from the Micro Beta scintillation counter. The incorporation of radioactive GTP directly correlates with the levels of polymerase activity. The "percent inhibition values" were obtained by dividing the mean value of each test compound by the RNP + 1% DMSO control. The mean obtained at each concentration of 2DFGTP was compared to the RNP + reaction control. The data was then imported into Microsoft Excel spreadsheet to calculate the IC50 values by linear regression analysis. Example 10. HCV Polymerase Inhibition Assay. Activity of compounds for inhibition of HCV polymerase was evaluated using methods previously described (Lam eta!.2010. Antimicrobial Agents and Chemotherapy 54(8):3187-3196). HCV NS5B polymerase assays were performed in 20 µL volumes in 96 well reaction plates. Each reaction contained 40 ng / µL purified recombinant NS5B∆22 genotype-1b polymerase, 20 ng / µL of HCV genotype-1b complimentary IRES template, 1 µM of each of the four natural ribonucleotides, 1 U / mL Optizyme RNAse inhibitor (Promega, Madison, WI), 1 mM MgCl2, 0.75 mM MnCl2, and 2 mM dithiothreitol (DTT) in 50 mM HEPES buffer (pH 7.5). Reaction mixtures were assembled on ice in two steps. Step 1 consisted of combining all reaction components except the natural nucleotides and labeled UTP in a polymerase reaction mixture. Ten microliters (10 µL) of the polymerase mixture was dispensed into individual wells of the 96 well reaction plate on ice. Polymerase reaction mixtures without NS5B polymerase were included as no enzyme controls. Serial half- logarithmic dilutions of test and control compounds, 2'-O-Methyl-CTP and 2'-O-Methyl-GTP (Trilink, San Diego, CA), were prepared in water and 5 µL of the serial diluted compounds or water alone (no compound control) were added to the wells containing the polymerase mixture. Five microliters of nucleotide mix (natural nucleotides and labeled UTP) was then added to the reaction plate wells and the plate was incubated at 27°C for 30 minutes. The reactions were quenched with the addition of 80 µL stop solution (12.5 mM EDTA, 2.25 M NaCl, and 225 mM sodium citrate) and the RNA products were applied to a Hybond-N+ membrane (GE Healthcare, Piscataway, N.J) under vacuum pressure using a dot blot apparatus. The membrane was removed from the dot blot apparatus and washed four times with 4X SSC (0.6 M NaCl, and 60 mM sodium citrate), and then rinsed one time with water and once with 100% ethanol. The membrane was air dried and exposed to a phosphoimaging screen and the image captured using a Typhoon 8600 Phospho imager. Following capture of the image, the membrane was placed into a Micro beta cassette along with scintillation fluid and the CPM in each reaction was counted on a Micro beta 1450. CPM data were imported into a custom Excel spreadsheet for determination of compound IC50s. Example 11. NS5B RNA-dependent RNA polymerase reaction conditions. Compounds were assayed for inhibition of NS5B-δ21 from HCV GT-1b Con-1. Reactions included purified recombinant enzyme, 1 u / µL negative-strand HCV IRES RNA template, and 1µM NTP substrates including either [32P]-CTP or [32P]-UTP. Assay plates were incubated at 27˚C for 1 hour before quench. [32P] incorporation into macromolecular product was assessed by filter binding. Example 12. Human DNA Polymerase Inhibition Assay. The human DNA polymerase alpha (catalog# 1075), beta (catalog# 1077), and gamma (catalog# 1076) were purchased from CHIMERx (Madison, WI). Inhibition of beta and gamma DNA polymerase activity was assayed in microtiter plates in a 50 uL reaction mixture containing 50 mM Tris-HCl (pH 8.7), KCl (10 mM for beta and 100mM for gamma), 10 mM MgCl2, 0.4 mg / mL BSA, 1 mM DTT, 15% glycerol, 0.05 mM of dCTP, dTTP, and dATP, 10 uCi [32P]-alpha-dGTP (800 Ci / mmol), 20 ug activated calf thymus DNA and the test compound at indicated concentrations. The alpha DNA polymerase reaction mixture was as follows in a 50 uL volume per sample: 20mM Tris-HCl (pH 8), 5 mM magnesium acetate, 0.3 mg / mL BSA, 1 mM DTT, 0.1 mM spermine, 0.05 mM of dCTP, dTTP, and dATP, 10 uCi [32P]-alpha-dGTP (800 Ci / mmol), 20 ug activated calf thymus DNA and the test compound at the indicated concentrations. For each assay, the enzyme reactions were allowed to proceed for 30 minutes at 37˚C followed by the transfer onto glass-fiber filter plates and subsequent precipitation with 10% trichloroacetic acid (TCA). The plate was then washed with 5% TCA followed by one wash with 95% ethanol. Once the filter had dried, incorporation of radioactivity was measured using a liquid scintillation counter (Microbeta). Example 13. HIV infected PBMC assay. Fresh human peripheral blood mononuclear cells (PBMCs) were obtained from a commercial source (Biological Specialty) and were determined to be seronegative for HIV and HBV. Depending on the volume of donor blood received, the leukophoresed blood cells were washed several times with PBS. After washing, the leukophoresed blood was diluted 1:1 with Dulbecco’s phosphate buffered saline (PBS) and layered over 15mL of Ficoll- Hypaque density gradient in a 50ml conical centrifuge tube. These tubes were centrifuged for 30 min at 600g. Banded PBMCs were gently aspirated from the resulting interface and washed three times with PBS. After the final wash, cell number was determined by Trypan Blue dye exclusion and cells were re-suspended at 1 x 10^6 cells / mL in RPMI 1640 with 15% Fetal Bovine Serum (FBS), 2 mmol / L L-glutamine, 2 ug / mL PHA-P, 100 U / mL penicillin and 100 ug / mL streptomycin and allowed to incubate for 48-72 hours at 37˚C. After incubation, PBMCs were centrifuged and resuspended in tissue culture medium. The cultures were maintained until use by half-volume culture changes with fresh IL-2 containing tissue culture medium every 3 days. Assays were initiated with PBMCs at 72 hours post PHA-P stimulation. To minimize effects due to donor variability, PBMCs employed in the assay were a mixture of cells derived from 3 donors. Immediately prior to use, target cells were resuspended in fresh tissue culture medium at 1 x 10^6 cells / mL and plated in the interior wells of a 96-well round bottom microtiter plate at 50 uL / well. Then, 100 uL of 2X concentrations of compound-containing medium was transferred to the 96-well plate containing cells in 50 uL of the medium. AZT was employed as an internal assay standard. Following addition of test compound to the wells, 50 uL of a predetermined dilution of HIV virus (prepared from 4X of final desired in-well concentration) was added, and mixed well. For infection, 50-150 TCID50of each virus was added per well (final MOI approximately 0.002). PBMCs were exposed in triplicate to virus and cultured in the presence or absence of the test material at varying concentrations as described above in the 96-well microtiter plates. After 7 days in culture, HIV-1 replication was quantified in the tissue culture supernatant by measurement of reverse transcriptase (RT) activity. Wells with cells and virus only served as virus controls. Separate plates were identically prepared without virus for drug cytotoxicity studies. Reverse Transcriptase Activity Assay – Reverse transcriptase activity was measured in cell-free supernatants using a standard radioactive incorporation polymerization assay. Tritiated thymidine triphosphate (TTP; New England Nuclear) was purchased at 1 Ci / mL and 1 uL was used per enzyme reaction. A rAdT stock solution was prepared by mixing 0.5mg / mL poly rAand 1.7 U / mL oligo dT in distilled water and was stored at -20˚C. The RT reaction buffer was prepared fresh daily and consists of 125 uL of 1 mol / L EGTA, 125 uL of dH2O, 125 uL of 20% Triton X-100, 50 uL of 1 mol / L Tris (pH 7.4), 50 uL of 1 mol / L DTT, and 40 uL of 1 mol / L MgCl2. For each reaction, 1 uL of TTP, 4 uL of dH2O, 2.5 uL of rAdT, and 2.5 uL of reaction buffer were mixed. Ten microliters of this reaction mixture was placed in a round bottom microtiter plate and 15 uL of virus-containing supernatant was added and mixed. The plate was incubated at 37˚C in a humidified incubator for 90 minutes. Following incubation, 10 uL of the reaction volume was spotted onto a DEAE filter mat in the appropriate plate format, washed 5 times (5 minutes each) in a 5% sodium phosphate buffer, 2 times (1 minute each) in distilled water, 2 times (1 minute each) in 70% ethanol, and then air dried. The dried filtermat was placed in a plastic sleeve and 4 mL of Opti-Fluor O was added to the sleeve. Incorporated radioactivity was quantified utilizing a Wallac 1450 Microbeta Trilux liquid scintillation counter. Example 14. HBV Assay. HepG2.2.15 cells (100µL) in RPMI1640 medium with 10% fetal bovine serum was added to all wells of a 96-well plate at a density of 1 x 104cells per well and the plate was incubated at 37°C in an environment of 5% CO2 for 24 hours. Following incubation, six ten- fold serial dilutions of test compound prepared in RPMI1640 medium with 10% fetal bovine serum were added to individual wells of the plate in triplicate. Six wells in the plate received medium alone as a virus only control. The plate was incubated for 6 days at 37°C in an environment of 5% CO2. The culture medium was changed on day 3 with medium containing the indicated concentration of each compound. One hundred microliters of supernatant was collected from each well for analysis of viral DNA by qPCR and cytotoxicity was evaluated by XTT staining of the cell culture monolayer on the sixth day. Ten microliters of cell culture supernatant collected on the sixth day was diluted in qPCR dilution buffer (40µg / mL sheared salmon sperm DNA) and boiled for 15 minutes. Quantitative real time PCR was performed in 386 well plates using an Applied Biosystems 7900HT Sequence Detection System and the supporting SDS 2.4 software. Five microliters (5 µL) of boiled DNA for each sample and serial 10-fold dilutions of a quantitative DNA standard were subjected to real time Q-PCR using Platinum Quantitative PCR SuperMix- UDG (Invitrogen) and specific DNA oligonucleotide primers (IDT, Coralville, ID) HBV- AD38-qF1 (5’-CCG TCT GTG CCT TCT CAT CTG-3’), HBV-AD38-qR1 (5’-AGT CCA AGA GTY CTC TTA TRY AAG ACC TT-3’), and HBV-AD38-qP1 (5’-FAM CCG TGT GCA / ZEN / CTT CGC TTC ACC TCT GC-3’BHQ1) at a final concentration of 0.2 µM for each primer in a total reaction volume of 15 µL. The HBV DNA copy number in each sample was interpolated from the standard curve by the SDS.24 software and the data were imported into an Excel spreadsheet for analysis. The 50% cytotoxic concentration for the test materials are derived by measuring the reduction of the tetrazolium dye XTT in the treated tissue culture plates. XTT is metabolized by the mitochondrial enzyme NADPH oxidase to a soluble formazan product in metabolically active cells. XTT solution was prepared daily as a stock of 1 mg / mL in PBS. Phenazine methosulfate (PMS) stock solution was prepared at 0.15 mg / mL in PBS and stored in the dark at -20°C. XTT / PMS solution was prepared immediately before use by adding 40 µL of PMS per 1 mL of XTT solution. Fifty microliters of XTT / PMS was added to each well of the plate and the plate incubated for 2-4 hours at 37°C. The 2-4 hour incubation has been empirically determined to be within linear response range for XTT dye reduction with the indicated numbers of cells for each assay. Adhesive plate sealers were used in place of the lids, the sealed plate was inverted several times to mix the soluble formazan product and the plate was read at 450 nm (650 nm reference wavelength) with a Molecular Devices SpectraMax Plus 384 spectrophotometer. Data were collected by Softmax 4.6 software and imported into an Excel spreadsheet for analysis. Example 15. Dengue RNA-dependent RNA polymerase reaction conditions. RNA polymerase assay was performed at 30 °C using 100µl reaction mix in 1.5ml tube. Final reaction conditions were 50mM Hepes (pH 7.0), 2mM DTT, 1mM MnCl2, 10mM KCl, 100nM UTR-Poly A (self-annealing primer), 10µM UTP, 26nM RdRp enzyme. The reaction mix with different compounds (inhibitors) was incubated at 30 °C for 1 hour. To assess amount of pyrophosphate generated during polymerase reaction, 30µl of polymerase reaction mix was mixed with a luciferase coupled-enzyme reaction mix (70µl). Final reaction conditions of luciferase reaction were 5mM MgCl2, 50mM Tris-HCl (pH 7.5), 150mM NaCl, 200µU ATP sulfurylase, 5µM APS, 10nM Luciferase, 100µM D-luciferin. White plates containing the reaction samples (100µl) were immediately transferred to the luminometer Veritas (Turner Biosystems, CA) for detection of the light signal. Example 16. Procedure for Cell Incubation and Analysis. Huh-7 cells were seeded at 0.5x10^6 cells / well in 1 mL of complete media in 12 well tissue culture treated plates. The cells were allowed to adhere overnight at 37o / 5% CO2. A 40 μM stock solution of test article was prepared in 100% DMSO. From the 40 μM stock solution, a 20 μM solution of test article in 25 ml of complete DMEM media was prepared. For compound treatment, the media was aspirated from the wells and 1 mL of the 20 μM solution was added in complete DMEM media to the appropriate wells. A separate plate of cells with “no” addition of the compound was also prepared. The plates were incubated at 37o / 5% CO2for the following time points: 1, 3, 6 and 24 hours. After incubation at the desired time points, the cells were washed 2X with 1 mL of DPBS. The cells were extracted by adding 500 µl of 70% methanol / 30% water spiked with the internal standard to each well treated with test article. The non-treated blank plate was extracted with 500 ul of 70% methanol / 30% water per well. Samples were centrifuged at 16,000 rpm for 10 minutes at 4oC. Samples were analyzed by LC-MS / MS using an ABSCIEX 5500 QTRAP LC-MS / MS system with a Hypercarb (PGC) column. Example 17. Zika RNA-dependent RNA polymerase reaction conditions. RNA polymerase assay was performed at 30 °C using 100µl reaction mix in 1.5ml tube. Final reaction conditions were 50mM Hepes (pH 7.0), 2mM DTT, 1mM MnCl2, 10mM KCl, 100nM UTR-Poly A (self-annealing primer), 10µM UTP, 26nM RdRp enzyme. The reaction mix with different compounds (inhibitors) was incubated at 30 °C for 1 hour. To assess amount of pyrophosphate generated during polymerase reaction, 30µl of polymerase reaction mix was mixed with a luciferase coupled-enzyme reaction mix (70µl). Final reaction conditions of luciferase reaction were 5mM MgCl2, 50mM Tris-HCl (pH 7.5), 150mM NaCl, 200µU ATP sulfurylase, 5µM APS, 10nM Luciferase, 100µM D-luciferin. White plates containing the reaction samples (100µl) were immediately transferred to the luminometer Veritas (Turner Biosystems, CA) for detection of the light signal. Example 18. Zika infectious assay conditions. Vero cells were passaged in DMEM medium in T-75 flasks prior to use in the antiviral assay. On the day preceding the assay, the cells were split 1:2 to assure they were in exponential growth phase at the time of infection. The cells were resuspended at 5 x 103cells per well in tissue culture medium and added to flat bottom microtiter plates in a volume of 100 mL. The plates were incubated at 37°C / 5% CO2 overnight to allow for cell adherence. Separately, Zika virus was titrated in LLCMK2 cells to define the inoculum for use in the antiviral assay. Virus was diluted in DMEM medium such that the amount of virus added to each well in a volume of 100 mL was the amount determined to achieve 85 to 95% cell killing at 5 days post-infection. Following incubation test plates were stained with XTT dye. XTT solution was prepared daily as a stock solution of 1 mg / mL in RPMI1640. PMS solution was prepared at 0.15 mg / mL in PBS and stored in the dark at -20°C. XTT / PMS stock was prepared immediately before use by adding 40 mL of PMS per mL of XTT solution. Fifty microliters of XTT / PMS was added to each well of the plate, and the plate was reincubated for 4 hours at 37°C. Plates were sealed with adhesive plate sealers ad shaken gently to mix the soluble formazan product, and the plate was read spectrophotometrically read 450 / 650 nm with a Molecular Devices Vmax plate reader. The raw data was collected from Softmax Pro and imported into a Microsoft Excel XLfit4 spreadsheet for analysis using four parameter curve fit calculations. Example 18. POLRMT methods. POLRMT enzyme purification: A variant of human POLRMT coding sequence was amplified from a POLRMT cDNA plasmid (Accession: BC098387, Clone ID: 5264127, Dharmacon, CO) and cloned into a pMal-c5X vector under control of the tac promoter. For protein expression, the plasmid was transformed into Stellar competent cells (Clontech). Expression vector pMal-c5X contains a lacI gene which allows inducible expression of POLRMT in Stellar cells. The transformed cells were grown in LB medium containing 100 µg / ml ampicillin at 35°C to an optical density of 1 at 600 nm. Cells were cooled down in a 4°C fridge for 1 hour. MgCl2 was added to final concentration of 1 mM. Protein expression was induced at 16°C overnight by the addition of 0.4 mM IPTG. Cells were harvested by centrifugation at 4000 × g for 20 min at 4°C. The cell pellet was stored at -80°C until further processed. For protein purification, the cell pellet was re-suspended in sonication buffer (20 mM Tris-HCl pH 7.5, 10% glycerol, 500 mM NaCl, 0.5% Triton X-100, 10 mM DTT, 10 mM MgCl2, 30 mM imidazole and 1X protease inhibitor cocktail). Cell disruption was performed on ice for 10 min using an ultrasound probe sonicator. The cell extract was clarified by centrifugation at 16,000 × g for 20 min at 4°C. The supernatant was incubated with HisPur Ni-NTA agarose resin with gentle rocking for 15 minutes at 4°C. The resin was then washed 5 times with 10 volumes of wash buffer (20 mM Tris-HCl pH 7.5, 10% glycerol, 500 mM NaCl, 0.1% Triton X-100, 1 mM DTT, 2 mM MgCl2) containing 30 mM imidazole and then once with the wash buffer containing 2M NaCl. The protein was eluted from the resin with 1 volume of elution buffer (20 mM Tris-HCl, pH 7.5, 10% glycerol, 50 mM NaCl, 0.5% Triton X-100, 10 mM DTT and 300 mM imidazole). The eluted enzyme was adjusted to 50% glycerol and stored at -80 °C before use. Protein identification was performed by mass spectrometry. The concentration of a targeted protein was measured by SDS-PAGE using BSA (Sigma, St. Louis, MO) as a standard. Measurement of ribonucleotide analog incorporation efficiency: Different templates were designed to test individual analog rNTPs, Table 1. Different concentrations of tested ribonucleotide analogs were added to reaction mixtures containing 10 nM P / T and 20 nM POLRMT in a reaction buffer (5 mM Tris-HCl, pH 7.5, 10 mM DTT, 20 mM MgCl2, 0.5% X-100, 10% glycerol) to initiate the reactions. The reactions were continued at 22°C for different time and subsequently quenched with quenching buffer (8 M Urea, 90 mM Tris base, 29 mM taurine, 10 mM EDTA, 0.02% SDS and 0.1% bromophenol blue). The quenched samples were denatured at 95°C for 15 min and the primer extension products were separated using 20% denaturing polyacrylamide gel electrophoresis (Urea PAGE) in 1X TTE buffer (90 mM Tris base, 29 mM Taurine and 0.5 mM EDTA). After electrophoresis, gels were scanned using an Odyssey infrared imaging system. The intensity of different RNA bands was quantified using Image Studio Software Lite version 4.0. The incorporation efficiencies of different rNTP analogs were evaluated by measurement the K1 / 2 and corresponding Discrimination Values (ref. G Lu). Primer extension polymerase activity assay: POLRMTs polymerase activity was determined in a primer extension reaction using a fluorescently labeled RNA primer / DNA template complex. A typical primer extension reaction was performed in a 20-µl reaction mixture containing reaction buffer (5 mM Tris-HCl, pH7.5, 10 mM DTT, 20mM MgCl2, 0.1% Triton X-100, 0.01 U RNasin, 10% glycerol), 10 nM P / T complex, and 20 nM POLRMT. The reaction was initiated by the addition of rNTPs at a final concentration of 100 µM, followed by incubation for 1 h at 22 °C. The reactions were quenched by the addition of 20 µl quenching buffer (8 M Urea, 90 mM Tris base, 29 mM taurine, 10 mM EDTA, 0.02% SDS and 0.1% bromophenol blue). The quenched samples were denatured at 95°C for 15 min and the primer extension products were separated using 20% denaturing polyacrylamide gel electrophoresis (Urea PAGE) in 1X TTE buffer (90 mM Tris base, 29 mM Taurine and 0.5 mM EDTA). After electrophoresis, gels were scanned using an Odyssey infrared imaging system (LI-COR Biosciences, Lincoln, NE). The images were analyzed and the proper RNA bands were quantified using Image Studio software Lite version 4.0 (LI-COR Biosciences, Lincoln, NE). Example 19. Protocol for Determining Plasma Stability. Test article, e.g., EIDD-3525, was incubated in triplicate at 1.00 µM in pooled mixed gender human plasma (BioIVT, K2EDTA), in pooled male CD-1 mouse plasma (BioIVT, K2EDTA, gender pool, e.g., Lot MSE463495), in pooled male Sprague-Dawley rat plasma (BioIVT, lithium heparin). Incubations were performed in 13 x 100 mm glass culture tubes. Samples were placed in a water bath shaker set at 37°C and shaken at 150 rpm. Procaine, Benfluorex or Enalapril (1 µM, each) were run in parallel as a positive controls for human, mouse or rat plasma activity, respectively. Aliquots of 100 µL were taken at the following time-points: 0, 5, 15, 30, 60, and 120 minutes. These aliquots were mixed with 400 µL of 100% acetonitrile in 1.7-mL conical polypropylene microcentrifuge tubes. Samples were vortexed for about 10 seconds and then clarified by centrifugation (2 minutes at 15,000 g). Supernatants were analyzed by LC- MS / MS. HPLC separation was performed on an Agilent 1200 system (Agilent Technologies, Santa Clara, CA, USA) equipped with a column oven, UV lamp, and binary pump. A Thermo Hypercarb PGC (150 x 4.6 mm, 5 µm) column (ThermoFisher, Waltham, MA USA) was used for the separation. Mobile Phase A consisted of 100 mM Ammonium Bicarbonate buffer in HPLC grade Water (pH 10) and Mobile phase B consisted of neat acetonitrile. A gradient 0-85% of B was run for 3 minutes followed by 0% B for 4 minutes was used for the separation. Mass Spectrometry analysis was performed on a Triple Quad 5500 Mass Spectrometer (AB Sciex, Farmingham, MA, USA) using Negative Mode Electrospray Ionization (ESI) in Multiple Reaction Monitoring (MRM) Mode. Data analysis was performed using Analyst Software (AB Sciex, Farmingham, MA, USA). Analyte concentrations were calculated based on standard curve. Half-lives (t1 / 2) were calculated by plotting the natural logarithm of the analyte concentration vs. time and obtaining the slope of the line. Assuming first-order kinetics, the elimination rate constant, k, is the negative (–) of the slope of the plot (ln [µM] vs. time). Half-life (t1 / 2) (min) =- 0.693 / (slope). EIDD-3525 stability in dog plasma: EIDD-3525 and positive control BTC were incubated in triplicate at 1.00 µM in gender pooled Beagle dog plasma (BioIVT, lithium heparin, Lot# BGL140749). Incubations were performed in 96-well, 2-mL deep well plates, maintained at 37°C by a heater-shaker module on a Hamilton STARlet liquid handler. Aliquots of 100 µL were taken at the following time-points: 0, 5, 15, 30, 60 and 120 (with and without NADPH) minutes. These aliquots were mixed with 400 µL of an internal standard (ISTD) solution in acetonitrile (1 µM each 2-fluoroadenosine and D5-7- ethoxycoumarin) in a separate 96-well plate, then transferred to a filtration plate (Biotage, PPT+) and processed via positive pressure manifold to remove precipitated protein. Filtered samples were analyzed by LC-MS / MS. Positive control levels at each time point were expressed as the percent of parent drug remaining from time zero, where t=0 samples were assigned the value of 100%. Half-lives (t1 / 2) were calculated by plotting the natural logarithm of the analyte concentration vs. time and obtaining the slope of the line. Assuming first-order kinetics, the elimination rate constant, k, is the negative (–) of the slope of the plot (ln [% parent remaining] vs. time). Half-life (t1 / 2) (min) = -0.693 / (slope). Example 20. Protocol for Determining Liver Microsome Stability. Test article was incubated in triplicate at 1.00 µM in 100 mM phosphate buffer (pH 7.4), Phase I cofactors (NADPH Regenerating System) and 0.5 mg (total protein) from pooled gender human liver microsomes (BioIVT), pooled male CD-1 mouse liver microsomes (XenoTech) or pooled male Sprague-Dawley rat liver microsomes (BioIVT). Incubations were performed in 13 x 100 mm glass culture tubes. Samples were placed in a water bath shaker set at 37°C and shaken at 150 rpm. Verapamil (1 µM) was run in parallel as a positive control. In some studies, test article, e.g., EIDD-3525, was incubated in triplicate at 1.00 µM in 100 mM phosphate buffer containing 3 mM MgCl2and 1 mM EDTA, 1 mM NADPH (or 2% (w / v) sodium bicarbonate in water for no-NADPH controls) and 0.5 mg of total protein from a pool of CD-1 female liver microsomes (BioIVT, Lot DVO, 880 pmol / mg protein / min for the 6-β-hydroxylation of testosterone = CYP3A4 probe). In some studies, test article, e.g., EIDD-2749 prodrug, was incubated in triplicate at 1.00 µM in 100 mM phosphate buffer containing 3 mM MgCl2and 1 mM EDTA, 1 mM NADPH (or 2% (w / v) sodium bicarbonate in water for no-NADPH controls) and 0.3 mg of total protein from a pool of CD-1 male intestinal microsomes (BioIVT, Lot 2210211, 1420 pmol / mg protein / min for the 6-β-hydroxylation of testosterone = CYP3A4 probe). Positive controls (1 µM verapamil and 1 mm 4-methylumbellifurone) to access the test systems competencies and to compare the metabolic efficiency and activities of the in...

Claims

1. CLAIMS What is claimed:

1. A compound having a structure represented by a formula:, Formula I or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, deuterium, or a structure represented by a formula selected from: ,, , , , ,,, optionally substituted esters, optionally substituted branched esters, optionally substituted carbonates, optionally substituted carbamates, optionally substituted thioesters, optionally substituted branched thioesters, optionally substituted thiocarbonates, optionally substituted S-thiocarbonate, optionally substituted dithiocarbonates, optionally substituted thiocarbamates, optionally substituted oxymethoxycarbonyl, optionally substituted oxymethoxythiocarbonyl, optionally substituted oxymethylcarbonyl, optionally substituted oxymethylthiocarbonyl, L-amino acid esters, D-amino acid esters, N-substituted L- amino acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, optionally substituted sulfenyl, optionally substituted imidate, optionally substituted hydrazonate, optionally substituted oximyl, optionally substituted imidinyl, optionally substituted imidyl, optionally substituted aminal, optionally susbstituted hemiaminal, optionally substituted acetal, optionally susbstituted hemiacetal, optionally substituted carbonimidate, optionally substituted thiocarbonimidate, optionally substituted carbonimidyl, optionally substituted carbamimidate, optionally substituted carbamimidyl, optionally substituted thioacetal, optionally substituted S-acyl-2- thioethyl, optionally substituted bis-(acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and BAB-esters, wherein R1is optionally substituted with one or more, the same or different, R10;wherein Ar1is selected from a 3-12 membered carbocycle, 3-12 membered heterocarbocycle, a 5-12 membered aryl, and a 5-12 heteroaryl; wherein Y is O or S; wherein Y1is OY3or BH3-M+; wherein M+is an alkali cation or an ammonium cation; wherein Y3is hydrogen, aryl, heteroaryl, or heterocyclyl; wherein Y3is optionally substituted with one or more, the same or different, R10; wherein Z1is selected from CR30aand N; wherein Z2is selected from CR30band N; wherein Z3is selected from C and N; wherein Z4is selected from CH and N; wherein Z5is selected from CH and N; provided that at least one of Z1, Z2, Z3, Z4, and Z5is N; wherein R1ais selected from hydrogen, deuterium, halogen, methyl, ethynyl, cyano, and hydroxy; wherein R2ais selected from hydrogen, deuterium, halogen, and hydroxy; wherein R2bis selected from hydrogen, deuterium, methyl, cyano, ethynyl, and fluoro; wherein R3ais selected from hydrogen, methyl, cyano, ethynyl, and fluoro; wherein R4ais selected from hydrogen, methyl, methoxy, azido, cyano, ethynyl, and fluoro; wherein each of R5, R5aand R5bis independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R5is optionally substituted with one or more, the same or different, R10; wherein each of R6, R6’, R6’’, and R6’’’is independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, formyl, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino,carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid; wherein R6, R6’, R6’’, and R6’’’can each be optionally substituted with one or more, the same or different, R10; wherein R7and R7’are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl, wherein each of R7and R7’is optionally substituted with one or more, the same or different, R10; wherein R8is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R8is optionally substituted with one or more, the same or different, R10; wherein R9is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio,cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R9is optionally substituted with one or more, the same or different, R10; wherein R7, R7’, R8, and R9can form a ring with the α-carbon they are attached to and the amino group attached to the α-carbon, wherein the ring is optionally substituted with one or more, the same or different, R10; wherein R10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R10is optionally substituted with one or more, the same or different, R11; wherein R11is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, and carbonyl; and wherein R20is selected from hydrogen, deuterium, hydroxy, =O, =S, C1-C6 alkyl, C1- C6haloalkyl, (C0-C6alkanediyl)C5-C8cycloalkyl, (C0-C6alkanediyl)C6-C12aryl, (C0- C6 alkanediyl)C3-C12 heterocyclyl, (C0-C6 alkanediyl)C3-C12 heteroaryl, and NR25aR25b; wherein R20is optionally substituted with one or more, the same or different, R10; wherein each of R25aand R25bis independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, and (C0-C6alkanediyl)C3-C12 heteroaryl;wherein each of R25aand R25bis optionally substituted with one or more, the same or different, R10; wherein each of R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, halogen, cyano, hydroxy, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl, -(C=O)NH2, and NR50aR50b; wherein R40is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, NR50aR50b, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12aryl, (C0-C6alkanediyl)C3-C12heterocyclyl, and (C0-C6alkanediyl)C3-C12 heteroaryl; wherein each occurrence of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C6-C12 aryl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and (C0-C6 alkanediyl)C3-C12 heteroaryl; wherein each of R50aand R50bis optionally substituted with one or more, the same or different, R10; wherein lipid is independently selected from C11-C22 alkyl, C11-C22 alkoxy, and aryl substituted with an C6-C18alkyl group; and wherein the dash line signifies a single or double bond according to the valence bond requirements of the molecular identities of the bonded atoms.

2. The compound of claim 1, wherein R1is a structure represented by a formula:wherein R20e, R20f, R20g, R20h, and R20iare each independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, -OAc, C1-C3alkyl, C1-C3alkoxy, C1-C3 alkylamino, (C1-C3 alkyl)2amino, C1-C3 carboxamide or lipid; wherein R20e, R20f, R20g, R20h, and R20ican each be optionally independently substituted with one or more, the same or different, R10; andwherein two of R20e, R20f, R20g, R20h, and R20iare optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 7- membered cycloalkyl or cycloheteroalkyl.

3. The compound of claim 2, wherein at least one of R20e, R20f, R20g, R20h, and R20iis not hydrogen.

4. The compound of any claims 2 or 3, wherein R20e, R20f, R20g, R20h, and R20iare each independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and combinations thereof.

5. The compound of claim 4, wherein R20e, R20f, R20g, R20h, and R20iare each independently selected from hydrogen, halogen, and combinations thereof.

6. The compound of claim 5, wherein halogen is selected from -Cl, -F, and -I.

7. The compound of claim 6, wherein halogen is -Cl.

8. The compound of claim 1, wherein R1is a structure represented by a formula:wherein R6is selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, and lipid; and wherein R6can each be optionally substituted with one or more, the same or different, R10.

9. The compound of claim 8, wherein R6is selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio,cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, and lipid; and wherein R6can each be optionally substituted with one or more, the same or different, R10.

10. The compound of claim 8, wherein R6 is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, benzyl, phenyl, cyclohexyl, and cyclopentyl; wherein R6can each be optionally substituted with one or more, the same or different, R10.

11. The compound of claim 10 wherein R6 is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, benzyl, phenyl, cyclohexyl, and cyclopentyl.

12. The compound of claim 1, wherein R1 is a structure represented by a formula:.

13. The compound of claim 12, wherein R1 is a structure represented by a formula:.

14. The compound of claim 12, wherein R1 is a structure represented by a formula:.

15. The compound of any one of claims 1 or 12-14, wherein Y is O.

16. The compound of any one of claims 1 or 12-14, wherein Y is S.

17. The compound of any one of claims 1 or 12-16, wherein Y1 is OY3.

18. The compound of claim 17, wherein Y3 is hydrogen.

19. The compound of claim 17, wherein Y3 is aryl.

20. The compound of claim 19, wherein Y3 is phenyl.

21. The compound of any one of claims 1 or 12-20, wherein Y is O and Y1 is OY3,wherein Y3is hydrogen, C6-C12aryl, or C6-C12heteroaryl.

22. The compound of any one of claims 1 or 12-21, wherein Y is O and Y1 is OY3,wherein Y3is hydrogen or phenyl, optionally substituted by one or more, the same or different, R10.

23. The compound of any one of claims 1 or 12-21, wherein Y is O and Y1is OY3, wherein Y3is hydrogen or unsubstituted phenyl.

24. The compound of any one of claims 1 or 12-21, wherein Y is O and Y1is OY3, wherein Y3is hydrogen or phenyl, substituted by one or more, the same or different, R10.

25. The compound of any one of claims 1 or 12-24, wherein R1is:, wherein the stereochemical purity at the phosphorous atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the depicted stereoisomer.

26. The compound of any one of claims 1 or 12-25, wherein R1is:,27. The compound of any one of claims 1 or 12-25, wherein R1is:wherein the stereochemical purity at the phosphorous atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the depicted stereoisomer.

28. The compound of claim 1, wherein R1is a structure represented by a formula:

29. The compound of claim 28, wherein R1is a structure represented by a formula:.

30. The compound of claim 28, wherein R1is a structure represented by a formula:.

31. The compound of claim 28, wherein R1is a structure represented by a formula:.

32. The compound of claim 1, wherein R1is a structure represented by a formula:, preferably wherein R5aand R5are C1-6alkyl.

33. The compound of any of claims 1-32, wherein Z1is CR30a.

34. The compound of any of claims 1-32, wherein Z1is N.

35. The compound of any of claims 1-34, wherein Z2is CR30b.

36. The compound of any of claims 1-34, wherein Z2is N.

37. The compound of any of claims 1-36, wherein Z3is C.

38. The compound of any of claims 1-36, wherein Z3is N.

39. The compound of any of claims 1-38, wherein Z4is CH.

40. The compound of any of claims 1-38, wherein Z4is N.

41. The compound of any of claims 1-40, wherein Z5is CH.

42. The compound of any of claims 1-40, wherein Z5is N.

43. The compound of any of claims 1-42, wherein one of Z1, Z2, Z3, Z4, and Z5is N.

44. The compound of any of claims 1-42, wherein one of Z1, Z2, and Z3is N.

45. The compound of any of claims 1-42, wherein one of Z4and Z5is N.

46. The compound of any of claims 1-42, wherein one of Z1, Z2, and Z3is N; and wherein one of Z4and Z5is N.

47. The compound of any of claims 1-42, wherein at least one of Z1, Z2, and Z3is N; and wherein at least one of Z4, and Z5is N.

48. The compound of any of claims 1-42, wherein at least two of Z1, Z2and Z3are N; and wherein each of Z4and Z5is N.

49. The compound of any of claims 1-42, wherein each of Z1and Z2is N; Z3is C; and wherein at each of Z4and Z5is N, or each of Z1and Z3is N; Z2is CR30band wherein at each of Z4and Z5is N.

50. The compound of any of claims 1-42, wherein two of Z1, Z2, Z3, Z4, and Z5are N.

51. The compound of any of claims 1-42, wherein three of Z1, Z2, Z3, Z4, and Z5are N.

52. The compound of any of claims 1-42, wherein four of Z1, Z2, Z3, Z4, and Z5are N.

53. The compound of any of claims 1-52, wherein R1ais selected from hydrogen, deuterium, halogen, cyano, and hydroxy.

54. The compound of claim 53, wherein R1ais selected from hydrogen and deuterium.

55. The compound of claim 53, wherein R1ais selected from hydrogen, deuterium,halogen, and cyano.

56. The compound of claim 53, wherein R1ais selected from halogen, cyano, and hydroxy 57. The compound of claim 53 or 56, wherein R1ais cyano.

58. The compound of claim 53 or 56, wherein R1ais hydroxy.

59. The compound of claim 53 or 56, wherein R1ais halogen.

60. The compound of claim 59, wherein halogen is selected from fluoro, chloro, and bromo.

61. The compound of claim 60, wherein halogen is fluoro.

62. The compound of any of claims 1-52, wherein R1ais selected from methyl and ethynyl.

63. The compound of claim 62, wherein R1ais methyl.

64. The compound of claim 62, wherein R1ais ethynyl.

65. The compound of any of claims 1-64, wherein R2ais selected from hydrogen, deuterium, and hydroxy.

66. The compound of claim 65, wherein R2ais hydrogen or deuterium.

67. The compound of claim 65, wherein R2ais hydroxy.

68. The compound of any of claims 1-64, wherein R2ais halogen.

69. The compound of claim 68, wherein halogen is selected from fluoro, chloro, and bromo.

70. The compound of claim 69, wherein halogen is fluoro.

71. The compound of any of claims 1-70, wherein R2bis selected from hydrogen, deuterium, fluoro, and cyano.

72. The compound of claim 71, wherein R2bis hydrogen or deuterium.

73. The compound of claim 71, wherein R2bis cyano.

74. The compound of claim 71, wherein R2bis fluoro.

75. The compound of any of claims 1-70, wherein R2bis selected from methyl and ethynyl.

76. The compound of claim 75, wherein R2bis methyl.

77. The compound of claim 75, wherein R2bis ethynyl.

78. The compound of any of claims 1-77, wherein R3ais selected from hydrogen, cyano, and fluoro.

79. The compound of claim 71, wherein R3ais hydrogen.

80. The compound of claim 71, wherein R3ais cyano.

81. The compound of claim 71, wherein R3ais fluoro.

82. The compound of any of claims 1-77, wherein R3ais selected from methyl and ethynyl.

83. The compound of claim 82, wherein R3ais methyl.

84. The compound of claim 82, wherein R3ais ethynyl.

85. The compound of any of claims 1-84, wherein R4ais selected from hydrogen, cyano, methoxy, azido, and fluoro.

86. The compound of claim 85, wherein R4ais hydrogen.

87. The compound of claim 85, wherein R4ais azido.

88. The compound of claim 85, wherein R4ais methoxy.

89. The compound of claim 85, wherein R4ais cyano.

90. The compound of claim 85, wherein R4ais fluoro.

91. The compound of any of claims 1-84, wherein R4ais selected from methyl and ethynyl.

92. The compound of claim 91, wherein R4ais methyl.

93. The compound of claim 91, wherein R3ais ethynyl.

94. The compound of any of claims 1-93, wherein each of R5aand R5bis independently selected from hydrogen and C1-C6 alkyl.

95. The compound of claim 94, wherein each of R5aand R5bis independently selected from hydrogen and C1-C4alkyl.

96. The compound of claim 94, wherein each of R5aand R5bis independently selectedfrom hydrogen and C1-C3 alkyl.

97. The compound of claim 94, wherein each of R5aand R5bis independently selected from hydrogen, methyl and ethyl.

98. The compound of claim 94, wherein each of R5aand R5bis independently selected from hydrogen, methyl, ethyl and t-butyl.

99. The compound of claim 94, wherein each of R5aand R5bis independently selected from hydrogen and methyl.

100. The compound of claim 94, wherein each of R5aand R5bis hydrogen.

101. The compound of claim 94, wherein each of R5aand R5bis methyl.

102. The compound of any of claims 1-101, wherein R6is hydrogen, C1-C8alkyl, C2- C8alkenyl, C2-C8alkynyl, C6-C12aryl, C6-C12heteroaryl, C2-C8heterocyclyl, C3- C8cycloalkyl, or C5-C8cycloalkenyl, and wherein R6is optionally substituted with one or more, the same or different, R10.

103. The compound of claim 102, wherein R6is hydrogen, C1-C8 alkyl, or C3-C8 cycloalkyl, optionally substituted with one or more, the same or different, R10.

104. The compound of claim 102, wherein R6is hydrogen, C1-C8 alkyl, or C3-C8 cycloalkyl.

105. The compound of claim 102, wherein R6is hydrogen or C1-C8alkyl.

106. The compound of claim 102, wherein R6is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3- pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or 2,6-dimethylphenyl.

107. The compound of claim 102, wherein R6is hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

108. The compound of claim 102, wherein R6is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3- pentyl, hexyl, t-hexyl, or 4-septyl.

109. The compound of claim 102, wherein R6is hydrogen, is phenyl or 2,6- dimethylphenyl.

110. The compound of claim 102, wherein R6 is hydrogen, methyl or ethyl.

111. The compound of any of claims 1-110, wherein R7 and R7’ are independentlyhydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C12aryl, C6-C12heteroaryl, C2- C8heterocyclyl, C3-C8cycloalkyl, or C5-C8cycloalkenyl, and wherein R7and R7’are optionally substituted with one or more, the same or different, R10.

112. The compound of 111, wherein R7 is hydrogen and R7’ is C1-C8alkyl, optionallysubstituted by R10.

113. The compound of 111, wherein R7 is hydrogen and R7’ is C1-C8alkyl substituted byR10.

114. The compound of 111, wherein R7 is C1-C8alkyl, optionally substituted by R10 and R7’is hydrogen.

115. The compound of 111, wherein R7 is C1-C8alkyl substituted by R10 and R7’ ishydrogen.

116. The compound of 111, wherein R7 and R7’ are each hydrogen.

117. The compound of 111, wherein R7 and R7’ are each independently C1-C8alkyl, eachoptionally substituted by R10.

118. The compound of 111, wherein R7 and R7’ are each independently C1-C8alkyl, eachsubstituted by R10.

119. The compound of 111, wherein R7 is C1-C8alkyl substituted by R10 and R7’ is C1-C8alkyl.

120. The compound of 111, wherein R7 is C1-C8alkyl and R7’ is C1-C8alkyl substituted byR10.

121. The compound of any of claims 1-120, wherein R20 is selected from hydrogen,deuterium, hydroxyl, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C0-C6 alkanediyl)C5-C8 cycloalkyl, (C0-C6 alkanediyl)C3-C12 heterocyclyl, and NR25aR25b.

122. The compound of claim 121, wherein R20 is hydrogen.

123. The compound of claim 121, wherein R20 is selected from =O, hydroxyl, and =S.

124. The compound of claim 123, wherein R20 is =O or hydroxyl.

125. The compound of claim 121, wherein R20 is selected hydrogen and C1-C6 alkyl.

126. The compound of claim 125, wherein R20 is selected hydrogen, methyl, ethyl, propyl,and isopropyl.

127. The compound of any of claims 1-120, wherein R20 is selected from hydrogen,hydroxyl, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkanediyl)C5-C8 cycloalkyl, (C1-C6alkanediyl)C6-C12aryl, (C1-C6alkanediyl)C3-C12heterocyclyl, (C1-C6alkanediyl)C3-C12 heteroaryl, and NR25aR25b.

128. The compound of claim 127, wherein R20 is hydrogen.

129. The compound of claim 127, wherein R20 is selected from =O, hydroxyl and =S.

130. The compound of claim 121, wherein R20 is =O or hydroxyl.

131. The compound of claim 127, wherein R20 is selected hydrogen and C1-C6 alkyl.

132. The compound of claim 143, wherein R20 is selected hydrogen, methyl, ethyl, propyl,and isopropyl.

133. The compound of any of claims 1-120, wherein R20 is selected from hydrogen,hydroxyl, =O, =S, C1-C6 alkyl, C1-C6 haloalkyl, C5-C8 cycloalkyl, C6-C12 aryl, C3-C12 heterocyclyl, C3-C12 heteroaryl, and NR25aR25b.

134. The compound of claim 133, wherein R20 is hydrogen.

135. The compound of claim 133, wherein R20 is selected from =O, hydroxyl, and =S.

136. The compound of claim 133, wherein R20 is =O or hydroxyl.

137. The compound of claim 133, wherein R20 is selected from hydrogen and C1-C6 alkyl.

138. The compound of claim 133, wherein R20 is selected from hydrogen, methyl, ethyl,propyl, and isopropyl.

139. The compound of any of claims 1-120, wherein R20 is NR25aR25b.

140. The compound of claim 127, wherein R20 is hydrogen.

141. The compound of claim 127, wherein R20 is selected from =O, hydroxyl, and =S.

142. The compound of claim 141, wherein R20 is =O or hydroxyl.

143. The compound of claim 127, wherein R20 is selected hydrogen and C1-C6 alkyl.

144. The compound of claim 143, wherein R20 is selected hydrogen, methyl, ethyl, propyl,and isopropyl.

145. The compound of any of claims 1-120, wherein R20 is selected from hydrogen, =O,hydroxyl, =S, C1-C6 alkyl, C1-C6 haloalkyl, C5-C8 cycloalkyl, C6-C12 aryl, C3-C12 heterocyclyl, C3-C12 heteroaryl, and NR25aR25b.

146. The compound of claim 145, wherein R20 is hydrogen.

147. The compound of claim 145, wherein R20 is selected from =O, hydroxyl, and =S.

148. The compound of claim 147, wherein R20 is =O or hydroxyl.

149. The compound of claim 145, wherein R20 is selected from hydrogen and C1-C6 alkyl.

150. The compound of claim 149, wherein R20 is selected from hydrogen, methyl, ethyl,propyl, and isopropyl.

151. The compound of claim 139, wherein each of R25a and R25b is independently selectedfrom hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkanediyl)C5-C8 cycloalkyl, (C1-C6alkanediyl)C6-C12aryl, (C1-C6alkanediyl)C3-C12heterocyclyl, and (C1-C6 alkanediyl)C3-C12 heteroaryl.

152. The compound of claim 151, wherein each of R25a and R25b is hydrogen.

153. The compound of claim 151, wherein each of R25a and R25b is independently selectedhydrogen and C1-C6 alkyl.

154. The compound of claim 153, wherein each of R25a and R25b is independently selectedhydrogen, methyl, ethyl, propyl, and isopropyl.

155. The compound of any of claims 1-150, wherein each of R25a and R25b is independentlyselected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C5-C8 cycloalkyl, C6-C12aryl, C3-C12heterocyclyl, and C3-C12heteroaryl.

156. The compound of any of claims 1-155, wherein each of R30a and R30b is independentlyselected from hydrogen, deuterium, ethynyl, cyano, hydroxy, -O-C1-C6 alkyl, C1-C6 alkyl, C1-C6alkenyl, C1-C6haloalkyl, -(C=O)NH2, and NR50aR50b.

157. The compound of any of claims 1-156, wherein each of R30a and R30b is wherein eachof R30aand R30bis independently selected from hydrogen, deuterium, ethynyl, cyano, hydroxy, C1-C6alkyl, C1-C6alkenyl, and C1-C6haloalkyl.

158. The compound of any of claims 1-155, wherein each of R30a and R30b is independentlyselected from hydrogen, deuterium, ethynyl, halogen, cyano, C1-C6 alkyl, C1-C6alkenyl, and C1-C6 haloalkyl.

159. The compound of claim 158, wherein each of R30a and R30b is independently selectedfrom hydrogen, deuterium, ethynyl, fluoro, chloro, bromo, and cyano.

160. The compound of claim 158, wherein each of R30a and R30b is independently selectedfrom hydrogen, deuterium, ethynyl, fluoro, and cyano.

161. The compound of claim 158, wherein each of R30a and R30b is independently selectedfrom hydrogen, deuterium, ethynyl, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, and isopropyl.

162. The compound of claim 158, wherein each of R30a and R30b is independently selectedfrom hydrogen, deuterium, ethynyl, fluoro, cyano, methyl, ethyl, propyl, and isopropyl.

163. The compound of any of claims 1-155, wherein each of R30a and R30b is independentlyselected from hydrogen, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, -(C=O)NH2, and NR50aR50b.

164. The compound of claim 163, wherein each of R30a and R30b is independently selectedfrom hydrogen, methyl, ethyl, propyl, isopropyl, -(C=O)NH2, NH2, N(CH3)2, and NHCH3.

165. The compound of any of claims 1-164, wherein R40 is selected from hydrogen,deuterium, cyano, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, (C1-C6alkanediyl)C5-C8165cycloalkyl, (C1-C6 alkanediyl)C6-C12 aryl, (C1-C6 alkanediyl)C3- C12heterocyclyl, and (C1-C6alkanediyl)C3-C12heteroaryl.

166. The compound of claim 165, wherein R40 is selected from hydrogen, deuterium,cyano, hydroxyl, C1-C5 alkyl, and C1-C5 haloalkyl.

167. The compound of claim 165, wherein R40 is selected from hydrogen, deuterium,cyano, hydroxyl, C1-C4alkyl, and C1-C4haloalkyl.

168. The compound of claim 165, wherein R40 is selected from hydrogen, deuterium,cyano, hydroxyl, C1-C3 alkyl, and C1-C3 haloalkyl.

169. The compound of claim 165, wherein R40 is selected from hydrogen, deuterium,cyano, hydroxyl, methyl, and ethyl.

170. The compound of claim 165, wherein R40is selected from hydrogen, cyano, hydroxyl, methyl, and ethyl.

171. The compound of claim 165, wherein R40is halogen.

172. The compound of claim 171, wherein R40is fluoro or chloro.

173. The compound of claim 171 or 172, wherein R40is fluoro.

174. The compound of claim 171 or 172, wherein R40is chloro.

175. The compound of any of claims 1-164, wherein R40is selected from hydrogen, deuterium, cyano, halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C5-C8 cycloalkyl, C6-C12 aryl, C3-C12 heterocyclyl, and C3-C12 heteroaryl.

176. The compound of any of claims 1-175, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10 alkyl, C1-C6 haloalkyl, (C1-C6 alkanediyl)C5-C8cycloalkyl, (C1-C6alkanediyl)C6-C12aryl, (C1-C6alkanediyl)C3-C12heterocyclyl, and (C1-C6 alkanediyl)C3-C12 heteroaryl.

177. The compound of claim 176, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, 178. The compound of claim 176, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C5 alkyl, and C1-C5 haloalkyl.

179. The compound of claim 176, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C4 alkyl, and C1-C4 haloalkyl.

180. The compound of claim 176, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C3alkyl, and C1-C3haloalkyl.

181. The compound of claim 176, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, methyl, and ethyl.

182. The compound of any of claims 1-175, wherein each of R50aand R50bis independently selected from hydrogen, deuterium, hydroxyl, C1-C10alkyl, C1-C6haloalkyl, (C0-C6alkanediyl)C5-C8 cycloalkyl, C6-C12 aryl, C3-C12 heterocyclyl, and C3-C12 heteroaryl.

183. The compound of any of claims 1-175, wherein the compound is selected from a structure represented by a formula:The compound of any of claims 1-175, wherein the compound is selected from astructure represented by a formula:.

185. The compound of any of claims 1-175, wherein the compound is selected from astructure represented by a formula:.

186. The compound of any of claims 1-185, with the proviso that a compound having astructure represented by a formula is excluded therefrom:,187. The compound of any of claims 1-186, wherein R25a is H and R25b is (C1-C6alkanediyl)C6-C12aryl, (C1-C6alkanediyl)C3-C12heterocyclyl, or (C1-C6alkanediyl)C3-C12 heteroaryl.

188. The compound of any of claims 1-187, wherein R25ais H and R25bis CH2C6-C12 aryl, CH2C3-C12heterocyclyl, or CH2C3-C12heteroaryl.

189. The compound of any of claims 1-187, wherein R25ais H and R25bis CH2C6-C12aryl, optionally substituted one or more times by deuterium, hydroxyl, amino, cyano, halogen, -OAc, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylamino, (C1-C3alkyl)2amino, C1-C3 carboxamide or lipid.

190. The compound of any of claims 187-189, wherein aryl has the formula:wherein R25e, R25f, R25g, R25h, and R25iare each independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, -OAc, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3alkoxy, C1-C3alkylamino, (C1-C3alkyl)2amino, C1-C3carboxamide or lipid; wherein R25e, R25f, R25g, R25h, and R25ican each be optionally independently substituted with one or more, the same or different, R10; and wherein two of R25e, R25f, R25g, R25h, and R25iare optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 7- membered cycloalkyl or cycloheteroalkyl.

191. The compound of claim 190, wherein R25e, R25f, R25g, R25h, and R25iare halogen, C1- C3 alkyl, or C1-C3 haloalkyl, preferably wherein 1 or 2 of R25e, R25f, R25g, R25h, and R25iare halogen, C1-C3alkyl, or C1-C3haloalkyl, and the rest are H.

192. The compound of claim 190, wherein 2 of R25e, R25f, R25g, R25h, and R25iare halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and the rest are H.

193. The compound of claim 190, wherein 1 of R25e, R25f, R25g, R25h, and R25iif halogen, C1-C3alkyl, or C1-C3haloalkyl, and the rest are H.

194. The compound of claim 190, wherein R25eand R25iare halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and the rest are H.

195. The compound of claim 190, wherein R25e is halogen, C1-C3 alkyl, or C1-C3 haloalkyl,and the rest are H.

196. The compound of any of claims 190-195, wherein halogen is F and C1-C3 haloalkyl isCF3.

197. The compound of claim 1, having the formula:,198. The compound of claim 1, having the formula:or a pharmaceutically acceptable salt thereof, wherein R1is not H or D.

199. The compound of claim 198, wherein R1 is:

200. The compound of claim 199, wherein R1 is a structure represented by a formula:wherein R6is selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, and lipid; andwherein R6can each be optionally substituted with one or more, the same or different, R10.

201. The compound of claim 200, wherein R6 is selected from alkyl, alkenyl, alkynyl,carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, and lipid; and wherein R6can each be optionally substituted with one or more, the same or different, R10.

202. The compound of claim 200, wherein R6 is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, benzyl, phenyl, cyclohexyl, and cyclopentyl; wherein R6can each be optionally substituted with one or more, the same or different, R10.

203. The compound of claim 202 wherein R6 is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, benzyl, phenyl, cyclohexyl, and cyclopentyl.

204. The compound of claim 199, wherein R1 is a structure represented by a formula:.

205. The compound of claim 204, wherein Y is O.

206. The compound of claim 204, wherein Y is S.

207. The compound of claim 204, wherein Y1 is OY3.

208. The compound of claim 204, wherein Y3 is hydrogen.

209. The compound of claim 204, wherein Y3 is aryl.

210. The compound of claim 204, wherein Y3 is phenyl.

211. The compound of any one of claims 204-210, wherein Y is O and Y1 is OY3, whereinY3is hydrogen, C6-C12aryl, or C6-C12heteroaryl.

212. The compound of any one of claims 204-210, wherein Y is O and Y1 is OY3, whereinY3is hydrogen or phenyl, optionally substituted by one or more, the same or different, R10.

213. The compound of any one of claims 204-210, wherein Y is O and Y1 is OY3, whereinY3is hydrogen or unsubstituted phenyl.

214. The compound of any one of claims 204-210, wherein Y is O and Y1 is OY3, whereinY3is hydrogen or phenyl, substituted by one or more, the same or different, R10.

215. The compound of any one of claims 204-210, wherein R1 is:, wherein the stereochemical purity at the phosphorous atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the depicted stereoisomer.

216. The compound of any one of claims 204-210, wherein R1 is:,217. The compound of any one of claims 204-210, wherein R1 is:wherein the stereochemical purity at the phosphorous atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the depictedstereoisomer.

218. The compound of claim 1, having the structure:

219. A compound having a structure represented by formula:, or a pharmaceutically acceptable salt thereof.

220. A pharmaceutical composition comprising a pharmaceutically acceptable excipientand the compound of any of claims 1-219 or a compound having a structure represented by a formula:, or combinations thereof, or a pharmaceutically acceptable salt thereof.

221. The pharmaceutical composition of claim 220, further comprising a propellant.

222. The pharmaceutical composition of claim 221, wherein the propellant is compressedair, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFA), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or combinations thereof.

223. A pressurized container comprising a pharmaceutical composition of claim 221 or222.

224. The container of claim 223, wherein the container is a manual pump spray, inhaler,meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.

225. A method of treating or preventing a viral infection comprising administering ineffective amount of the compound of any one of claims 1-219 or 220-224 or a compound having a structure represented by a formula:, or combinations thereof, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 220-222.

226. The method of claim 225, wherein the viral infection is a Togaviridae infection.

227. The method of claim 226, wherein the Togaviridae infection is an infection with a virus selected from Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus.

228. The method of claim 225, wherein the viral infection is a Coronaviridae.

229. The method of claim 228, wherein the viral infection is a human coronavirus infection, SARS coronavirus infection, or MERS coronavirus infection.

230. The method of claim 228 or claim 229, wherein the SARS coronavirus infection is an infection with a SARS-CoV2 virus.

231. The method of claim 230, wherein the SARS-CoV2 virus comprises variants of SARS-CoV-2, including, but are not limited to, the more virulent strain originating in Brazil, known as P.1; the variant originating in the United Kingdom, known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7; and the variant originating in South Africa, known as 20H / 501Y.V2 or B.1.351; as well as further variants and lineages that derive therefrom.

232. The method of claim 225, wherein the viral infection is an Orthomyxoviridae virus.

233. The method of claim 225, wherein the viral infection is influenza A virus and influenza B virus.

234. The method of claim 225, wherein the viral infection is a Pneumoviridae.

235. The method of claim 225, wherein the viral infection is RSV.

236. The method of claim 225, wherein the viral infection is an Arenaviridae.

237. The method of claim 225, wherein the viral infection is Tacaribe virus, Pichinde virus, Junin virus, Lassa fever virus, and Lymphocytic Choriomeningitis virus.

238. The method of claim 225, wherein the viral infection is Bunyaviridae.

239. The method of claim 225, wherein the viral infection is Rift Valley fever virus, Punta Toro virus, LaCrosse virus, Maporal virus, Heartland virus, and Severe Fever Thrombocytopenia Syndrome virus.

240. The method of claim 225, wherein the viral infection is Flaviviridae.

241. The method of claim 225, wherein the viral infection is Zika virus, Dengue virus 1, Dengue virus 2, Dengue virus 3, Dengue virus 4, West Nile virus, Yellow fever virus, Japanese encephalitis virus, Powassen virus, Usutu virus, and tick-borne encephalitis virus.

242. The method of claim 225, wherein the viral infection is Picornaviridae.

243. The method of claim 225, wherein the viral infection is poliovirus, Coxsackie virus, enterovirus.

244. The method of claim 225, wherein the viral infection is comprises an infection with a human coronavirus, SARS coronavirus, MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Ross River virus, RSV, influenza A virus, influenza B virus, Tacaribe virus, Pichinde virus, Junin virus, Lassa fever virus, Lymphocytic Choriomeningitis virus, Rift Valley fever virus, Punta Toro virus, LaCrosse virus, Maporal virus, Heartland virus, and Severe Fever Thrombocytopenia Syndrome virus, poliovirus, norovirus, enterovirus, a coxsackie virus A, B and C, coxsackie A16, EV- D68, EV-A71, rhinovirus, poliovirus, echovirus, picornaviruses, cardioviruses, enteroviruses, erboviruses, hepatovirus, kobuviruses, parechoviruses, teschoviruses, caliciviruses, which include noroviruses, sapoviruses, lagoviruses, vesiviruses,astroviruses, togaviruses, flaviviruses, hepacivirus, coronaviruses, arteriviruses, rhabdoviruses, paramyxoviruses, orthomyxoviruses, hantaviruses, reoviruses, rotaviruses, birnaviruses, chrysoviruses, cystoviruses, hypoviruses partitiviruses, totoviruses, lentiviruses, polyomaviruses, papillomaviruses, adenoviruses, circoviruses ,parvoviruses, erythroviruses, betaparvoviruses, amdoviruses, densoviruses, iteraviruses, brevidensoviruses, pefudensoviruses, herpes viruses 1, 2, 3, 4, 5, 6, 7 and 8, poxviruses, hepadnaviruses, pneumovirus, bunyavirus, arenavirus, or orthomyxovirus.

245. The method of any one of claims 225-244, wherein the method further comprises administering a second antiviral agent.

246. The method of claim 245, wherein the second antiviral agent is selected from remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, ritonavir, remdesivir, paxlovid, molnupiravir, ABX464, favilavir, niclosamide, laninamivir, oseltamivir, zanamivir, peramivir, CS-8958, ribavirin, amantadine, rimantadine, tamiphosphor guanidine monoester, or phosphazanamivir or its monoester, disoxaril, pleconaril, pirodavir, vapendavir, pocapavir, azaglutamine, S-nitroso-N-acetyl- penicillamine (SNAP), glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), glycerrhizin, 5-(3,4-dichlorophenyl) methylhydantoin, AG7088, pleconaril, 3- methylthio-5-aryl-4-isothiazolecarbonitrile, a pyridyl imidazolidinone, ribavirin, mycophenolic acid, 6-azauridine, pyrazofurin, 3-methylkaempferol, and derivatives, physiological or pharmaceutical salts, or prodrugs thereof, and combinations thereof.

247. The method of claim 245, wherein the second antiviral agent is selected from remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, ritonavir, remdesivir, paxlovid, molnupiravir, ABX464, favilavir, and niclosamide, and derivatives, physiological or pharmaceutical salts, or prodrugs thereof, and combinations thereof.

248. The method of claim 245, wherein the second antiviral agent is selected from laninamivir, oseltamivir, zanamivir, peramivir, CS-8958, ribavirin, amantadine, rimantadine, tamiphosphor guanidine monoester, and phosphazanamivir or its monoester, and derivatives, physiological or pharmaceutical salts, or prodrugs thereof, and combinations thereof.

249. A method of treating or preventing a viral infection comprising administering to asubject in need thereof an effective amount of the compound of any one of claims 1- 219, a compound having a structure represented by a formula:, or combinations thereof, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 220-224; wherein the subject is administered a loading dose of the compound or the pharmaceutical composition in a first treatment period; and wherein the subject is administered a treatment dose of the pharmaceutical composition in a second treatment period following the first treatment period.

250. The method of claim 249, wherein the first treatment period is days 1-5 following diagnosis of the viral infection or presentation for preventing the viral infection.

251. The method of claim 249, wherein the first treatment period is days 1-2 following diagnosis of the viral infection or presentation for preventing the viral infection.

252. The method of claim 249, wherein the first treatment period is day 1 following diagnosis of the viral infection or presentation for preventing the viral infection.

253. The method of any one of claims 249-252, wherein the loading dose is about 1.1-fold to about 10-fold the treatment dose.

254. The method of claim 253, wherein the loading dose is about 1.5-fold to about 5-fold the treatment dose.

255. The method of claim 253, wherein the loading dose is about 1.5-fold to about 2.5-fold the treatment dose.

256. The method of any one of claims 249-255, wherein the loading dose is administered once daily, two times daily, three times daily, or four times daily.

257. The method of any one of claims 249-255, wherein the loading dose is administered at least twice daily.

258. The method of claim 256 or claim 257, wherein the loading dose divided equally among the number of times administered daily.

259. The method of claim 249-258, wherein the first treatment period is days 1-5 following diagnosis of the viral infection or presentation for preventing the viral infection.

260. The method of claim 259, wherein the first treatment period is days 1-2 following diagnosis of the viral infection or presentation for preventing the viral infection.

261. The method of claim 259, wherein the first treatment period is day 1 following diagnosis of the viral infection or presentation for preventing the viral infection.

262. The method of any one of claims 249-261, wherein the loading dose is about 1.1-fold to about 10-fold the treatment dose.

263. The method of claim 262, wherein the loading dose is about 1.5-fold to about 5-fold the treatment dose.

264. The method of claim 262, wherein the loading dose is about 1.5-fold to about 2.5-fold the treatment dose.

265. The method of any one of claims 249-264, wherein the loading dose is administered once daily, two times daily, three times daily, or four times daily.

266. The method of any one of claims 249-264, wherein the loading dose is administered at least twice daily.

267. The method of claim 249-266, wherein the loading dose divided equally among the number of times administered daily.

268. A method for inhibiting a viral polymerase activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of claims 1-219, a compound having a structure represented by a formula:, , , or combinations thereof, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 200-204.

269. The method of claim 268, wherein the mammal is a human.

270. The method of claim 268 or 269, wherein the mammal has been diagnosed with a need for inhibiting a viral polymerase activity prior to the administering step.

271. The method of claim 269, further comprising the step of identifying a mammal in need for inhibiting a viral polymerase activity.

272. A method for inhibiting a viral polymerase activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one compound of any of claims 1-219, a compound having a structure represented by a formula:, or combinations thereof; or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 200-204.

273. The method of claim 272, wherein the cell is mammalian.

274. The method of claim 273, wherein the cell is human.

275. The method of claim 273, wherein the cell has been isolated from a mammal prior to the contacting step.

276. The method of claim 273, wherein contacting is via administration to a mammal.

277. The method of claim 276, wherein the mammal has been diagnosed with a need for inhibiting a viral polymerase activity prior to the administering step.

278. The method of claim 276, wherein the mammal has been diagnosed with a need for treatment of a disorder related to a viral polymerase activity prior to the administering step.

279. A kit comprising at least one compound of any of claims 1-219 a compound having a structure represented by a formula:, or combinations thereof; or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 200-204; and one or more of: a. at least one agent known to inhibit a viral polymerase activity; b. at least one agent known to inhibit a viral encoded enzyme activity; c. at least one agent known to treat a viral infection; and / or d. instructions for treating a disorder associated with a viral infection.

280. The kit of claim 279, wherein the at least one compound or the at least one product and the at least one agent are co-formulated.

281. The kit of claim 279, wherein the at least one compound or the at least one product and the at least one agent are co-packaged.

282. Use of a compound of at least one compound of any of claims 1-199, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a viral infection in a mammal.

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